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  • 1.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Alzrigat, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Párraga, Alba Atienza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Singh, Umashankar
    Ungerstedt, Johanna
    Österborg, Anders
    Brown, Peter J
    Ma, Anqi
    Jin, Jian
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 6, p. 6809-6923Article in journal (Refereed)
    Abstract [en]

    Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

  • 2.
    Alzrigat, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Párraga, Alba Atienza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Agarwal, Prasoon
    Zureigat, Hadil
    Österborg, Anders
    Nahi, Hareth
    Ma, Anqi
    Jin, Jian
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jernberg Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 6, p. 10213-10224Article in journal (Refereed)
    Abstract [en]

    Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

  • 3.
    Alzrigat, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University.
    Párraga, Alba Atienza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Majumder, Muntasir
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
    Ma, Anqi
    Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA..
    Jin, Jian
    Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA..
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Heckman, Caroline
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Jernberg Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 61, p. 103731-103743Article in journal (Refereed)
    Abstract [en]

    Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.

  • 4.
    Bersani, Cinzia
    et al.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Sivars, Lars
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Haeggblom, Linnea
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    DiLorenzo, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mints, Michael
    Karolinska Inst, Dept Med, Stockholm, Sweden.;Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden..
    Ährlund-Richter, Andreas
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Tertipis, Nikolaos
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Munck-Wikland, Eva
    Karolinska Inst, Dept Clin Sci & Technol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Otorhinolaryngol Head & Neck Surg, Stockholm, Sweden..
    Näsman, Anders
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Ramqvist, Torbjörn
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Dalianis, Tina
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Targeted sequencing of tonsillar and base of tongue cancer and human papillomavirus positive unknown primary of the head and neck reveals prognostic effects of mutated FGFR32017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 21, p. 35339-35350Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Human papillomavirus positive (HPV+) tonsillar cancer (TSCC), base of tongue cancer (BOTSCC) and unknown primary cancer of the head and neck (HNCUP) have better outcome than corresponding HPV- cancers. To find predictive markers for response to treatment, and correlations and differences in mutated oncogenes and suppressor genes between HPV+ TSCC/BOTSSCC and HPV+ HNCUP and HPV- TSCC/BOTSCC targeted next-generation sequencing was performed of frequently mutated regions in 50 cancer related genes.

    PATIENTS AND METHODS: DNA from 348 TSCC/BOTSCC and 20 HNCUP from patients diagnosed 2000-2011, was sequenced by the Ion Proton sequencing platform using the Ion AmpliSeq Cancer Hotspot Panel v2 to identify frequently mutated regions in 50 cancer related genes. Ion Torrent Variant Caller software was used to call variants.

    RESULTS: 279 HPV+ TSCC/BOTSCC, 46 HPV- TSCC/BOTSCC and 19 HPV+ HNCUP samples qualified for further analysis. Mutations/tumor were fewer in HPV+ TSCC/BOTSCC and HNCUP, compared to HPV- tumors (0.92 vs. 1.32 vs. 1.68). Differences in mutation frequency of TP53 and PIK3CA were found between HPV+ TSCC/BOTSCC and HNCUP and HPV- TSCC/BOTSCC. In HPV+ TSCC/BOTSCC presence of FGFR3 mutations correlated to worse prognosis. Other correlations to survival within the groups were not disclosed.

    CONCLUSIONS: In HPV+ TSCC/BOTSCC mutation of PIK3CA was most frequently observed, while TP53 mutations dominated in HPV- TSCC/BOTSCC. In HPV+ TSCC/ BOTSCC and HNCUP, mutations/tumor were similar in frequency and fewer compared to that in HPV- TSCC/BOTSCC. Notably, FGFR3 mutations in HPV+ TSCC/BOTSCC indicated worse prognosis.

  • 5. Bieghs, Liesbeth
    et al.
    Lub, Susanne
    Fostier, Karel
    Maes, Ken
    Van Valckenborgh, Els
    Menu, Eline
    Johnsen, Hans E
    Overgaard, Michael T
    Larsson, Olle
    Axelson, Magnus
    Nyegaard, Mette
    Schots, Rik
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Vanderkerken, Karin
    De Bruyne, Elke
    The IGF-1 receptor inhibitor picropodophyllin potentiates the anti-myeloma activity of a BH3-mimetic2014In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 22, p. 11193-11208Article in journal (Refereed)
    Abstract [en]

    The ABT-analogous 737, 263 and 199 are BH3 mimetics showing potent anti-myeloma (MM) activity, but only on defined molecular subgroups of MM patients presenting a Bcl-2high/Mcl-1low profile. IGF-1 is a major survival factor in MM regulating the expression of Bcl-2 proteins and might therefore be a resistance factor to these ABT-analogous. We first show that IGF-1 protected human MM cell lines (HMCLs) against ABT-737. Concurrently, the IGF-1 receptor inhibitor picropodophyllin (PPP) synergistically sensitized HMCL, primary human MM and murine 5T33MM cells to ABT-737 and ABT-199 by further decreasing cell viability and enhancing apoptosis. Knockdown of Bcl-2 by shRNA protected MM cells to ABT-737, while Mcl-1 shRNA sensitized the cells. PPP overcame the Bcl-2 dependency of ABT-737, but failed to completely overcome the protective effect of Mcl-1. In vivo, co-treatment of 5T33MM bearing mice significantly decreased tumor burden and prolonged overall survival both in a prophylactic and therapeutic setting. Interestingly, proteasome inhibitor resistant CD138- 5T33MM cells were more sensitive to ABT-737, whereas PPP alone targeted the CD138+ cells more effectively. After co-treatment, both subpopulations were targeted equally. Together, the combination of an IGF-1R inhibitor and an ABT-analogue displays synergistic anti-myeloma activity providing the rational for further (pre)clinical testing.

  • 6.
    Blanco, Gonzalo
    et al.
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Hosp del Mar, IMIM, Canc Res Programme, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain.;Univ Pompeu Fabra, Dept Expt & Hlth Sci, Barcelona, Spain..
    Puiggros, Anna
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Hosp del Mar, IMIM, Canc Res Programme, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain..
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Athanasiadou, Anastasia
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Garcia-Malo, MaDolores
    Hosp Univ Morales Meseguer, Serv Hematol, Murcia, Spain..
    Collado, Rosa
    Consorcio Hosp Gen Univ, Serv Hematol, Valencia, Spain..
    Xochelli, Aliki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rodriguez-Rivera, Maria
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Hosp del Mar, IMIM, Canc Res Programme, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain..
    Ortega, Margarita
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Jose Calasanz, Ma
    Univ Navarra, Dept Genet, Serv Citogenet, Pamplona, Spain..
    Luno, Elisa
    Hosp Univ Cent Asturias, Serv Hematol, Oviedo, Spain..
    Vargas, MaTeresa
    Hosp Univ Virgen del Rocio, Inst Biomed Sevilla IBIS, UGC Hematol, Seville, Spain..
    Grau, Javier
    Univ Autonoma Barcelona, Inst Recerca Leucemia Josep Carreras IJC, ICO Hosp Germans Trias & Pujol, Serv Hematol, Badalona, Spain..
    Martinez-Laperche, Carolina
    Hosp GU Gregorio Maranon, Inst Invest Sanitaria Gregorio Maranon, Serv Hematol, Lab Genet Hematol, Madrid, Spain..
    Valiente, Alberto
    Complejo Hospitalario Navarra, Serv Genet & Hematol, Pamplona, Spain..
    Cervera, Jose
    Hosp Univ La Fe, Unidad Genet, Valencia, Spain..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Gimeno, Eva
    Hosp del Mar, Serv Hematol, Barcelona, Spain..
    Abella, Eugenia
    Hosp del Mar, Serv Hematol, Barcelona, Spain..
    Stalika, Evangelia
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Ma Hernandez-Rivas, Jesus
    Univ Salamanca, Hosp Univ Salamanca, Ctr Invest Canc, CSIC,Serv Hematol,IBSAL,IBMCC, Salamanca, Spain..
    Jose Ortuno, Francisco
    Hosp Univ Morales Meseguer, Serv Hematol, Murcia, Spain..
    Robles, Diego
    Hosp Txagorritxu, Serv Hematol, Vitoria, Spain..
    Ferrer, Ana
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Hosp del Mar, IMIM, Canc Res Programme, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain..
    Ivars, David
    Consorcio Hosp Gen Univ, Serv Hematol, Valencia, Spain..
    Gonzalez, Marcos
    Univ Salamanca, Hosp Univ Salamanca, Ctr Invest Canc, CSIC,Serv Hematol,IBSAL,IBMCC, Salamanca, Spain..
    Bosch, Francesc
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Abrisqueta, Pau
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.;CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Espinet, Blanca
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Hosp del Mar, IMIM, Canc Res Programme, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain..
    Karyotypic complexity rather than chromosome 8 abnormalities aggravates the outcome of chronic lymphocytic leukemia patients with TP53 aberrations2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 49, p. 80916-80924Article in journal (Refereed)
    Abstract [en]

    Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations (TP53abs; chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p-) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p- and 8q+ was 14.7% and 17.8% respectively. Both were associated with a significantly (P < 0.05) higher incidence of a complex karyotype (CK, >= 3 abnormalities) detected by chromosome banding analysis (CBA) compared to cases with normal 8p (N-8p) and 8q (N-8q), respectively. In univariate analysis for 10- year overall survival (OS), 8p- (P = 0.002), 8q+ (P = 0.012) and CK (P = 0.009) were associated with shorter OS. However, in multivariate analysis only CK (HR = 2.47, P = 0.027) maintained independent significance, being associated with a dismal outcome regardless of chromosome 8 abnormalities. In conclusion, our results highlight the association of chromosome 8 abnormalities with CK amongst CLL patients with TP53abs, while also revealing that CK can further aggravate the prognosis of this aggressive subgroup.

  • 7.
    Boldrup, Linda
    et al.
    Umea Univ, Dept Med Biosci Pathol, SE-90185 Umea, Sweden..
    Gu, Xiaolian
    Umea Univ, Dept Med Biosci Pathol, SE-90185 Umea, Sweden..
    Coates, Philip J.
    Masaryk Mem Canc Inst, RECAMO, Brno 65653, Czech Republic..
    Norberg-Spaak, Lena
    Umea Univ, Dept Clin Sci ENT, SE-90185 Umea, Sweden..
    Fahraeus, Robin
    Umea Univ, Dept Med Biosci Pathol, SE-90185 Umea, Sweden.;Masaryk Mem Canc Inst, RECAMO, Brno 65653, Czech Republic.;Univ Paris 07, Hop St Louis, Inst Genet Mol, F-75010 Paris, France..
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Umea Univ, Dept Clin Sci ENT, SE-90185 Umea, Sweden.
    Wilms, Torben
    Umea Univ, Dept Clin Sci ENT, SE-90185 Umea, Sweden..
    Nylander, Karin
    Umea Univ, Dept Med Biosci Pathol, SE-90185 Umea, Sweden..
    Gene expression changes in tumor free tongue tissue adjacent to tongue squamous cell carcinoma2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 12, p. 19389-19402Article in journal (Refereed)
    Abstract [en]

    Due to the high frequency of loco-regional recurrences, which could be explained by changes in the field surrounding the tumor, patients with squamous cell carcinoma of head and neck show poor survival. Here we identified a total of 554 genes as dysregulated in clinically tumor free tongue tissue in patients with tongue tumors when compared to healthy control tongue tissue. Among the top dysregulated genes when comparing control and tumor free tissue were those involved in apoptosis (CIDEC, MUC1, ZBTB16, PRNP, ECT2), immune response (IFI27) and differentiation (KRT36). Data suggest that these are important findings which can aid in earlier diagnosis of tumor development, a relapse or a novel squamous cell carcinoma of the tongue, in the absence of histological signs of a tumor.

  • 8.
    Busse, Niels
    et al.
    Univ Bremen, Islet Biol Lab, Bremen, Germany..
    Paroni, Federico
    Univ Bremen, Islet Biol Lab, Bremen, Germany..
    Richardson, Sarah J.
    Univ Exeter, Islet Biol Exeter, Med, Exeter EX4 4QJ, Devon, England..
    Laiho, Jutta E.
    Univ Tampere, Sch Med, Dept Virol, Tampere, Finland..
    Oikarinen, Maarit
    Univ Tampere, Sch Med, Dept Virol, Tampere, Finland..
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hyoty, Heikki
    Univ Tampere, Sch Med, Dept Virol, Tampere, Finland.;Pirkanmaa Hosp Dist, Fimlab Labs, Tampere, Finland..
    de Koning, Eelco
    Leiden Univ, Med Ctr, Dept Internal Med, Leiden, Netherlands.;Univ Med Ctr Utrecht, Hubrecht Inst, Utrecht, Netherlands..
    Morgan, Noel G.
    Univ Exeter, Islet Biol Exeter, Med, Exeter EX4 4QJ, Devon, England..
    Maedler, Kathrin
    Univ Bremen, Islet Biol Lab, Bremen, Germany..
    Detection and localization of viral infection in the pancreas of patients with type 1 diabetes using short fluorescently-labelled oligonucleotide probes2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 8, p. 12620-12636Article in journal (Refereed)
    Abstract [en]

    Enteroviruses, specifically of the Coxsackie B virus family, have been implicated in triggering islet autoimmunity and type 1 diabetes, but their presence in pancreata of patients with diabetes has not been fully confirmed. To detect the presence of very low copies of the virus genome in tissue samples from T1D patients, we designed a panel of fluorescently labeled oligonucleotide probes, each of 17-22 nucleotides in length with a unique sequence to specifically bind to the enteroviral genome of the picornaviridae family. With these probes enteroviral RNA was detected with high sensitivity and specificity in infected cells and tissues, including in FFPE pancreas sections from patients with T1D. Detection was not impeded by variations in sample processing and storage thereby overcoming the potential limitations of fragmented RNA. Co-staining of small RNA probes in parallel with classical immunstaining enabled virus detection in a cell-specific manner and more sensitively than by viral protein.

  • 9.
    Carlier, Charlotte
    et al.
    Univ Ghent, Dept Surg, Expt Surg Lab, Ghent, Belgium..
    Strese, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Viktorsson, Kristina
    Karolinska Inst, Dept Pathol & Oncol, Karolinska Biom Ctr, Stockholm, Sweden..
    Velander, Ebba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Uustalu, Maria
    Oncopeptides AB, Stockholm, Sweden..
    Juntti, Therese
    Karolinska Inst, Dept Pathol & Oncol, Karolinska Biom Ctr, Stockholm, Sweden.;Oncopeptides AB, Stockholm, Sweden..
    Lewensohn, Rolf
    Karolinska Inst, Dept Pathol & Oncol, Karolinska Biom Ctr, Stockholm, Sweden..
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Spira, Jack
    InSpira Med AB, Tyreso, Sweden..
    De Vlieghere, Elly
    Univ Ghent, Lab Expt Canc Res, Radiat Oncol & Expt Canc Res, Ghent, Belgium..
    Ceelen, Wim P.
    Univ Ghent, Dept Surg, Expt Surg Lab, Ghent, Belgium..
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Preclinical activity of melflufen (J1) in ovarian cancer2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 37, p. 59322-59335Article in journal (Refereed)
    Abstract [en]

    Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra-and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration.

  • 10.
    Chan, Owen T. M.
    et al.
    Univ Hawaii, Ctr Canc, Clin & Translat Res Program, Honolulu, HI 96822 USA..
    Furuya, Hideki
    Univ Hawaii, Ctr Canc, Clin & Translat Res Program, Honolulu, HI 96822 USA..
    Pagano, Ian
    Univ Hawaii, Ctr Canc, Canc Prevent & Control Program Res Program, Honolulu, HI 96822 USA..
    Shimizu, Yoshiko
    Univ Hawaii, Ctr Canc, Clin & Translat Res Program, Honolulu, HI 96822 USA.;Univ Hawaii Manoa, Dept Mol Biosci & Bioengn, Honolulu, HI 96822 USA..
    Hokutan, Kanani
    Univ Hawaii, Ctr Canc, Clin & Translat Res Program, Honolulu, HI 96822 USA.;Univ Hawaii Manoa, Dept Mol Biosci & Bioengn, Honolulu, HI 96822 USA..
    Dyrskjot, Lars
    Aarhus Univ Hosp, Dept Mol Med, Aarhus, Denmark..
    Jensen, Jorgen Bjerggaard
    Aarhus Univ Hosp, Dept Urol, Aarhus, Denmark..
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Janku, Filip
    Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USA..
    Rosser, Charles J.
    Univ Hawaii, Ctr Canc, Clin & Translat Res Program, Honolulu, HI 96822 USA..
    Association of MMP-2, RB and PAI-1 with decreased recurrence-free survival and overall survival in bladder cancer patients2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 59, p. 99707-99721Article in journal (Refereed)
    Abstract [en]

    Background: We previously reported an accurate urine-based bladder cancer (BCa)-associated diagnostic signature that can be used to non-invasively detect BCa. In this study, we investigated whether a component of this signature could risk stratify patients with BCa. Methods: Utilizing immunohistochemistry, we investigated angiogenin, MMP-2, p53, RB and PAI-1 expression from 939 patients with BCa. The expression levels were scored by assigning a proportion score and an intensity score to yield a total staining score for each protein. The expressions of each protein individually and as an aggregate were then correlated with progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Results: Differential expressions of these markers were noted in BCa. With multivariate analysis in non-muscle invasive bladder cancer (NMIBC) age, tumor grade portended a worse PFS, while age, tumor grade, nodal status, MMP2, RB and PAI-1 expression portended a worse OS. As for multivariate analysis in muscle invasive bladder cancer (MIBC), age MMP-2 and RB were associated with a worse PFS, while age, nodal status, MMP-2, RB and PAI-1 were associated with a worse OS. Using Kaplan-Meier survival analysis, we noted a significant reduction in OS as more of the five biomarkers were expressed in a tumor. Thus, overall, high expressions of MMP-2, RB and/or PAI-1 in bladder tumors were markers of poor prognosis. Conclusion: Individually, MMP-2, RB and PAI-1, as well as in aggregate correlated with poor survival in patients with BCa. Thus, patients whose bladder tumors express these biomarkers may benefit from early radical treatment and/or neoadjuvant or adjuvant therapies.

  • 11.
    Chen, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab. Shanghai Jiao Tong Univ, Sch Med, Xin Hua Hosp, Minist Educ, Shanghai, Peoples R China.;Shanghai Jiao Tong Univ, Sch Med, Xin Hua Hosp, Shanghai Key Lab Childrens Environm Hlth, Shanghai, Peoples R China..
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Liu, Han
    Shanghai Jiao Tong Univ, Sch Med, Xin Hua Hosp, Minist Educ, Shanghai, Peoples R China.;Shanghai Jiao Tong Univ, Sch Med, Xin Hua Hosp, Shanghai Key Lab Childrens Environm Hlth, Shanghai, Peoples R China..
    Sun, Yang
    Yunnan Univ, Sch Life Sci, Lab Biochem & Mol Biol, Kunming, Peoples R China..
    Wang, Huibo
    Nanjing Med Univ, Dept Neurosurg, Affiliated Hosp 1, Nanjing, Jiangsu, Peoples R China..
    Yu, Min
    Yunnan Univ, Sch Life Sci, Lab Biochem & Mol Biol, Kunming, Peoples R China..
    Deng, Lian
    Chinese Acad Sci, Key Lab Computat Biol, Max Planck Independent Res Grp Populat Genom, CAS MPG Partner Inst Computat Biol PICB,Shanghai, Shanghai, Peoples R China..
    Xu, Shuhua
    Chinese Acad Sci, Key Lab Computat Biol, Max Planck Independent Res Grp Populat Genom, CAS MPG Partner Inst Computat Biol PICB,Shanghai, Shanghai, Peoples R China.;Univ Chinese Acad Sci, Beijing, Peoples R China.;Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China.;Collaborat Innovat Ctr Genet & Dev, Shanghai, Peoples R China..
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pooled analysis of genome-wide association studies of cervical intraepithelial neoplasia 3 (CIN3) identifies a new susceptibility locus2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 27, p. 42216-42224Article in journal (Refereed)
    Abstract [en]

    Recent genome-wide association studies (GWASs) in subjects of European descent have identified associations between cervical cancer risk and three independent loci as well as multiple classical human leukocyte antigen (HLA) alleles at 6p21.3. To search for novel loci associated with development of cervical cancer, we performed a pooled analysis of data from two GWASs by imputing over 10 million genetic variants and 424 classical HLA alleles, for 1,553 intraepithelial neoplasia 3 (CIN3), 81 cervical cancer and 4,442 controls from the Swedish population. Notable findings were validated in an independent study of 961 patients (827 with CIN3 and 123 with cervical cancer) and 1,725 controls. Our data provided increased support for previously identified loci at 6p21.3 (rs9271898, P = 1.2 x 10(-24); rs2516448, 1.1 x 10(-15); and rs3130196, 2.3 x 10(-9), respectively) and also confirmed associations with reported classical HLA alleles including HLA-B*07:02, -B*15:01, -DRB1*13:01, -DRB1*15:01, -DQA1*01:03, -DQB1*06:03 and -DQB1*06:02. In addition, we identified and subsequently replicated an independent signal at rs73730372 at 6p21.3 (odds ratio = 0.60, 95% confidence interval = 0.54-0.67, P = 3.0 x 10(-19)), which was found to be an expression quantitative trait locus (eQTL) of both HLA-DQA1 and HLA-DQB1. This is one of the strongest common genetic protective variants identified so far for CIN3. We also found HLA-C*07:02 to be associated with risk of CIN3. The present study provides new insights into pathogenesis of CIN3.

  • 12.
    Christianson, Helena C.
    et al.
    Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden..
    Menard, Julien A.
    Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden..
    Chandran, Vineesh Indira
    Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden..
    Bourseau-Guilmain, Erika
    Montpellier Univ, CNRS, UMR 5237, CRBM, Montpellier, France..
    Shevela, Dmitry
    Umea Univ, Chem Biol Ctr, Dept Chem, Umea, Sweden..
    Lidfeldt, Jon
    Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden..
    Mansson, Ann-Sofie
    Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden..
    Pastorekova, Silvia
    Slovak Acad Sci, Inst Virol, Biomed Res Ctr, Bratislava, Slovakia..
    Messinger, Johannes
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics. Umea Univ, Chem Biol Ctr, Dept Chem, Umea, Sweden.
    Belting, Mattias
    Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden.;Skane Univ Hosp, Dept Oncol, Lund, Sweden..
    Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 40, p. 66960-66974Article in journal (Refereed)
    Abstract [en]

    Aggressive cancers are characterized by hypoxia, which is a key driver of tumor development and treatment resistance. Proteins specifically expressed in the hypoxic tumor microenvironment thus represent interesting candidates for targeted drug delivery strategies. Carbonic anhydrase (CAIX) has been identified as an attractive treatment target as it is highly hypoxia specific and expressed at the cell-surface to promote cancer cell aggressiveness. Here, we find that cancer cell internalization of CAIX is negatively regulated by post-translational modification with chondroitin or heparan sulfate glycosaminoglycan chains. We show that perturbed glycosaminoglycan modification results in increased CAIX endocytosis. We hypothesized that perturbation of CAIX glycosaminoglycan conjugation may provide opportunities for enhanced drug delivery to hypoxic tumor cells. In support of this concept, pharmacological inhibition of glycosaminoglycan biosynthesis with xylosides significantly potentiated the internalization and cytotoxic activity of an antibody-drug conjugate (ADC) targeted at CAIX. Moreover, cells expressing glycosaminoglycan-deficient CAIX were significantly more sensitive to ADC treatment as compared with cells expressing wild-type CAIX. We find that inhibition of CAIX endocytosis is associated with an increased localization of glycosaminoglycan-conjugated CAIX in membrane lipid raft domains stabilized by caveolin-1 clusters. The association of CAIX with caveolin-1 was partially attenuated by acidosis, i.e. another important feature of malignant tumors. Accordingly, we found increased internalization of CAIX at acidic conditions. These findings provide first evidence that intracellular drug delivery at pathophysiological conditions of malignant tumors can be attenuated by tumor antigen glycosaminoglycan modification, which is of conceptual importance in the future development of targeted cancer treatments.

  • 13.
    Coyle, Krysta M.
    et al.
    Dalhousie Univ, Dept Pathol, Halifax, NS, Canada..
    Murphy, J. Patrick
    Dalhousie Univ, Dept Microbiol & Immunol, Halifax, NS, Canada..
    Vidovic, Dejan
    Dalhousie Univ, Dept Pathol, Halifax, NS, Canada..
    Vaghar-Kashani, Ahmad
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre. Dalhousie Univ, Dept Pathol, Halifax, NS, Canada.
    Dean, Cheryl A.
    Dalhousie Univ, Dept Pathol, Halifax, NS, Canada.;Dalhousie Univ, Dept Microbiol & Immunol, Halifax, NS, Canada..
    Sultan, Mohammad
    Dalhousie Univ, Dept Pathol, Halifax, NS, Canada..
    Clements, Derek
    Dalhousie Univ, Dept Pathol, Halifax, NS, Canada..
    Wallace, Melissa
    Dalhousie Univ, Dept Microbiol & Immunol, Halifax, NS, Canada..
    Thomas, Margaret L.
    Dalhousie Univ, Dept Pathol, Halifax, NS, Canada..
    Hundert, Amos
    Dalhousie Univ, Dept Psychol & Neurosci & Psychiat, Halifax, NS, Canada..
    Giacomantonio, Carman A.
    Dalhousie Univ, Dept Pathol, Halifax, NS, Canada.;Dalhousie Univ, Dept Surg, Halifax, NS, Canada..
    Helyer, Lucy
    Dalhousie Univ, Dept Surg, Halifax, NS, Canada..
    Gujar, Shashi A.
    Dalhousie Univ, Dept Pathol, Halifax, NS, Canada.;Dalhousie Univ, Dept Microbiol & Immunol, Halifax, NS, Canada.;IWK Hlth Ctr, Dept Qual & Syst Performance, Halifax, NS, Canada..
    Lee, Patrick W. K.
    Dalhousie Univ, Dept Pathol, Halifax, NS, Canada.;Dalhousie Univ, Dept Microbiol & Immunol, Halifax, NS, Canada..
    Weaver, Ian C. G.
    Dalhousie Univ, Dept Psychol & Neurosci & Psychiat, Halifax, NS, Canada..
    Marcato, Paola
    Dalhousie Univ, Dept Pathol, Halifax, NS, Canada..
    Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES12016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 28, p. 44096-44112Article in journal (Refereed)
    Abstract [en]

    Breast cancer subtyping, based on the expression of hormone receptors and other genes, can determine patient prognosis and potential options for targeted therapy. Among breast cancer subtypes, tumors of basal-like and claudin-low subtypes are typically associated with worse patient outcomes, are primarily classified as triple-negative breast cancers (TNBC), and cannot be treated with existing hormone-receptor-targeted therapies. Understanding the molecular basis of these subtypes will lead to the development of more effective treatment options for TNBC. In this study, we focus on retinoic acid receptor responder 1 (RARRES1) as a paradigm to determine if breast cancer subtype dictates protein function and gene expression regulation. Patient tumor dataset analysis and gene expression studies of a 26 cell-line panel, representing the five breast cancer subtypes, demonstrate that RARRES1 expression is greatest in basal-like TNBCs. Cell proliferation and tumor growth assays reveal that RARRES1 is a tumor suppressor in TNBC. Furthermore, gene expression studies, Illumina HumanMethylation450 arrays, and chromatin immunoprecipitation demonstrate that expression of RARRES1 is retained in basal-like breast cancers due to hypomethylation of the promoter. Additionally, expression of the cancer stem cell marker, aldehyde dehydrogenase 1A3, which provides the required ligand (retinoic acid) for RARRES1 transcription, is also specific to the basal-like subtype. We functionally demonstrate that the combination of promoter methylation and retinoic acid signaling dictates expression of tumor suppressor RARRES1 in a subtype-specific manner. These findings provide a precedent for a therapeutically-inducible tumor suppressor and suggest novel avenues of therapeutic intervention for patients with basal-like breast cancer.

  • 14.
    Cui, Hao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tan, Ying-xia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Beijing Inst Transfus Med, Dept Tissue Engn, Beijing, Peoples R China..
    Österholm, Cecilia
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Nova SE Univ, Cell Therapy Inst, Ft Lauderdale, FL 33314 USA..
    Zhang, Xiao-Qun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hedin, Ulf
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Vlodavsky, Israel
    Technion Israel Inst Technol, Fac Med, Canc & Vasc Biol Res Ctr Rappaport, Haifa, Israel..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparanase expression upregulates platelet adhesion activity and thrombogenicity2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 26, p. 39486-39496Article in journal (Refereed)
    Abstract [en]

    Heparanase is an endo-glucuronidase that specifically cleaves heparan sulfate (HS) and heparin polysaccharides. The enzyme is expressed at low levels in normal tissues, but is often upregulated under pathological conditions such as cancer and inflammation. Normal human platelets express exceptionally high levels of heparanase, but the functional consequences of this feature remain unknown. We investigated functional roles of heparanase by comparing the properties of platelets expressing high (Hpa-tg) or low (Ctr) levels of heparanase. Upon activation, Hpa-tg platelets exhibited a much stronger adhesion activity as compared to Ctr platelets, likely contributing to a higher thrombotic activity in a carotid thrombosis model. Furthermore, we found concomitant upregulated expression of both heparanase and CD62P (P-selectin) upon activation of mouse and human platelets. As platelets play important roles in tumor metastasis, these findings indicate contribution of the platelet heparanase to hyper-thrombotic conditions often seen in patients with metastatic cancer.

  • 15.
    Davanian, Haleh
    et al.
    Karolinska Inst, Dept Dent Med, Huddinge, Sweden..
    Balasiddaiah, Anangi
    Karolinska Inst, Dept Dent Med, Huddinge, Sweden.;Karolinska Inst, Dept Lab Med, Huddinge, Sweden..
    Heymann, Robert
    Karolinska Inst, Dept Dent Med, Huddinge, Sweden.;Karolinska Univ Hosp, Clin Oral & Maxillofacial Surg, Huddinge, Sweden..
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Uppsala Hosp, Dept Pathol, Mol Pathol Unit, Rudbecklab, Uppsala, Sweden..
    Redenström, Poppy
    Karolinska Inst, Dept Dent Med, Huddinge, Sweden..
    Silfverberg, Mikael
    Karolinska Inst, Dept Dent Med, Huddinge, Sweden..
    Brodin, David
    Karolinska Inst, Dept Biosci & Nutr, Bioinformat & Express Anal SciLifeLab, Huddinge, Sweden..
    Sällberg, Matti
    Karolinska Inst, Dept Lab Med, Huddinge, Sweden..
    Lindskog, Sven
    Karolinska Inst, Dept Pathol & Oncol, Huddinge, Sweden.;Karolinska Univ Hosp, Clin Pathol & Cytol, Solna, Sweden..
    Weiner, Carina Kruger
    Karolinska Inst, Dept Dent Med, Huddinge, Sweden.;Karolinska Univ Hosp, Clin Oral & Maxillofacial Surg, Huddinge, Sweden..
    Chen, Margaret
    Karolinska Inst, Dept Dent Med, Huddinge, Sweden.;Karolinska Inst, Dept Lab Med, Huddinge, Sweden..
    Ameloblastoma RNA profiling uncovers a distinct non-coding RNA signature2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 3, p. 4530-4542Article in journal (Refereed)
    Abstract [en]

    Ameloblastoma of the jaws remains the top difficult to treat odontogenic tumour and has a high recurrence rate. New evidence suggests that non-coding RNAs (ncRNAs) play a critical role in tumourgenesis and prognosis of cancer. However, ameloblastoma ncRNA expression data is lacking. Here we present the first report of ameloblastoma ncRNA signatures. A total of 95 ameloblastoma cases and a global array transcriptome technology covering > 285.000 full-length transcripts were used in this two-step analysis. The analysis first identified in a test cohort 31 upregulated ameloblastoma-associated ncRNAs accompanied by signalling pathways of cancer, spliceosome, mRNA surveillance and Wnt. Further validation in an independent cohort points out the long non-coding (lncRNAs) and small nucleolar RNA (snoRNAs): LINC340, SNORD116-25, SNORA11, SNORA21, SNORA47 and SNORA65 as a distinct ncRNA signature of ameloblastoma. Importantly, the presence of these ncRNAs was independent of BRAFV600E and SMO-L412F mutations, histology type or tumour location, but was positively correlated with the tumour size. Taken together, this study shows a systematic investigation of ncRNA expression of ameloblastoma, and illuminates new diagnostic and therapeutic targets for this invasive odontogenic tumour.

  • 16. Durán-Acevedo, Cristhian Manuel
    et al.
    Jaimes-Mogollón, Aylen Lisset
    Gualdrón-Guerrero, Oscar Eduardo
    Welearegay, Tesfalem Geremariam
    Martinez-Marín, Julián Davíd
    Caceres-Tarazona, Juan Martín
    Sánchez-Acevedo, Zayda Constanza
    Beleño-Saenz, Kelvin de Jesus
    Cindemir, Umut
    Österlund, Lars
    Ionescu, Radu
    Exhaled breath analysis for gastric cancer diagnosis in Colombian patients.2018In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 48, p. 28805-28817Article in journal (Refereed)
    Abstract [en]

    We present here the first study that directly correlates gastric cancer (GC) with specific biomarkers in the exhaled breath composition on a South American population, which registers one of the highest global incidence rates of gastric affections. Moreover, we demonstrate a novel solid state sensor that predicts correct GC diagnosis with 97% accuracy. Alveolar breath samples of 30 volunteers (patients diagnosed with gastric cancer and a controls group formed of patients diagnosed with other gastric diseases) were collected and analyzed by gas-chromatography/mass-spectrometry (GC-MS) and with an innovative chemical gas sensor based on gold nanoparticles (AuNP) functionalized with octadecylamine ligands. Our GC-MS analyses identified 6 volatile organic compounds that showed statistically significant differences between the cancer patients and the controls group. These compounds were different from those identified in previous studied performed on other populations with high incidence rates of this malady, such as China (representative for Eastern Asia region) and Latvia (representative for Baltic States), attributable to lifestyle, alimentation and genetics differences. A classification model based on principal component analysis of our sensor data responses to the breath samples yielded 97% accuracy, 100% sensitivity and 93% specificity. Our results suggest a new and non-intrusive methodology for early diagnosis of gastric cancer that may be deployed in regions lacking well-developed health care systems as a prediagnosis test for selecting the patients that should undergo deeper investigations (e.g., endoscopy and biopsy).

  • 17.
    Eleftheriou, Nikolas M.
    et al.
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Sjolund, Jonas
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Bocci, Matteo
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Cortez, Eliane
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Lee, Se-Jin
    Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA..
    Cunha, Sara I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Pietras, Kristian
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Compound genetically engineered mouse models of cancer reveal dual targeting of ALK1 and endoglin as a synergistic opportunity to impinge on angiogenic TGF-beta signaling2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 51, p. 84314-84325Article in journal (Refereed)
    Abstract [en]

    Angiogenesis occurs early in tumor development, sustains primary tumor growth and provides a route for metastatic escape. The TGF-beta family receptors modulate angiogenesis via endothelial-cell specific pathways. Here we investigate the interaction of two such receptors, ALK1 and endoglin, in pancreatic neuroendocrine tumors (PanNET). Independently, ALK1 and endoglin deficiencies exhibited genetically divergent phenotypes, while both highly correlate to an endothelial metagene in human and mouse PanNETs. A concurrent deficiency of both receptors synergistically decreased tumor burden to a greater extent than either individual knockdown. Furthermore, the knockout of Gdf2 (BMP9), the primary ligand for ALK1 and endoglin, exhibited a mixed phenotype from each of ALK1 and endoglin deficiencies; overall primary tumor burden decreased, but hepatic metastases increased. Tumors lacking BMP9 display a hyperbranching vasculature, and an increase in vascular mesenchymal-marker expression, which may be implicit in the increase in metastases. Taken together, our work cautions against singular blockade of BMP9 and instead demonstrates the utility of dual blockade of ALK1 and endoglin as a strategy for anti-angiogenic therapy in PanNET.

  • 18.
    Femel, Julia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Huijbers, Elisabeth JM
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Saupe, Falk
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cedervall, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Roswall, Pernilla
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Olofsson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Pietras, Kristian
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer.2014In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 23, p. 12418-12427Article in journal (Refereed)
    Abstract [en]

    Therapeutic vaccination targeting self-molecules is an attractive alternative to monoclonal antibody-based therapies for cancer and various inflammatory diseases. However, development of cancer vaccines targeting self-molecules has proven difficult. One complicating factor is that tumor cells have developed strategies to escape recognition by the immune system. Antigens specifically expressed by the tumor vasculature can therefore provide alternative targets. The alternatively spliced extra domain-A and B (ED-A and ED-B) of fibronectin are expressed during vasculogenesis in the embryo, but essentially undetectable under normal conditions in the adult. However, these domains are re-expressed during tumor angiogenesis and matrix remodeling, which renders them highly interesting for targeted cancer therapies. Using the MMTV-PyMT transgenic model of metastatic mammary carcinoma, we show that tumor burden can be significantly decreased by immunization against ED-A in a therapeutic setting. Furthermore, we found that in mice carrying anti-ED-A antibodies the number of metastases was reduced. ED-A immunization increased infiltration of macrophages and compromised tumor blood vessel function. These findings implicate an attack of the tumor vasculature by the immune system, through a polyclonal antibody response. We conclude that tumor vascular antigens are promising candidates for development of therapeutic vaccines targeting growth of primary tumors as well as disseminated disease.

  • 19.
    Fristedt Duvefelt, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lub, Susanne
    Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, (VUB) Belgium..
    Prasoon, Agarwal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Arngården, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Hammarberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Maes, Ken
    Van Valckenborgh, Els
    Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, (VUB) Belgium..
    Vanderkerekn, Karin
    Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, (VUB) Belgium..
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Increased resistance to proteaome inhibitors in multiple myeloma mediated by cIAP2: implications for a combinatorial treatment2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 24, p. 20621-20635Article in journal (Refereed)
    Abstract [en]

    Despite the introduction of new treatment options for multiple myeloma (MM), a majority of patients relapse due to the development of resistance. Unraveling new mechanisms underlying resistance could lead to identification of possible targets for combinatorial treatment. Using TRAF3 deleted/mutated MM cell lines, we evaluated the role of the cellular inhibitor of apoptosis 2 (cIAP2) in drug resistance and uncovered the plausible mechanisms underlying this resistance and possible strategies to overcome this by combinatorial treatment. In MM, cIAP2 is part of the gene signature of aberrant NF-kappa B signaling and is heterogeneously expressed amongst MM patients. In cIAP2 overexpressing cells a decreased sensitivity to the proteasome inhibitors bortezomib, MG132 and carfilzomib was observed. Gene expression analysis revealed that 440 genes were differentially expressed due to cIAP2 overexpression. Importantly, the data imply that cIAPs are rational targets for combinatorial treatment in the population of MM with deleted/mutated TRAF3. Indeed, we found that treatment with the IAP inhibitor AT-406 enhanced the anti-MM effect of bortezomib in the investigated cell lines. Taken together, our results show that cIAP2 is an important factor mediating bortezomib resistance in MM cells harboring TRAF3 deletion/mutation and therefore should be considered as a target for combinatorial treatment.

  • 20. Ghoshal, Arunangshu
    et al.
    Garmo, Hans
    Arthur, Rhonda
    Carroll, Paul
    Holmberg, Lars
    Kings Coll London, Sch Canc & Pharmaceut Sci, Translat Oncol & Urol Res, London, England.
    Hammar, Niklas
    Jungner, Ingmar
    Malmström, Håkan
    Lambe, Mats
    Walldius, Göran
    Van Hemelrijck, Mieke
    Thyroid cancer risk in the Swedish AMORIS study: the role of inflammatory biomarkers in serum.2018In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 1, p. 774-782Article in journal (Refereed)
    Abstract [en]

    Chronic inflammation is one of the underlying risks associated with thyroid cancer. We ascertained the association between commonly measured serum biomarkers of inflammation and the risk of thyroid cancer in Swedish Apolipoprotein-related MORtality RISk (AMORIS) study. 226,212 subjects had baseline measurements of C-reactive protein, albumin and haptoglobin. Leukocytes were measured in a subgroup of 63,845 subjects. Associations between quartiles and dichotomized values of inflammatory markers and risk of thyroid cancer were analysed using multivariate Cox proportional hazard models. 202 individuals were diagnosed with thyroid cancer during a mean follow-up of 19.6 years. There was a positive association between lower albumin levels and risk of developing thyroid cancer [Hazard Ratio for albumin ≤ 40 g/L: 1.50 (95% Confidence Interval = 1.04-2.16)]. When stratified by a metabolic score, we observed similar association for albumin with higher HR among those with metabolic score ≥ 1, as compared to those with metabolic score of 0 [HR 1.98 (95% CI = 1.11-3.54) vs 1.17 (95% CI = 0.72-1.89)] (P = 0.19). Apart from albumin, none of the serum markers of inflammation studied showed a link with the risk of developing thyroid cancer-suggesting that the role of inflammation may be more complicated and requires assessment of more specialised measurements of inflammation.

  • 21.
    Grujic, Mirjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Paivandy, Aida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gustafson, Ann-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Thomsen, Allan R.
    Univ Copenhagen, Dept Immunol & Microbiol, Copenhagen, Denmark..
    Öhrvik, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    The combined action of mast cell chymase, tryptase and carboxypeptidase A3 protects against melanoma colonization of the lung2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 15, p. 25066-25079Article in journal (Refereed)
    Abstract [en]

    Mast cell secretory granules are densely packed with various bioactive mediators including proteases of chymase, tryptase and CPA3 type. Previous studies have indicated that mast cells can affect the outcome of melanoma but the contribution of the mast cell granule proteases to such effects has not been clear. Here we addressed this issue by assessing mice lacking either the chymase Mcpt4, the tryptase Mcpt6 or carboxypeptidase A3 (Cpa3), as well as mice simultaneously lacking all three proteases, in a model of melanoma dissemination from blood to the lung. Although mice with individual deficiency in the respective proteases did not differ significantly from wildtype mice in the extent of melanoma colonization, mice with multiple protease deficiency (Mcpt4/Mcpt6/Cpa3-deficient) exhibited a higher extent of melanoma colonization in lungs as compared to wildtype animals. This was supported by higher expression of melanoma-specific genes in lungs of Mcpt4/Mcpt6/CPA3-deficient vs. wildtype mice. Cytokine profiling showed that the levels of CXCL16, a chemokine with effects on T cell populations and NKT cells, were significantly lower in lungs of Mcpt4/Mcpt6/Cpa3-deficient animals vs. controls, suggesting that multiple mast cell protease deficiency might affect T cell or NKT cell populations. In line with this, we found that the Mcpt4/Mcpt6/Cpa3-deficiency was associated with a reduction in cells expressing CD1d, a MHC class 1-like molecule that is crucial for presenting antigen to invariant NKT (iNKT) cells. Together, these findings indicate a protective role of mast cell-specific proteases in melanoma dissemination, and suggest that this effect involves a CXCL16/CD1d/NKT cell axis.

  • 22.
    Gudey, Shyam Kumar
    et al.
    Umea Univ, Dept Med Biosci, Umea, Sweden..
    Sundar, Reshma
    Umea Univ, Dept Med Biosci, Umea, Sweden..
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergh, Anders
    Umea Univ, Dept Med Biosci, Umea, Sweden..
    Landström, Marene
    Umea Univ, Dept Med Biosci, Umea, Sweden..
    Pro-invasive properties of Snail1 are regulated by sumoylation in response to TGF beta stimulation in cancer2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 58, p. 97703-97726Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor beta (TGF beta) is a key regulator of epithelial-tomesenchymal transition (EMT) during embryogenesis and in tumors. The effect of TGF beta, on EMT, is conveyed by induction of the pro-invasive transcription factor Snail1. In this study, we report that TGF beta stimulates Snail1 sumoylation in aggressive prostate, breast and lung cancer cells. Sumoylation of Snail1 lysine residue 234 confers its transcriptional activity, inducing the expression of classical EMT genes, as well as TGF beta receptor I (T beta RI) and the transcriptional repressor Hes1. Mutation of Snail1 lysine residue 234 to arginine (K234R) abolished sumoylation of Snail1, as well as its migratory and invasive properties in human prostate cancer cells. An increased immunohistochemical expression of Snail1, Sumo1, T beta RI, Hes1, and c-Jun was observed in aggressive prostate cancer tissues, consistent with their functional roles in tumorigenesis.

  • 23.
    Gupta, Deepesh Kumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Du, Jian
    Kamranvar, Siamak A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tension-induced cytokinetic abscission in human fibroblasts2018In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553Article in journal (Other academic)
  • 24.
    Haylock, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Nilvebrant, Johan
    Royal Inst Technol, Sch Biotechnol, Div Prot Technol, Stockholm, Sweden..
    Mortensen, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Falk, Ronny
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Generation and evaluation of antibody agents for molecular imaging of CD44v6-expressing cancers2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 39, p. 65152-65170Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of this study was to generate and characterize scFv antibodies directed to human CD44v6, as well as to radiolabel and evaluate top candidates in vitro and in vivo for their potential use in CD44v6-targeted molecular imaging in cancer patients.

    Materials and methods: Phage display selections were used to isolate CD44v6-specific scFvs. A chain shuffling strategy was employed for affinity maturation based on a set of CD44v6-specific first-generation clones. Two second-generation scFv clones were then chosen for labeling with 111In or 125I and assessed for CD44v6-specific binding on cultured tumor cells. In vivo uptake and distribution was evaluated in tumor-bearing mice using a dual tumor model. Finally, a proof-of-concept small animal PET-CT study was performed on one of the candidates labeled with 124I.

    Results: Two affinity-matured clones, CD44v6-scFv-A11 and CD44v6-scFv-H12, displayed promising binding kinetics. Seven out of eight radiolabeled conjugates demonstrated CD44v6-specific binding. In vivo studies on selected candidates demonstrated very advantageous tumor-to-organ ratios, in particular for iodinated conjugates, where 125I-labeled scFvs exhibited favorable kinetics and tumor-to-blood ratios above five already at 24 hours p. i.. The small animal PET-CT study using 124I-labeled CD44v6-scFv-H12 was in line with the biodistribution data, clearly visualizing the high CD44v6-expressing tumor.

    Conclusion: The single chain fragments, CD44v6-scFv-A11 and CD44v6-scFv-H12 specifically bind to CD44v6, and the radiolabeled counterparts provide high tumor-to-blood ratios and fast clearance from organs and blood. We conclude that radioiodinated CD44v6-scFv-A11 and CD44v6-scFv-H12 possess features highly suitable for stringent molecular imaging.

  • 25.
    Heiland, Dieter H.
    et al.
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Ferrarese, Roberto
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Claus, Rainer
    Univ Freiburg, Med Ctr, Dept Hematol Oncol & Stem Cell Transplantat, Freiburg, Germany..
    Dai, Fangping
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Masilamani, Anie P.
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Kling, Eva
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Weyerbrock, Astrid
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Kling, Teresia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carro, Maria S.
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 4, p. 6940-6954Article in journal (Refereed)
    Abstract [en]

    High-grade gliomas (HGG) are the most common brain tumors, with an average survival time of 14 months. A glioma-CpG island methylator phenotype (G-CIMP), associated with better clinical outcome, has been described in low and high-grade gliomas. Mutation of IDH1 is known to drive the G-CIMP status. In some cases, however, the hypermethylation phenotype is independent of IDH1 mutation, suggesting the involvement of other mechanisms. Here, we demonstrate that DNMT1 expression is higher in low-grade gliomas compared to glioblastomas and correlates with phosphorylated c-Jun. We show that phospho-c-Jun binds to the DNMT1 promoter and causes DNA hypermethylation. Phospho-c-Jun activation by Anisomycin treatment in primary glioblastoma-derived cells attenuates the aggressive features of mesenchymal glioblastomas and leads to promoter methylation and downregulation of key mesenchymal genes (CD44, MMP9 and CHI3L1). Our findings suggest that phospho-c-Jun activates an important regulatory mechanism to control DNMT1 expression and regulate global DNA methylation in Glioblastoma.

  • 26.
    Irenaeus, Sandra
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schiza, Aglaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mangsbo, Sara M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wenthe, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svensson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Krause, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Tötterman, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Loskog, Angelica S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 45, p. 78573-78587Article in journal (Refereed)
    Abstract [en]

    Background: AdCD40L is an immunostimulatory gene therapy under evaluation for advanced melanoma, including ocular melanoma. Herein, we present the final data of a Phase I/IIa trial using AdCD40L alone or in combination with low dose cyclophosphamide +/- radiation therapy.

    Methods: AdCD40L is a replication-deficient adenovirus carrying the gene for CD40 ligand (CD40L). Twenty-four patients with advanced melanoma were enrolled and treated with AdCD40L monotherapy, or combined with cyclophosphamide +/- single fraction radiotherapy. The patients were monitored for 10 weeks using immunological and radiological evaluations and thereafter for survival.

    Results: AdCD40L treatment was safe and well tolerated both alone and in combination with cyclophosphamide as well as local radiotherapy. Four out of twenty-four patients had >1 year survival. Addition of cyclophosphamide was beneficial but adding radiotherapy did not further extend survival. High initial plasma levels of IL12 and MIP3b correlated to overall survival, whereas IL8 responses post-treatment correlated negatively with survival. Interestingly, antibody reactions to the virus correlated negatively with post IL6 and pre IL1b levels in blood.

    Conclusions: AdCD40L was safely administered to patients and effect was improved by cyclophosphamide but not by radiotherapy. Immune activation profile at baseline may predict responders better than shortly after treatment.

  • 27.
    Jiao, Xiang
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Aravidis, Christos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Marikkannu, Rajeshwari
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Rantala, Johanna
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Picelli, Simone
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Adamovic, Tatjana
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Liu, Tao
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Maguire, Paula
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Kremeyer, Barbara
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Luo, Liping
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Von Holst, Susanna
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Kontham, Vinaykumar
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Thutkawkorapin, Jessada
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Margolin, Sara
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Du, Quan
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Lundin, Johanna
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Michailidou, Kyriaki
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England.;Cyprus Inst Neurol & Genet, Dept Elect Microscopy Mol Pathol, Nicosia, Cyprus..
    Bolla, Manjeet K.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Wang, Qin
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Dennis, Joe
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Lush, Michael
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Ambrosone, Christine B.
    Roswell Pk Canc Inst, Buffalo, NY 14263 USA..
    Andrulis, Irene L.
    Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Fred A Litwin Ctr Canc Genet, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
    Anton-Culver, Hoda
    Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA..
    Antonenkova, Natalia N.
    NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, Byelarus..
    Arndt, Volker
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany..
    Beckmann, Matthias W.
    Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, Dept Gynaecol & Obstet, Erlangen, Germany..
    Blomqvist, Carl
    Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland..
    Blot, William
    Vanderbilt Univ, Sch Med, Div Epidemiol,Dept Med, Vanderbilt Ingram Canc Ctr,Vanderbilt Epidemiol C, Nashville, TN 37212 USA.;Int Epidemiol Inst, Rockville, MD USA..
    Boeckx, Bram
    VIB, VIB Ctr Canc Biol, Leuven, Belgium.;Univ Leuven, Dept Human Genet, Lab Translat Genet, Leuven, Belgium..
    Bojesen, Stig E.
    Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark.;Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Bonanni, Bernardo
    Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy..
    Brand, Judith S.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany.;Univ Tubingen, Tubingen, Germany.;German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany..
    Brenner, Hermann
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.;German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany.;German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis NCT, Heidelberg, Germany..
    Broeks, Annegien
    Antoni Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands..
    Bruning, Thomas
    Ruhr Univ Bochum, Inst Prevent & Occupat Med, German Social Accid Insurance, Bochum, Germany..
    Burwinkel, Barbara
    Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany.;German Canc Res Ctr, Mol Epidemiol Grp, C080, Heidelberg, Germany..
    Cai, Qiuyin
    Vanderbilt Univ, Sch Med, Div Epidemiol,Dept Med, Vanderbilt Ingram Canc Ctr,Vanderbilt Epidemiol C, Nashville, TN 37212 USA..
    Chang-Claude, Jenny
    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany.;Univ Canc Ctr Hamburg, Univ Med Ctr Hamburg Eppendorf, Res Grp Genet Canc Epidemiol, Hamburg, Germany. Haukeland Hosp, Dept Oncol, Bergen, Norway. Univ Bergen, Inst Med, Sect Oncol, Bergen, Norway. Akershus Univ Hosp, Dept Pathol, Lorenskog, Norway. Akershus Univ Hosp, Dept Breast Endocrine Surg, Lorenskog, Norway..
    Couch, Fergus J.
    Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA..
    Cox, Angela
    Univ Sheffield, Dept Oncol & Metab, Sheffield Inst Nucle Acids SInFoNiA, Sheffield, S Yorkshire, England..
    Cross, Simon S.
    Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England..
    Deming-Halverson, Sandra L.
    Vanderbilt Univ, Sch Med, Div Epidemiol,Dept Med, Vanderbilt Ingram Canc Ctr,Vanderbilt Epidemiol C, Nashville, TN 37212 USA..
    Devilee, Peter
    Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands..
    dos-Santos-Silva, Isabel
    London Sch Hyg & Trop Med, Dept Noncommun Dis Epidemiol, London, England..
    Dork, Thilo
    Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany..
    Eriksson, Mikael
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Fasching, Peter A.
    Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, Dept Gynaecol & Obstet, Erlangen, Germany.;Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Div Hematol & Oncol, Los Angeles, CA USA..
    Figueroa, Jonine
    Univ Edinburgh, Med Sch, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.;NCI, Div Canc Epidemiol & Genet, Rockville, MD USA..
    Flesch-Janys, Dieter
    Univ Med Ctr Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany.;Univ Med Ctr Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany..
    Flyger, Henrik
    Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Breast Surg, Herlev, Denmark..
    Gabrielson, Marike
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Garcia-Closas, Montserrat
    NCI, Div Canc Epidemiol & Genet, Rockville, MD USA..
    Giles, Graham G.
    Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.;Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia..
    Gonzalez-Neira, Anna
    Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain..
    Guenel, Pascal
    Univ Paris Saclay, Univ Paris Sud, INSERM, Ctr Res Epidemiol & Populat Hlth CESP,Canc & Envi, Villejuif, France..
    Guo, Qi
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England..
    Gundert, Melanie
    Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany.;German Canc Res Ctr, Mol Epidemiol Grp, C080, Heidelberg, Germany..
    Haiman, Christopher A.
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA..
    Hallberg, Emily
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA..
    Hamann, Ute
    German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany..
    Harrington, Patricia
    Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England..
    Hooning, Maartje J.
    Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands..
    Hopper, John L.
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia..
    Huang, Guanmengqian
    German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany..
    Jakubowska, Anna
    Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland..
    Jones, Michael E.
    Inst Canc Res, Div Genet & Epidemiol, London, England..
    Kerin, Michael J.
    Natl Univ Ireland, Sch Med, Galway, Ireland..
    Kosma, Veli-Matti
    Univ Eastern Finland, Translat Canc Res Area, Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio, Finland..
    Kristensen, Vessela N.
    Univ Oslo, Hosp Radiumhosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway. Oslo Univ Hosp, Dept Breast & Endocrine Surg, Oslo, Norway. Vestre Viken Hosp, Dept Res, Drammen, Norway. Univ Oslo, Hosp Radiumhosp, Inst Canc Res, Dept Tumor Biol, Oslo, Norway.;Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway.;Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway. Univ Oslo, Hosp Radiumhosp, Natl Advisory Unit Late Effects Canc Treatment, Oslo, Norway. Univ Oslo, Hosp Radiumhosp, Dept Oncol, Oslo, Norway. Univ Oslo, Hosp Radiumhosp, Dept Radiol & Nucl Med, Oslo, Norway. Oslo Univ Hosp, Oslo, Norway..
    Lambrechts, Diether
    VIB, VIB Ctr Canc Biol, Leuven, Belgium.;Univ Leuven, Dept Human Genet, Lab Translat Genet, Leuven, Belgium..
    Le Marchand, Loic
    Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA..
    Lubinski, Jan
    Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland..
    Mannermaa, Arto
    Univ Eastern Finland, Translat Canc Res Area, Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio, Finland..
    Martens, John W. M.
    Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands..
    Meindl, Alfons
    Tech Univ Munich, Div Gynaecol & Obstet, Munich, Germany..
    Milne, Roger L.
    Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.;Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia..
    Mulligan, Anna Marie
    Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada.;Univ Hlth Network, Lab Med Program, Toronto, ON, Canada..
    Neuhausen, Susan L.
    Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA..
    Nevanlinna, Heli
    Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland..
    Peto, Julian
    London Sch Hyg & Trop Med, Dept Noncommun Dis Epidemiol, London, England..
    Pylkaes, Katri
    Univ Oulu, Bioctr Oulu, Canc & Translat Med Res Unit, Lab Canc Genet & Tumor Biol, Oulu, Finland.;Northern Finland Lab Ctr Oulu, Lab Canc Genet & Tumor Biol, Oulu, Finland..
    Radice, Paolo
    INT, Fdn IRCCS, Ist Ricovero Cura Carattere Sci, Dept Res, Milan, Italy..
    Rhenius, Valerie
    Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England..
    Sawyer, Elinor J.
    Kings Coll London, Guys Hosp, Res Oncol, London, England..
    Schmidt, Marjanka K.
    Antoni Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands.;Antoni Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands..
    Schmutzler, Rita K.
    Univ Hosp Cologne, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany.;Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany.;Univ Cologne, Ctr Mol Med Cologne, Cologne, Germany..
    Seynaeve, Caroline
    Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands..
    Shah, Mitul
    Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England..
    Simard, Jacques
    Laval Univ, Univ Quebec, Res Ctr, Ctr Hosp,Gen Ctr, Quebec City, PQ, Canada..
    Southey, Melissa C.
    Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia..
    Swerdlow, Anthony J.
    Inst Canc Res, Div Genet & Epidemiol, London, England.;Inst Canc Res, Div Breast Canc Res, London, England. Peter MacCallum Canc Ctr, Melbourne, Vic, Australia..
    Truong, Therese
    Univ Paris Saclay, Univ Paris Sud, INSERM, Ctr Res Epidemiol & Populat Hlth CESP,Canc & Envi, Villejuif, France..
    Wendt, Camilla
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Winqvist, Robert
    Univ Oulu, Bioctr Oulu, Canc & Translat Med Res Unit, Lab Canc Genet & Tumor Biol, Oulu, Finland.;Northern Finland Lab Ctr Oulu, Lab Canc Genet & Tumor Biol, Oulu, Finland..
    Zheng, Wei
    Vanderbilt Univ, Sch Med, Div Epidemiol,Dept Med, Vanderbilt Ingram Canc Ctr,Vanderbilt Epidemiol C, Nashville, TN 37212 USA..
    Benitez, Javier
    Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain.;Ctr Invest Red Enfermedades Raras CIBERER, Valencia, Spain..
    Dunning, Alison M.
    Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England..
    Pharoah, Paul D. P.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England.;Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England..
    Easton, Douglas F.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England.;Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England..
    Czene, Kamila
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Hall, Per
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Lindblom, Annika
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    PHIP - a novel candidate breast cancer susceptibility locus on 6q14.12017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 61, p. 102769-102782Article in journal (Refereed)
    Abstract [en]

    Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.

  • 28.
    Kamranvar, Siamak A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gupta, Deepesh Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Biomed Ctr, Dept Med Biochem & Microbiol, Uppsala, Sweden..
    Huang, Ying
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gupta, Rajesh Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Integrin signaling via FAK-Src controls cytokinetic abscission by decelerating PLK1 degradation and subsequent recruitment of CEP55 at the midbody2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 21, p. 30820-30830Article in journal (Refereed)
    Abstract [en]

    Adhesion to extracellular matrix is required for cell cycle progression through the G1 phase and for the completion of cytokinesis in normal adherent cells. Cancer cells acquire the ability to proliferate anchorage-independently, a characteristic feature of malignantly transformed cells. However, the molecular mechanisms underlying this escape of the normal control mechanisms remain unclear. The current study aimed to identify adhesion-induced reactions regulating the cytokinesis of non-transformed human fibroblasts. The adhesion-dependent control of cytokinesis was found to occur at a late stage close to the abscission, during which the endosomal sorting complex required for transport (ESCRT) severs the thin intercellular bridge connecting two nascent daughter cells. CEP55, a key protein involved in the abscission process, was localized at the midbody in both adherent and non-adherent fibroblasts, but it was unable to efficiently recruit ALIX, TSG101, and consequently the ESCRT-III subunit CHMP4B was missing in the non-adherent cells. PLK1, a kinase that prevents premature recruitment of CEP55 to the midbody, disappeared from this site more rapidly in the non-adherent cells. A FAK-Src signaling pathway downstream of integrin-mediated cell adhesion was found to decelerate both PLK1 degradation and CEP55 accumulation at the midbody. These data identify the regulation of PLK1 and CEP55 as steps where integrins exert control over the cytokinetic abscission.

  • 29.
    Karlsson, Henning
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Strese, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Westman, Gunnar
    Chalmers, Dept Chem & Chem Engn, Gothenburg, Sweden..
    Bremberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Pandzic, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 18, p. 30217-30234Article in journal (Refereed)
    Abstract [en]

    Background: The thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties.

    Materials and Methods: The cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50.

    Results: VLX60 showed >= 3-fold higher cytotoxic activity than VLX50 in 2-D cultures and, in contrast to VLX50, retained its activity in the presence of additional iron. VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model. In contrast to VLX50, gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen. VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells.

    Conclusions: The cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug, notably against BRAF mutated colorectal cancer.

  • 30.
    Kashif, Muhammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Andersson, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Mansoori, Sharmineh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Gustafsson, Mats G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Bliss and Loewe interaction analyses of clinically relevant drug combinations in human colon cancer cell lines reveal complex patterns of synergy and antagonism2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 61, p. 103952-103967Article in journal (Refereed)
    Abstract [en]

    We analyzed survival effects for 15 different pairs of clinically relevant anticancer drugs in three iso-genic pairs of human colorectal cancer carcinoma cell lines, by applying for the first time our novel software (R package) called COMBIA. In our experiments iso-genic pairs of cell lines were used, differing only with respect to a single clinically important KRAS or BRAF mutation. Frequently, concentration dependent but mutation independent joint Bliss and Loewe synergy/antagonism was found statistically significant. Four combinations were found synergistic/antagonistic specifically to the parental (harboring KRAS or BRAF mutation) cell line of the corresponding iso-genic cell lines pair. COMBIA offers considerable improvements over established software for synergy analysis such as MacSynergy (TM) II as it includes both Bliss (independence) and Loewe (additivity) analyses, together with a tailored non-parametric statistical analysis employing heteroscedasticity, controlled resampling, and global (omnibus) testing. In many cases Loewe analyses found significant synergistic as well as antagonistic effects in a cell line at different concentrations of a tested drug combination. By contrast, Bliss analysis found only one type of significant effect per cell line. In conclusion, the integrated Bliss and Loewe interaction analysis based on non-parametric statistics may provide more robust interaction analyses and reveal complex patterns of synergy and antagonism.

  • 31.
    Koos, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Closing in on life - proximity dependent methods for life sciences2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 20, p. 17867-17868Article in journal (Other academic)
  • 32.
    Li, Xiujuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Soochow University, Suzhou, China.
    Singh, Kailash
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Luo, Zhengkang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mejia Cordova, Mariela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jamalpour, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lindahl, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Zhang, Ganlin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pro-tumoral immune cell alterations in wild type and Shb-deficient mice in response to 4T1 breast carcinomas2018In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 27, p. 18720-18733Article in journal (Refereed)
    Abstract [en]

    To assess mechanisms responsible for breast carcinoma metastasis, 4T1 breast carcinomas were grown orthotopically in wild type or Shb knockout mice. Tumor growth, metastasis, vascular characteristics and immune cell properties were analyzed. Absence of Shb did not affect tumor growth although it increased lung metastasis. Shb knockout mouse tumors showed decreased redness and less developed vascular plexa located at the periphery of the tumors. No difference in overall tumor vascular density, leakage or pericyte coverage was noted between the genotypes although the average vessel size was smaller in the knockout. Tumors induced an increase of CD11b+ cells in spleen, lymph node, thymus, bone marrow and blood. Numbers of Shb knockout CD11b/CD8+ cells were decreased in lymph nodes and bone marrow of tumor bearing mice. Mice with tumors had reduced numbers of CD4+ lymphocytes in blood/lymphoid organs, whereas in most of these locations the proportion of CD4+ cells co-expressing FoxP3 was increased, suggesting a relative increase in Treg cells. This finding was reinforced by increased blood interleukin-35 (IL-35) in wild type tumor bearing mice. Shb knockout blood showed in addition an increased proportion of IL-35 expressing Treg cells, supporting the notion that absence of Shb further promotes tumor evasion from immune cell recognition. This could explain the increased number of lung metastases observed under these conditions. In conclusion, 4T1 tumors alter immune cell responses that promote tumor expansion, metastasis and escape from T cell recognition in an Shb dependent manner. 

  • 33.
    Lindqvist, C. Mårten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Ekman, Diana
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Almlöf, Jonas Carlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Raine, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Övernäs, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Dept Pediat, Gothenburg, Sweden..
    Frost, Britt-Marie
    Univ Childrens Hosp, Dept Womens & Childrens Hlth, Uppsala, Sweden..
    Grander, Dan
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Heyman, Mats
    Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Dept Women & Child Hlth, Childhood Canc Res Unit, Stockholm, Sweden..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden.;Univ Childrens Hosp, Dept Womens & Childrens Hlth, Uppsala, Sweden..
    Forestier, Erik
    Umea Univ, Dept Med Biosci, Umea, Sweden..
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Berglund, Eva C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 39, p. 64071-64088Article in journal (Refereed)
    Abstract [en]

    To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few mutations in driver genes compared to other BCP-ALL patients. Specifically in BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an association between somatic mutations in the Notch signaling pathway at ALL diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A and SH2B3 as relapse-associated genes. The genes highlighted in our study were frequently involved in epigenetic regulation, associated with germline susceptibility to ALL, and present in minor subclones at diagnosis that became dominant at relapse. We observed a high degree of clonal heterogeneity and evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could have implications for the treatment efficiency.

  • 34.
    Liu, Fang
    et al.
    Binzhou Med Univ, Med & Pharm Res Ctr, Yantai 264003, Shandong, Peoples R China.;Binzhou Med Univ, Dept Radiol, Affiliated Hosp, Binzhou 256603, Shandong, Peoples R China..
    Zhang, Yuan
    Binzhou Med Univ, Med & Pharm Res Ctr, Yantai 264003, Shandong, Peoples R China..
    Men, Tingting
    Binzhou Med Univ, Med & Pharm Res Ctr, Yantai 264003, Shandong, Peoples R China..
    Jiang, Xingyue
    Binzhou Med Univ, Dept Radiol, Affiliated Hosp, Binzhou 256603, Shandong, Peoples R China..
    Yang, Chunhua
    Binzhou Med Univ, Med & Pharm Res Ctr, Yantai 264003, Shandong, Peoples R China..
    Li, He
    Binzhou Med Univ, Yantai Affiliated Hosp, Dept Gastr & Intestine, Yantai 264003, Shandong, Peoples R China..
    Wei, Xiaodan
    Binzhou Med Univ, Med & Pharm Res Ctr, Yantai 264003, Shandong, Peoples R China..
    Yan, Dong
    Binzhou Med Univ, Med & Pharm Res Ctr, Yantai 264003, Shandong, Peoples R China..
    Feng, Gangming
    China Agr Univ, Yantai Inst, Yantai 264670, Shandong, Peoples R China..
    Yang, Jianke
    Binzhou Med Univ, Med & Pharm Res Ctr, Yantai 264003, Shandong, Peoples R China..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Wang, Bin
    Binzhou Med Univ, Dept Radiol, Affiliated Hosp, Binzhou 256603, Shandong, Peoples R China..
    Jiang, Wenguo
    Binzhou Med Univ, Med & Pharm Res Ctr, Yantai 264003, Shandong, Peoples R China..
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Binzhou Med Univ, Med & Pharm Res Ctr, Yantai 264003, Shandong, Peoples R China..
    Tian, Geng
    Binzhou Med Univ, Med & Pharm Res Ctr, Yantai 264003, Shandong, Peoples R China..
    Quantitative proteomic analysis of gastric cancer tissue reveals novel proteins in platelet-derived growth factor B signaling pathway2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 13, p. 22059-22075Article in journal (Refereed)
    Abstract [en]

    Gastric cancer is one of the most common cancers in Asian countries. Searching for reliable biomarkers involving the development of gastric cancer is important for clinical practice. Quantitative proteomics has become an important method contributed to the discovery of novel diagnostic or therapeutic targets for the management of cancer. Here, we identified differently expressed proteins in gastric cancer and normal gastric tissues by using the high resolution mass spectrometer. Among the total of 2280 identified proteins, 87 were differentially expressed between gastric cancer and normal gastric tissues. Notably, several significant proteins are in the PDGF-B signaling pathway, including peroxiredoxin5 (PRDX5), S100A6, calreticulin (CALR) and cathepsin D (CTSD), which were validated by western blot. Furthermore, upstream regulators including PDGF-B, PDGFR-beta, Akt, eIF4E and p70s6K were found significantly increased in the gastric cancer tissues. In addition, silencing of PRDX5 and PDGF-B suppressed the proliferation of gastric cancer cells in vitro. The administration of exogenous PDGF-BB recovered the reduced expression of PDGF-B signaling pathway in PDGF-B knockdown cells. Taken together, our findings suggested that PDGF-B signaling pathway plays an important role in the regulation of gastric cancer proliferation and the inhibition of this pathway may be a potential approach for treatment of gastric cancer.

  • 35. Lyberg, Katarina
    et al.
    Ali, Hani Abdulkadir
    Grootens, Jennine
    Kjellander, Matilda
    Tirfing, Malin
    Arock, Michel
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Ungerstedt, Johanna
    Histone deacetylase inhibitor SAHA mediates mast cell death and epigenetic silencing of constitutively active D816V KIT in systemic mastocytosis.2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 6, p. 9647-9659Article in journal (Refereed)
    Abstract [en]

    Systemic mastocytosis (SM) is a clonal bone marrow disorder, where therapeutical options are limited. Over 90% of the patients carry the D816V point mutation in the KIT receptor that renders this receptor constitutively active. We assessed the sensitivity of primary mast cells (MC) and mast cell lines HMC1.2 (D816V mutated), ROSA (KIT WT) and ROSA (KIT D816V) cells to histone deacetylase inhibitor (HDACi) treatment. We found that of four HDACi, suberoyl anilide hydroxamic acid (SAHA) was the most effective in killing mutated MC. SAHA downregulated KIT, followed by major MC apoptosis. Primary SM patient MC cultured ex vivo were even more sensitive to SAHA than HMC1.2 cells, whereas primary MC from healthy subjects were less affected. There was a correlation between cell death and SM disease severity, where cell death was more pronounced in the case of aggressive SM, with almost 100% cell death among MC from the mast cell leukemia patient. Additionally, ROSA (KIT D816V) was more affected by HDACi than ROSA (KIT WT) cells. Using ChIP qPCR, we found that the level of active chromatin mark H3K18ac/H3 decreased significantly in the KIT region. This epigenetic silencing was seen only in the KIT region and not in control genes upstream and downstream of KIT, indicating that the downregulation of KIT is exerted by specific epigenetic silencing. In conclusion, KIT D816V mutation sensitized MC to HDACi mediated killing, and SAHA may be of value as specific treatment for SM, although the specific mechanism of action requires further investigation.

  • 36.
    Mezheyeuski, Artur
    et al.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Belarusian State Med Univ, Dept Pathol, Minsk, Byelarus..
    Lindh, Maja Bradic
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Guren, Tormod Kyrre
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway..
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Pfeiffer, Per
    Univ Southern Denmark, Dept Oncol, Odense, Denmark..
    Kure, Elin H.
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway..
    Ikdahl, Tone
    Akershus Univ Hosp, Lorenskog, Norway..
    Skovlund, Eva
    Univ Oslo, Sch Pharm, Oslo, Norway.;Norwegian Inst Publ Hlth, Oslo, Norway..
    Corvigno, Sara
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Strell, Carina
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Pietras, Kristian
    Lund Univ, Div Translat Canc Res, Lund, Sweden..
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Mulder, Jan
    Karolinska Inst, Sci Life Lab, Dept Neurosci, Stockholm, Sweden..
    Qvortrup, Camilla
    Univ Southern Denmark, Dept Oncol, Odense, Denmark..
    Portyanko, Anna
    Belarusian State Med Univ, Dept Pathol, Minsk, Byelarus..
    Tveit, Kjell Magne
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway..
    Östman, Arne
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Survival-associated heterogeneity of marker-defined perivascular cells in colorectal cancer2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 27, p. 41948-41958Article in journal (Refereed)
    Abstract [en]

    Perivascular cells (PC) were recently implied as regulators of metastasis and immune cell activity. Perivascular heterogeneity in clinical samples, and associations with other tumor features and outcome, remain largely unknown. Here we report a novel method for digital quantitative analyses of vessel characteristics and PC, which was applied to two collections of human metastatic colorectal cancer (mCRC). Initial analyses identified marker-defined subsets of PC, including cells expressing PDGFR-beta or alpha-SMA or both markers. PC subsets were largely independently expressed in a manner unrelated to vessel density and size. Association studies implied specific oncogenic mutations in malignant cells as determinants of PC status. Semi-quantitative and digital-image-analyses-based scoring of the NORDIC-VII cohort identified significant associations between low expression of perivascular PDGFR-alpha and -beta and shorter overall survival. Analyses of the SPCRC cohort confirmed these findings. Perivascular PDGFR-alpha and -beta remained independent factors for survival in multivariate analyses. Overall, our study identified host vasculature and oncogenic status as determinants of tumor perivascular features. Perivascular PDGFR-alpha and -beta were identified as novel independent markers predicting survival in mCRC. The novel methodology should be suitable for similar analyses in other tumor collections.

  • 37.
    Mosrati, Mohamed Ali
    et al.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Willander, Kerstin
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.;Linkoping Univ, Dept Haematol, Linkoping, Sweden..
    Falk, Ingrid Jakobsen
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stockelberg, Dick
    Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Dept Internal Med, Gothenburg, Sweden..
    Wei, Yuan
    Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Dept Internal Med, Gothenburg, Sweden..
    Lotfi, Kourosh
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.;Cty Council Ostergotland, Dept Hematol, Linkoping, Sweden..
    Soderkvist, Peter
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Association between TERT promoter polymorphisms and acute myeloid leukemia risk and prognosis2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 28, p. 25109-25120Article in journal (Refereed)
    Abstract [en]

    Telomerase reverse transcriptase gene (TERT) promoter mutations are identified in many malignancies but not in hematological malignancies. Here we analyzed TERT and protection of telomeres 1 gene (POT1) mutations, and four different TERT SNVs in 226 acute myeloid leukemia (AML) patients and 806 healthy individuals in a case referent design, where also overall survival was assessed. A significant association for increased risk of AML was found for TERT SNVs, rs2853669 (OR = 2.45, p = 0.00015) and rs2736100 (OR = 1.5, p = 0.03). The overall survival for patients with CC genotype of rs2853669 was significantly shorter compared to those with TT or TC genotypes (p = 0.036 and 0.029 respectively). The influence of TERT rs2853669 CC on survival was confirmed in multivariable Cox regression analysis as an independent risk biomarker in addition to high risk group, higher age and treatment. No hot spot TERT promoter mutations at -228C>T or -250C>T or POT1 mutations could be identified in this AML cohort. We show that rs2853669 CC may be a risk factor for the development of AML that may also be used as a prognostic marker to identify high risk normal karyotype -AML (NK-AML) patients, for treatment guidance.

  • 38.
    Pandzic, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rendo, Verónica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lim, Jinyeong
    Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyangsi, Republic of Korea.
    Larsson, Chatarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stoimenov, Ivaylo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kundu, Snehangshu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ali, Muhammad Akhtar
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindroth, Anders M.
    Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyangsi, Republic of Korea.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Somatic PRDM2 c.4467delA mutations in colorectal cancers control histone methylation and tumor growth2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 58, p. 98646-98659Article in journal (Refereed)
    Abstract [en]

    The chromatin modifier PRDM2/RIZ1 is inactivated by mutation in several forms of cancer and is a putative tumor suppressor gene. Frameshift mutations in the C-terminal region of PRDM2, affecting (A)8 or (A)9 repeats within exon 8, are found in one third of colorectal cancers with microsatellite instability, but the contribution of these mutations to colorectal tumorigenesis is unknown. To model somatic mutations in microsatellite unstable tumors, we devised a general approach to perform genome editing while stabilizing the mutated nucleotide repeat. We then engineered isogenic cell systems where the PRDM2 c.4467delA mutation in human HCT116 colorectal cancer cells was corrected to wild-type by genome editing. Restored PRDM2 increased global histone 3 lysine 9 dimethylation and reduced migration, anchorage-independent growth and tumor growth in vivo. Gene set enrichment analysis revealed regulation of several hallmark cancer pathways, particularly of epithelial-to-mesenchymal transition (EMT), with VIM being the most significantly regulated gene. These observations provide direct evidence that PRDM2 c.4467delA is a driver mutation in colorectal cancer and confirms PRDM2 as a cancer gene, pointing to regulation of EMT as a central aspect of its tumor suppressive action.

  • 39.
    Papakonstantinou, Nikos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Ntoufa, Stavroula
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Chartomatsidou, Elisavet
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Kotta, Konstantia
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Agathangelidis, Andreas
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Giassafaki, Lefki
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Karamanli, Tzeni
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Bele, Panagiota
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Moysiadis, Theodoros
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sutton, Lesley Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stavroyianni, Niki
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Makris, Antonios M.
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Ghia, Paolo
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Rosenquist, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stamatopoulos, Kostas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    The histone methyltransferase EZH2 as a novel prosurvival factor in clinically aggressive chronic lymphocytic leukemia2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 24, p. 35946-35959Article in journal (Refereed)
    Abstract [en]

    The histone methyltransferase EZH2 induces gene repression through trimethylation of histone H3 at lysine 27 (H3K27me3). EZH2 overexpression has been reported in many types of cancer and associated with poor prognosis. Here we investigated the expression and functionality of EZH2 in chronic lymphocytic leukemia (CLL). Aggressive cases with unmutated IGHV genes (U-CLL) displayed significantly higher EZH2 expression compared to indolent CLL cases with mutated IGHV genes (M-CLL); furthermore, in U-CLL EZH2 expression was upregulated with disease progression. Within U-CLL, EZH2(high) cases harbored significantly fewer (p = 0.033) TP53 gene abnormalities compared to EZH2(low) cases. EZH2(high) cases displayed high H3K27me3 levels and increased viability suggesting that EZH2 is functional and likely confers a survival advantage to CLL cells. This argument was further supported by siRNA-mediated downmodulation of EZH2 which resulted in increased apoptosis. Notably, at the intraclonal level, cell proliferation was significantly associated with EZH2 expression. Treatment of primary CLL cells with EZH2 inhibitors induced downregulation of H3K27me3 levels leading to increased cell apoptosis. In conclusion, EZH2 is overexpressed in adverse-prognosis CLL and associated with increased cell survival and proliferation. Pharmacologic inhibition of EZH2 catalytic activity promotes apoptosis, highlighting EZH2 as a novel potential therapeutic target for specific subgroups of patients with CLL.

  • 40.
    Pellegrini, Paola
    et al.
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
    Dyczynski, Matheus
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
    Sbrana, Francesca Vittoria
    Ist Ortoped Rizzoli, Bologna, Italy..
    Karlgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Buoncervello, Maria
    Ist Super Sanita, Viale Regina Elena 299, I-00161 Rome, Italy..
    Hagg-Olofsson, Maria
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
    Ma, Ran
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
    Hartman, Johan
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
    Bajalica-Lagercrantz, Svetlana
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
    Grander, Dan
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
    Kharaziha, Pedram
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
    De Milito, Angelo
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
    Tumor acidosis enhances cytotoxic effects and autophagy inhibition by salinomycin on cancer cell lines and cancer stem cells2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 24, p. 35703-35723Article in journal (Refereed)
    Abstract [en]

    Sustained autophagy contributes to the metabolic adaptation of cancer cells to hypoxic and acidic microenvironments. Since cells in such environments are resistant to conventional cytotoxic drugs, inhibition of autophagy represents a promising therapeutic strategy in clinical oncology. We previously reported that the efficacy of hydroxychloroquine (HCQ), an autophagy inhibitor under clinical investigation is strongly impaired in acidic tumor environments, due to poor uptake of the drug, a phenomenon widely associated with drug resistance towards many weak bases. In this study we identified salinomycin (SAL) as a potent inhibitor of autophagy and cytotoxic agent effective on several cancer cell lines under conditions of transient and chronic acidosis. Since SAL has been reported to specifically target cancer-stem cells (CSC), we used an established model of breast CSC and CSC derived from breast cancer patients to examine whether this specificity may be associated with autophagy inhibition. We indeed found that CSC-like cells are more sensitive to autophagy inhibition compared to cells not expressing CSC markers. We also report that the ability of SAL to inhibit mammosphere formation from CSC-like cells was dramatically enhanced in acidic conditions. We propose that the development and use of clinically suitable SAL derivatives may result in improved autophagy inhibition in cancer cells and CSC in the acidic tumor microenvironment and lead to clinical benefits.

  • 41.
    Pfankuchen, Daniel Bastian
    et al.
    Rheinische Friedrich Wilhelms Univ Bonn, Pharmaceut Inst, Bonn, Germany..
    Baltes, Fabian
    Rheinische Friedrich Wilhelms Univ Bonn, Pharmaceut Inst, Bonn, Germany..
    Batool, Tahira
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Jin-Ping
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Schlesinger, Martin
    Rheinische Friedrich Wilhelms Univ Bonn, Pharmaceut Inst, Bonn, Germany..
    Bendas, Gerd
    Rheinische Friedrich Wilhelms Univ Bonn, Pharmaceut Inst, Bonn, Germany..
    Heparin antagonizes cisplatin resistance of A2780 ovarian cancer cells by affecting the Wnt signaling pathway2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 40, p. 67553-67566Article in journal (Refereed)
    Abstract [en]

    Low molecular weight heparin (LMWH), the guideline based drug for prophylaxis and treatment of cancer-associated thrombosis, was recently shown to sensitize cisplatin resistant A2780cis human ovarian cancer cells for cisplatin cytotoxicity upon 24 h pretreatment with 50 mu g x mL(-1) of the LMWH tinzaparin in vitro, equivalent to a therapeutic dosage. Thereby, LMWH induced sensitization by transcriptional reprogramming of A2780cis cells via not yet elucidated mechanisms that depend on cellular proteoglycans. Here we aim to illuminate the underlying molecular mechanisms of LMWH in sensitizing A2780cis cells for cisplatin. Using TCF/LEF luciferase promotor assay (Top/Flash) we show that resistant A2780cis cells possess a threefold higher Wnt signaling activity compared to A2780 cells. Furthermore, Wnt pathway blockade by FH535 leads to higher cisplatin sensitivity of A2780cis cells. Glypican-3 (GPC3) is upregulated in A2780cis cells in response to LMWH treatment, probably as counter-regulation to sustain the high Wnt activity against LMWH. Hence, LMWH reduces the cisplatin-induced rise in Wnt activity and TCF-4 expression in A2780cis cells, but keeps sensitive A2780 cells unaffected. Consequently, Wnt signaling pathway appears as primary target of LMWH in sensitizing A2780cis cells for cisplatin toxicity. Considering the outstanding role of LMWH in clinical oncology, this finding appears as promising therapeutic option to hamper chemoresistance.

  • 42.
    Raja, Erna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Tzavlaki, Kalliopi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Molecular Cell Biology.
    Vuilleumier, Robin
    Edlund, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Kahata, Kaoru
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Zieba, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Morén, Anita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Watanabe, Yukihide
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Voytyuk, Iryna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Pyrowolakis, George
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The protein kinase LKB1 negatively regulates bone morphogenetic protein receptor signaling2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 2, p. 1120-1143Article in journal (Refereed)
    Abstract [en]

    The protein kinase LKB1 regulates cell metabolism and growth and is implicated in intestinal and lung cancer. Bone morphogenetic protein (BMP) signaling regulates cell differentiation during development and tissue homeostasis. We demonstrate that LKB1 physically interacts with BMP type I receptors and requires Smad7 to promote downregulation of the receptor. Accordingly, LKB1 suppresses BMP-induced osteoblast differentiation and affects BMP signaling in Drosophila wing longitudinal vein morphogenesis. LKB1 protein expression and Smad1 phosphorylation analysis in a cohort of non-small cell lung cancer patients demonstrated a negative correlation predominantly in a subset enriched in adenocarcinomas. Lung cancer patient data analysis indicated strong correlation between LKB1 loss-of-function mutations and high BMP2 expression, and these two events further correlated with expression of a gene subset functionally linked to apoptosis and migration. This new mechanism of BMP receptor regulation by LKB1 has ramifications in physiological organogenesis and disease.

  • 43.
    Roodakker, Kenney R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Elsir, Tamador
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Canc Ctr Karolinska R8 05, Stockholm, Sweden.
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hägerstrand, Daniel
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Canc Ctr Karolinska R8 05, Stockholm, Sweden.
    Carlson, Joseph
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Canc Ctr Karolinska R8 05, Stockholm, Sweden.
    Lysiak, Malgorzata
    Linkoping Univ, Dept Cell Biol, Linkoping, Sweden.
    Henriksson, Roger
    Umea Univ, Dept Radiat Sci & Oncol, Umea, Sweden.; Reg Canc Ctr, Stockholm, Sweden.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosell, Johan
    Linkoping Univ, Reg Canc Ctr South East Sweden, Linkoping, Sweden.; Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Söderkvist, Peter
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.; Linkoping Univ, Dept Adv Home Care, Linkoping, Sweden.
    Stupp, Roger
    Univ Zurich Hosp, Dept Oncol, Zurich, Switzerland.
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nistér, Monica
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Canc Ctr Karolinska R8 05, Stockholm, Sweden.
    Malmström, Annika
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.; Linkoping Univ, Dept Adv Home Care, Linkoping, Sweden.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Univ Gothenburg, Sahlgrenska Acad, Dept Clin Neurosci & Rehabil, Inst Neurosci & Physiol, Gothenburg, Sweden.
    PROX1 is a novel pathway-specific prognostic biomarker for high-grade astrocytomas; results from independent glioblastoma cohorts stratified by age and IDH mutation status.2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 45, p. 72431-72442Article in journal (Refereed)
    Abstract [en]

    PROX1 is a transcription factor with an essential role in embryonic development and determination of cell fate. In addition, PROX1 has been ascribed suppressive as well as oncogenic roles in several human cancers, including brain tumors. In this study we explored the correlation between PROX1 expression and patient survival in high-grade astrocytomas. For this purpose, we analyzed protein expression in tissue microarrays of tumor samples stratified by patient age and IDH mutation status. We initially screened 86 unselected high-grade astrocytomas, followed by 174 IDH1-R132H1 immunonegative glioblastomas derived from patients aged 60 years and older enrolled in the Nordic phase III trial of elderly patients with newly diagnosed glioblastoma. Representing the younger population of glioblastomas, we studied 80 IDH-wildtype glioblastomas from patients aged 18-60 years. There was no correlation between PROX1 protein and survival for patients with primary glioblastomas included in these cohorts. In contrast, high expression of PROX1 protein predicted shorter survival in the group of patients with IDH-mutant anaplastic astrocytomas and secondary glioblastomas. The prognostic impact of PROX1 in IDH-mutant 1p19q non-codeleted high-grade astrocytomas, as well as the negative findings in primary glioblastomas, was corroborated by gene expression data extracted from the Cancer Genome Atlas. We conclude that PROX1 is a new prognostic biomarker for 1p19q non-codeleted high-grade astrocytomas that have progressed from pre-existing low-grade tumors and harbor IDH mutations.

  • 44.
    Roy, Ananya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Uppsala, Sweden..
    Attarha, Sanaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Weishaupt, Holger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bergqvist, Michael
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Siebzehnrubl, Florian A.
    Cardiff Univ, Sch Biosci, European Canc Stem Cell Res Inst, Cardiff, S Glam, Wales..
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Gothenburg Univ, Sahlgrenska Acad, Dept Clin Neurosci, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Serglycin as a potential biomarker for glioma: association of serglycin expression, extent of mast cell recruitment and glioblastoma progression2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 15, p. 24815-24827Article in journal (Refereed)
    Abstract [en]

    Serglycin is an intracellular proteoglycan with a unique ability to adopt highly divergent structures by glycosylation with variable types of glycosaminoglycans (GAGs) when expressed by different cell types. Serglycin is overexpressed in aggressive cancers suggesting its protumorigenic role. In this study, we explored the expression of serglycin in human glioma and its correlation with survival and immune cell infiltration. We demonstrate that serglycin is expressed in glioma and that increased expression predicts poor survival of patients. Analysis of serglycin expression in a large cohort of low- and high-grade human glioma samples reveals that its expression is grade dependent and is positively correlated with mast cell (MC) infiltration. Moreover, serglycin expression in patient-derived glioma cells is significantly increased upon MC co-culture. This is also accompanied by increased expression of CXCL12, CXCL10, as well as markers of cancer progression, including CD44, ZEB1 and vimentin.In conclusion, these findings indicate the importance of infiltrating MCs in glioma by modulating signaling cascades involving serglycin, CD44 and ZEB1. The present investigation reveals serglycin as a potential prognostic marker for glioma and demonstrates an association with the extent of MC recruitment and glioma progression, uncovering potential future therapeutic opportunities for patients.

  • 45.
    Roy, Ananya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Coum, Antoine
    Marinescu, Voichita D
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Põlajeva, Jelena
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nelander, Sven
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Glioma-derived plasminogen activator inhibitor-1 (PAI-1) regulates the recruitment of LRP1 positive mast cells2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 27, p. 23647-23661Article in journal (Refereed)
    Abstract [en]

    Glioblastoma (GBM) is a high-grade glioma with a complex microenvironment, including various inflammatory cells and mast cells (MCs) as one of them. Previously we had identified glioma grade-dependent MC recruitment. In the present study we investigated the role of plasminogen activator inhibitor 1 (PAI-1) in MC recruitment.PAI-1, a primary regulator in the fibrinolytic cascade is capable of forming a complex with fibrinolytic system proteins together with low-density lipoprotein receptor-related protein 1 (LRP1). We found that neutralizing PAI-1 attenuated infiltration of MCs. To address the potential implication of LRP1 in this process, we used a LRP1 antagonist, receptor-associated protein (RAP), and demonstrated the attenuation of MC migration. Moreover, a positive correlation between the number of MCs and the level of PAI-1 in a large cohort of human glioma samples was observed. Our study demonstrated the expression of LRP1 in human MC line LAD2 and in MCs in human high-grade glioma. The activation of potential PAI-1/LRP1 axis with purified PAI-1 promoted increased phosphorylation of STAT3 and subsequently exocytosis in MCs.These findings indicate the influence of the PAI-1/LRP1 axis on the recruitment of MCs in glioma. The connection between high-grade glioma and MC infiltration could contribute to patient tailored therapy and improve patient stratification in future therapeutic trials.

  • 46.
    Schmidt, Linnéa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Baskaran, Sathishkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Padhan, Narendra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Matuszewski, Damian J.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Green, Lydia C.
    Elfineh, Ludmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wee, Shimei
    Häggblad, Maria
    Martens, Ulf
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andäng, Michael
    Sintorn, Ida-Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Lundgren, Bo
    Lönnstedt, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Krona, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Case-specific potentiation of glioblastoma drugs by pterostilbene2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 45, p. 73200-73215Article in journal (Refereed)
  • 47.
    Song, Jie
    et al.
    Umea Univ, Med Biosci, Umea, Sweden..
    Mu, Yabing
    Umea Univ, Med Biosci, Umea, Sweden..
    Li, Chunyan
    Jilin Univ, Stomatol Hosp, Implant Ctr, Changchun 130023, Peoples R China..
    Bergh, Anders
    Umea Univ, Med Biosci, Umea, Sweden..
    Miaczynska, Marta
    Int Inst Mol & Cell Biol, Cell Biol Lab, Warsaw, Poland..
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Landstrom, Marene
    Umea Univ, Med Biosci, Umea, Sweden..
    APPL proteins promote TGF beta-induced nuclear transport of the TGF beta type I receptor intracellular domain2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 1, p. 279-292Article in journal (Refereed)
    Abstract [en]

    The multifunctional cytokine transforming growth factor-beta (TGF beta) is produced by several types of cancers, including prostate cancer, and promote tumour progression in autocrine and paracrine manners. In response to ligand binding, the TGF beta type I receptor (T beta RI) activates Smad and non-Smad signalling pathways. The ubiquitin-ligase tumour necrosis factor receptor-associated factor 6 (TRAF6) was recently linked to regulate intramembrane proteolytic cleavage of the T beta RI in cancer cells. Subsequently, the intracellular domain (ICD) of T beta RI enters in an unknown manner into the nucleus, where it promotes the transcription of pro-invasive genes, such as MMP2 and MMP9. Here we show that the endocytic adaptor molecules APPL1 and APPL2 are required for TGF beta-induced nuclear translocation of T beta RI-ICD and for cancer cell invasiveness of human prostate and breast cancer cell lines. Moreover, APPL proteins were found to be expressed at high levels in aggressive prostate cancer tissues, and to be associated with T beta RI in a TRAF6-dependent manner. Our results suggest that the APPL-T beta RI complex promotes prostate tumour progression, and may serve as a prognostic marker.

  • 48.
    Spiegelberg, Diana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Dascalu, Adrian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mortensen, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Abramenkovs, Andris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Kuku, Gamze
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    The novel HSP90 inhibitor AT13387 potentiates radiation effects in squamous cell carcinoma and adenocarcinoma cells2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 34, p. 35652-35666Article in journal (Refereed)
    Abstract [en]

    Overexpression of heat shock protein 90 (HSP90) is associated with increased tumor cell survival and radioresistance. In this study we explored the efficacy of the novel HSP90 inhibitor AT13387 and examined its radiosensitizing effects in combination with gamma-radiation in 2D and 3D structures as well as mice-xenografts. AT13387 induced effective cytotoxic activity and radiosensitized cancer cells in monolayer and tumor spheroid models, where low drug doses triggered significant synergistic effects on cell survival together with radiation. Furthermore, AT13387 treatment resulted in G2/M-phase arrest and significantly reduced the migration capacity. The expression of selected client proteins involved in DNA repair, cell-signaling and cell growth was downregulated in vitro, though the expression of most investigated proteins recurred after 8-24 h. These results were confirmed in vivo where AT13387 treated tumors displayed effective downregulation of HSP90 and its oncogenic client proteins. In conclusion, our results demonstrate that AT13387 is a potent new cancer drug and effective radiosensitizer in vitro with an excellent in vivo efficacy. AT13387 treatment has the potential to improve external beam therapy and radionuclide therapy outcomes and restore treatment efficacy in cancers that are resistant to initial therapeutic regimes.

  • 49.
    Strese, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Hassan, Saadia Bashir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Velander, Ebba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Haglund, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 4, p. 6341-6352Article in journal (Refereed)
    Abstract [en]

    The novel aminopeptidase potentiated alkylating agent melflufen, was evaluated for activity in acute myeloid leukemia in a range of in vitro models, as well as in a patient derived xenograft study. All tested AML cell lines were highly sensitive to melflufen while melphalan was considerably less potent. In the HL-60 cell line model, synergy was observed for the combination of melflufen and cytarabine, an interaction that appeared sequence dependent with increased synergy when melflufen was added before cytarabine. Also, in primary cultures of AML cells from patients melflufen was highly active, while normal PBMC cultures appeared less sensitive, indicating a 7-fold in vitro therapeutic index. Melphalan, on the other hand, was only 2-fold more potent in the AML patient samples compared with PBMCs. Melflufen was equally active against non-malignant, immature CD34(+) progenitor cells and a more differentiated CD34(+) derived cell population (GM14), whereas the stem cell like cells were less sensitive to melphalan. Finally, melflufen treatment showed significant anti-leukemia activity and increased survival in a patient derived xenograft of AML in mice. In conclusion, melflufen demonstrates high and significant preclinical activity in AML and further clinical evaluation seem warranted in this disease.

  • 50.
    Sun, Xu
    et al.
    Capital Med Univ, Dept Oncol, Beijing Hosp Tradit Chinese Med, Beijing, Peoples R China..
    Zhang, Ganlin
    Capital Med Univ, Dept Oncol, Beijing Hosp Tradit Chinese Med, Beijing, Peoples R China..
    Nian, Jiayun
    Capital Med Univ, Dept Oncol, Beijing Hosp Tradit Chinese Med, Beijing, Peoples R China.;Beijing Univ Chinese Med, Sch Grad, Beijing, Peoples R China..
    Yu, Mingwei
    Capital Med Univ, Dept Oncol, Beijing Hosp Tradit Chinese Med, Beijing, Peoples R China..
    Chen, Shijian
    Guangxi Med Univ, Dept Neurol, Affiliated Hosp 4, Liuzhou, Peoples R China..
    Zhang, Yi
    Capital Med Univ, Dept Oncol, Beijing Hosp Tradit Chinese Med, Beijing, Peoples R China..
    Yang, Guowang
    Capital Med Univ, Dept Oncol, Beijing Hosp Tradit Chinese Med, Beijing, Peoples R China..
    Yang, Lin
    Capital Med Univ, Dept Oncol, Beijing Hosp Tradit Chinese Med, Beijing, Peoples R China..
    Cheng, Peiyu
    Capital Med Univ, Dept Oncol, Beijing Hosp Tradit Chinese Med, Beijing, Peoples R China..
    Yan, Chen
    Capital Med Univ, Dept Oncol, Beijing Hosp Tradit Chinese Med, Beijing, Peoples R China.;Beijing Univ Chinese Med, Sch Grad, Beijing, Peoples R China..
    Ma, Yunfei
    Capital Med Univ, Dept Oncol, Beijing Hosp Tradit Chinese Med, Beijing, Peoples R China..
    Meng, Hui
    Capital Med Univ, Dept Oncol, Beijing Hosp Tradit Chinese Med, Beijing, Peoples R China.;Beijing Univ Chinese Med, Sch Grad, Beijing, Peoples R China..
    Wang, Xiaomin
    Capital Med Univ, Dept Oncol, Beijing Hosp Tradit Chinese Med, Beijing, Peoples R China..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Capital Med Univ, Dept Oncol, Beijing Hosp Tradit Chinese Med, Beijing, Peoples R China..
    Elevated heparanase expression is associated with poor prognosis in breast cancer: a study based on systematic review and TCGA data2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 26, p. 43521-43535Article, review/survey (Refereed)
    Abstract [en]

    Heparanase promotes tumorigenesis, angiogenesis, and metastasis. Here, we conducted a study based on systematic review and the Cancer Genome Atlas (TCGA) data that examined heparanase expression in clinical samples to determine its prognostic value. According to the meta-analysis and TCGA data, we found that heparanase expression was up-regulated in most breast cancer specimens, and elevated heparanase expression was associated with increased lymph node metastasis, larger tumor size, higher histological grade, and poor survival. These results suggest that targeting heparanase might improve treatments for breast cancer patients.

12 1 - 50 of 63
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