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  • 1. Akhoondi, Shahab
    et al.
    Sun, Dahui
    von der Lehr, Natalie
    Apostolidou, Sophia
    Klotz, Kathleen
    Maljukova, Alena
    Cepeda, Diana
    Fiegl, Heidi
    Dofou, Dimitra
    Marth, Christian
    Mueller-Holzner, Elisabeth
    Corcoran, Martin
    Dagnell, Markus
    Nejad, Sepideh Zabihi
    Nayer, Babak Noori
    Zali, Mohammad Reza
    Hansson, Johan
    Egyhazi, Susanne
    Petersson, Fredrik
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grander, Dan
    Reed, Steven I
    Widschwendter, Martin
    Sangfelt, Olle
    Spruck, Charles
    FBXW7/hCDC4 is a general tumor suppressor in human cancer2007In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 67, no 19, p. 9006-9012Article in journal (Refereed)
    Abstract [en]

    The ubiquitin-proteasome system is a major regulatory pathway of protein degradation and plays an important role in cellular division. Fbxw7 (or hCdc4), a member of the F-box family of proteins, which are substrate recognition components of the multisubunit ubiquitin ligase SCF (Skpl-Cdc53/ Cullin-F-box-protein), has been shown to mediate the ubiquitin-dependent proteolysis of several oncoproteins including cyclin El, c-Myc, c-Jun, and Notch. The oncogenic potential of Fbxw7 substrates, frequent allelic loss in human cancers, and demonstration that mutation of FBXW7 cooperates with p53 in mouse tumorigenesis have suggested that Fbxw7 could function as a tumor suppressor in human cancer. Here, we carry out an extensive genetic screen of primary tumors to evaluate the role of FBXW7 as a tumor suppressor in human tumorigenesis. Our results indicate that FBXW7 is inactivated by mutation in diverse human cancer types with an overall mutation frequency of ∼ 6%. The highest mutation frequencies were found in tumors of the bile duct (cholangio-carcinomas, 35%), blood (T-cell acute lymphocytic leukemia, 31%), endometrium (9%), colon (9%), and stomach (6%). Approximately 43% of all mutations occur at two mutational "hotspots," which alter Arg residues (Arg465 and Arg479) that are critical for substrate recognition. Furthermore, we show that Fbxw7Arg465 hotspot mutant can abrogate wild-type Fbxw7 function through a dominant negative mechanism. Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer.

  • 2. Andersson, Torbjörn
    et al.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Lindgren, PG
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Effects of Interferon on Tumor Tissue Content in Liver Metastases of Human Carcinoid Tumors1990In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, no 50, p. 3413-3415Article in journal (Refereed)
    Abstract [en]

    In 21 patients ultrasound-guided cutting biopsies, from carcinoid metastases of the liver, were taken before and after therapy with α-interferon. Each biopsy was examined under light microscopy and the amount of tumor tissue and connective tissue was quantified and then correlated to objective response to interferon therapy. A significant reduction of the amount of tumor tissue, in spite of unaltered metastatic size and a corresponding increase in connective tissue, was seen after interferon therapy. A more pronounced reduction of tumor tissue occurred after long-term interferon therapy. A positive correlation between objective therapy response and tumor tissue reduction was also present. Patients responding poorly, or not at all, to therapy did not show any significant decrease in tumor tissue.

    Since treatment with immune response modifiers is expected to increase in the near future, it is important to choose the right investigations for therapy monitoring, and since all patients in this investigation had unchanged tumor size on repeated radiological examinations, it is obvious that microscopic examination of core biopsies is a better method for evaluating effects of long-term therapy than tumor size measurement with radiological techniques. Further, the results may indicate that interferon exerts a cytotoxic effect on carcinoid tumor cells in vivo.

  • 3. Antoniou, Antonis C.
    et al.
    Beesley, Jonathan
    McGuffog, Lesley
    Sinilnikova, Olga M.
    Healey, Sue
    Neuhausen, Susan L.
    Ding, Yuan Chun
    Rebbeck, Timothy R.
    Weitzel, Jeffrey N.
    Lynch, Henry T.
    Isaacs, Claudine
    Ganz, Patricia A.
    Tomlinson, Gail
    Olopade, Olufunmilayo I
    Couch, Fergus J.
    Wang, Xianshu
    Lindor, Noralane M.
    Pankratz, Vernon S
    Radice, Paolo
    Manoukian, Siranoush
    Peissel, Bernard
    Zaffaroni, Daniela
    Barile, Monica
    Viel, Alessandra
    Allavena, Anna
    Dall'Olio, Valentina
    Peterlongo, Paolo
    Szabo, Csilla I
    Zikan, Michal
    Claes, Kathleen
    Poppe, Bruce
    Foretova, Lenka
    Mai, Phuong L.
    Greene, Mark H.
    Rennert, Gad
    Lejbkowicz, Flavio
    Glendon, Gord
    Ozcelik, Hilmi
    Andrulis, Irene L.
    Thomassen, Mads
    Gerdes, Anne-Marie
    Sunde, Lone
    Cruger, Dorthe
    Birk Jensen, Uffe
    Caligo, Maria
    Friedman, Eitan
    Kaufman, Bella
    Laitman, Yael
    Milgrom, Roni
    Dubrovsky, Maya
    Cohen, Shimrit
    Borg, Ake
    Jernström, Helena
    Lindblom, Annika
    Rantala, Johanna
    Stenmark-Askmalm, Marie
    Melin, Beatrice
    Nathanson, Kate
    Domchek, Susan
    Jakubowska, Ania
    Lubinski, Jan
    Huzarski, Tomasz
    Osorio, Ana
    Lasa, Adriana
    Durán, Mercedes
    Tejada, Maria-Isabel
    Godino, Javier
    Benitez, Javier
    Hamann, Ute
    Kriege, Mieke
    Hoogerbrugge, Nicoline
    van der Luijt, Rob B
    van Asperen, Christi J
    Devilee, Peter
    Meijers-Heijboer, E J
    Blok, Marinus J
    Aalfs, Cora M
    Hogervorst, Frans
    Rookus, Matti
    Cook, Margaret
    Oliver, Clare
    Frost, Debra
    Conroy, Don
    Evans, D Gareth
    Lalloo, Fiona
    Pichert, Gabriella
    Davidson, Rosemarie
    Cole, Trevor
    Cook, Jackie
    Paterson, Joan
    Hodgson, Shirley
    Morrison, Patrick J
    Porteous, Mary E
    Walker, Lisa
    Kennedy, M John
    Dorkins, Huw
    Peock, Susan
    Godwin, Andrew K
    Stoppa-Lyonnet, Dominique
    de Pauw, Antoine
    Mazoyer, Sylvie
    Bonadona, Valérie
    Lasset, Christine
    Dreyfus, Hélène
    Leroux, Dominique
    Hardouin, Agnès
    Berthet, Pascaline
    Faivre, Laurence
    Loustalot, Catherine
    Noguchi, Tetsuro
    Sobol, Hagay
    Rouleau, Etienne
    Nogues, Catherine
    Frénay, Marc
    Vénat-Bouvet, Laurence
    Hopper, John L
    Daly, Mary B
    Terry, Mary B
    John, Esther M
    Buys, Saundra S
    Yassin, Yosuf
    Miron, Alexander
    Goldgar, David
    Singer, Christian F
    Dressler, Anne Catharina
    Gschwantler-Kaulich, Daphne
    Pfeiler, Georg
    Hansen, Thomas V O
    Jønson, Lars
    Agnarsson, Bjarni A
    Kirchhoff, Tomas
    Offit, Kenneth
    Devlin, Vincent
    Dutra-Clarke, Ana
    Piedmonte, Marion
    Rodriguez, Gustavo C
    Wakeley, Katie
    Boggess, John F
    Basil, Jack
    Schwartz, Peter E
    Blank, Stephanie V
    Toland, Amanda Ewart
    Montagna, Marco
    Casella, Cinzia
    Imyanitov, Evgeny
    Tihomirova, Laima
    Blanco, Ignacio
    Lazaro, Conxi
    Ramus, Susan J
    Sucheston, Lara
    Karlan, Beth Y
    Gross, Jenny
    Schmutzler, Rita
    Wappenschmidt, Barbara
    Engel, Christoph
    Meindl, Alfons
    Lochmann, Magdalena
    Arnold, Norbert
    Heidemann, Simone
    Varon-Mateeva, Raymonda
    Niederacher, Dieter
    Sutter, Christian
    Deissler, Helmut
    Gadzicki, Dorothea
    Preisler-Adams, Sabine
    Kast, Karin
    Schönbuchner, Ines
    Caldes, Trinidad
    de la Hoya, Miguel
    Aittomäki, Kristiina
    Nevanlinna, Heli
    Simard, Jacques
    Spurdle, Amanda B
    Holland, Helene
    Chen, Xiaoqing
    Platte, Radka
    Chenevix-Trench, Georgia
    Easton, Douglas F
    Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 23, p. 9742-9754Article in journal (Refereed)
    Abstract [en]

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

  • 4. Aust, Gabriela
    et al.
    Eichler, Wolfram
    Laue, Sandy
    Lehmann, Irina
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lotz, Oliver
    Scherbaum, Werner A.
    Dralle, Henning
    Hoang-Vu, Cuong
    CD97: A dedifferentiation marker in human thyroid carcinomas1997In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 57, no 9, p. 1798-1806Article in journal (Refereed)
    Abstract [en]

    CD97 is a dimeric glycoprotein of Mr 75,000-85,000 and 28,000 belonging to a novel subfamily of seven-span transmembrane region leukocyte cell surface molecules. It is expressed abundantly in cells of hematopoietic origin. This is the first report demonstrating the expression of CD97 outside the hematopoetic system. CD97 was studied in normal human and neoplastic follicular epithelium of the thyroid and anaplastic (n = 3) and papillary (n = 1) thyroid carcinoma cell lines. In normal thyroid tissue (n = 11), no immunoreactivity of CD97 could be found, whereas in differentiated thyroid carcinomas (n = 10), CD97 expression was either lacking or low. Eleven of 12 undifferentiated anaplastic carcinomas revealed high CD97 presentation. CD97 was absent or only weakly present in patients with postoperative T1 tumors but increased greatly with the progression to postoperative T4 tumors. CD97 is clearly present in thyroid carcinoma cell lines but only at a very low level in normal human thyrocytes. Quantitation of CD97 cell surface expression levels revealed that C 643 and SW 1736 cells showed a two to four times higher specific antibody-binding capacity than did 8505 C and HTh 74 cells and a nearly 20 times higher specific antibody-binding capacity than normal thyrocytes. Phorbol 12-myristate 13-acetate treatment progressively caused a decrease of CD97 antigen expression in all cell lines to about 30% of their initial levels after 48 h. Immunohistochemical staining of SW 1736 cells revealed that CD97 is located in most of the cell compartments and suggested a CD97 internalization process after phorbol 12-myristate 13-acetate treatment. Semiquantitative reverse transcription-PCR showed a correlation of CD97 mRNA and cell surface CD97 expression level in the cell lines. SW 1736, HTh 74, and 8505 C cells apparently expressed CD97 with alternative glycosylation compared to peripheral lymphocytes, whereas most of the CD97 antigen presented on thyrocytes and C 643 cells had glycosylation sites resembling those of lymphocytes. The data suggest that CD97 expression may be a sensitive marker of dedifferentiation and of lymph node involvement in human thyroid tumors.

  • 5.
    Baranowska-Kortylewicz, Janina
    et al.
    Departments of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska.
    Abe, Michio
    Departments of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska.
    Pietras, Kristian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Kortylewicz, Zbigniew P
    Departments of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska.
    Kurizaki, Takashi
    Department of Surgery II, National Hospital Organization, Kumamoto University Medical School, Kumamoto, Japan.
    Nearman, Jessica
    Departments of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska.
    Paulsson, Janna
    Department of Pathology-Oncology, Karolinska Institute, Stockholm, Sweden.
    Mosley, R Lee
    Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
    Enke, Charles A
    Departments of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska.
    Östman, Arne
    Department of Pathology-Oncology, Karolinska Institute, Stockholm, Sweden.
    Effect of platelet-derived growth factor receptor-beta inhibition with STI571 on radioimmunotherapy2005In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 65, no 17, p. 7824-7831Article in journal (Refereed)
    Abstract [en]

    Whereas radioimmunotherapy of hematologic malignancies has evolved into a viable treatment option, the responses of solid tumors to radioimmunotherapy are discouraging. The likely cause of this problem is the interstitial hypertension inherent to all solid tumors. Remarkable improvements in tumor responses to radioimmunotherapy were discovered after the inclusion of STI571 in the therapy regimen. A combination of the tumor stroma-reactive STI571, a potent platelet-derived growth factor receptor-beta (PDGFr-beta) antagonist, and the tumor-seeking radiolabeled antibody B72.3 yielded long-lasting growth arrest of the human colorectal adenocarcinoma LS174T grown as s.c. xenografts in athymic mice. The interaction of STI571 with the stromal PDGFr-beta reduced tumor interstitial fluid pressure (P(IF)) by >50% and in so doing improved the uptake of B72.3. The attenuation of P(IF) also had a positive effect on the homogeneity of antibody distribution. These effects were dose-dependent and under optimized dosing conditions allowed for a 2.45 times increase in the tumor uptake of B72.3 as determined in the biodistribution studies. Single-photon emission computed tomography imaging studies substantiated these results and indicated that the homogeneity of the radioisotope distribution was also much improved when compared with the control mice. The increased uptake of radioimmunotherapy into the tumor resulted in >400% increase in the tumor absorbed radiation doses in STI571 + radioimmunotherapy-treated mice compared with PBS + radioimmunotherapy-treated mice. The improved antibody uptake in response to the attenuation of tumor P(IF) was identified as the primary reason for the growth arrest of the STI571 + radioimmunotherapy-treated tumors. Two related causes were also identified: (a) the improved homogeneity of monoclonal antibody distribution in tumor and (b) the increased tumor radiosensitivity resulting from the improved tumor oxygenation.

  • 6. Berglund, Erik
    et al.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Akcakaya, Pinar
    Ghaderi, Mehran
    Dare, Elisabetta
    Berggren, Per-Olof
    Aspinwall, Craig A.
    Lui, Weng-Onn
    Zedenius, Jan
    Larsson, Catharina
    Branstrom, Robert
    Evidence for intracellular calcium-regulated secretion in gastrointestinal stromal tumor.2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8Article in journal (Other academic)
  • 7.
    Bolin, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Lau, Jasmine
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Chen, Justin
    Persson, Anders I.
    Hede, Sanna-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Weiss, William A.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    A glial origin for medulloblastoma and inhibition of MYCN stabilization2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8Article in journal (Other academic)
  • 8.
    Bolin, Sara M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Lau, Jasmine
    Chen, Justin
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Persson, Anders I.
    Hede, Sanna-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Weiss, William A.
    Swartling, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Glial origin for MYCN-driven medulloblastoma and targeted prosenescence therapies2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 9. Borgquist, Signe
    et al.
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jirstrom, Karin
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sollie, Thomas
    Sorlie, Therese
    Butt, Saima
    Blomqvist, Carl
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    The prognostic role of HER2 expression in ductal breast carcinoma in situ2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 9, article id P6-13-03Article in journal (Other academic)
  • 10. Boyango, Ilanit
    et al.
    Barash, Uri
    Naroditsky, Inna
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hammond, Edward
    Ilan, Neta
    Vlodavsky, Israel
    Heparanase Cooperates with Ras to Drive Breast and Skin Tumorigenesis2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 16, p. 4504-4514Article in journal (Refereed)
    Abstract [en]

    Heparanase has been implicated in cancer but its contribution to the early stages of cancer development is uncertain. In this study, we utilized nontransformed human MCF10A mammary epithelial cells and two genetic mouse models [Hpa-transgenic (Hpa-Tg) and knockout mice] to explore heparanase function at early stages of tumor development. Heparanase overexpression resulted in significantly enlarged asymmetrical acinar structures, indicating increased cell proliferation and decreased organization. This phenotype was enhanced by coexpression of heparanase variants with a mutant H-Ras gene, which was sufficient to enable growth of invasive carcinoma in vivo. These observations were extended in vivo by comparing the response of Hpa-Tg mice to a classical two-stage 12-dimethylbenz(a)anthracene (DMBA)/12-o-tetradecanoylphorbol-13-acetate (TPA) protocol for skin carcinogenesis. Hpa-Tg mice overexpressing heparanase were far more sensitive than control mice to DMBA/TPA treatment, exhibiting a 10-fold increase in the number and size of tumor lesions. Conversely, DMBA/TPA-induced tumor formation was greatly attenuated in Hpa-KO mice lacking heparanase, pointing to a critical role of heparanase in skin tumorigenesis. In support of these observations, the heparanase inhibitor PG545 potently suppressed tumor progression in this model system. Taken together, our findings establish that heparanase exerts protumorigenic properties at early stages of tumor initiation, cooperating with Ras to dramatically promote malignant development.

  • 11.
    Brodin, Greger
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    ten Dijke, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Funa, Keiko
    Institute of Anatomy and Cell Biology, Göteborg University, SE-405 30 Göteborg, Sweden.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Landström, Maréne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Increased Smad Expression and Activation are Associated with Apoptosis in Normal and Malignant Prostate after Castration1999In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 59, no 11, p. 2731-2738Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor (TGF)-beta1 is induced in the prostate after castration and has been implicated in apoptosis of epithelial cells during involution. TGF-beta1-mediated receptor activation induces phosphorylation of Smad2 and Smad3, which form complexes with Smad4, that translocate to the nucleus to regulate transcription of target genes. Smad6 and Smad7 antagonize the action of signal-transducing Smads. We have examined the immunohistochemical expression of different Smad molecules in the epithelium of rat ventral prostate before and after castration, in androgen-sensitive Dunning R3327 PAP prostatic tumor cells from untreated and castrated rats, and after treatment with estrogen. In the ventral prostate, a significant increase of phosphorylated Smad2 (P-Smad2) was observed after castration. In prostatic tumor cells we observed an increased expression of Smad2 and P-Smad2 after treatment. The levels of Smad3 and, in particular, Smad4 were enhanced in the normal ventral prostate, as well as in the tumors after castration. Interestingly, Smad6 and Smad7 expression was also up-regulated in cells with increased Smad2 activation. The staining for Smad2, P-Smad2, Smad3, Smad4, and Smad7 was nuclear in some cells and was present in areas with a large number of apoptotic cells identified by various morphological criteria, formation of apoptotic bodies and, in adjacent sections, by terminal deoxynucleotidyl transferase-mediated nick end labeling assay. Our results suggest that the signal transduction pathway for TGF-beta, leading to apoptosis, is activated in the normal prostate after castration and in the tumor model after castration, without or with estrogen treatment.

  • 12. Bruzzese, Francesca
    et al.
    Hagglof, Christina
    Leone, Alessandra
    Sjoberg, Elin
    Roca, Maria Serena
    Kiflemariam, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Hammarsten, Peter
    Egevad, Lars
    Bergh, Anders
    Ostman, Arne
    Budillon, Alfredo
    Augsten, Martin
    Local and Systemic Protumorigenic Effects of Cancer-Associated Fibroblast-Derived GDF152014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 13, p. 3408-3417Article in journal (Refereed)
    Abstract [en]

    The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGF beta/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15-expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer. 

  • 13.
    Buckley, Patrick
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jarbo, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mathiesen, Tiit
    Scott, Carol
    Gregory, Simon
    Langford, Cordelia
    Dumanski, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Comprehensive DNA copy number profiling of meningioma using a chromosome 1 tiling path microarray identifies novel candidate tumor suppressor loci2005In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 65, no 7, p. 2653-2661Article in journal (Refereed)
    Abstract [en]

    Meningiomas are common neoplasms of the meninges lining of the central nervous system. Deletions of 1p have been established as important for the initiation and/or progression of meningioma. The rationale of this array-CGH study was to characterize copy number imbalances of chromosome 1 in meningioma, using a full-coverage genomic microarray containing 2,118 distinct measurement points. In total, 82 meningiomas were analyzed, making this the most detailed analysis of chromosome 1 in a comprehensive series of tumors. We detected a broad range of aberrations, such as deletions and/or gains of various sizes. Deletions were the predominant finding and ranged from monosomy to a 3.5-Mb terminal 1p homozygous deletion. Although multiple aberrations were observed across chromosome 1, every meningioma in which imbalances were detected harbored 1p deletions. Tumor heterogeneity was also observed in three recurrent meningiomas, which most likely reflects a progressive loss of chromosomal segments at different stages of tumor development. The distribution of aberrations supports the existence of at least four candidate loci on chromosome 1, which are important for meningioma tumorigenesis. In one of these regions, our results already allow the analysis of a number of candidate genes. In a large series of cases, we observed an association between the presence of segmental duplications and deletion breakpoints, which suggests their role in the generation of these tumor-specific aberrations. As 1p is the site of the genome most frequently affected by tumor-specific aberrations, our results indicate loci of general importance for cancer development and progression.

  • 14. Caja, Laia
    et al.
    Sancho, Patricia
    Univ Barcelona, Barcelona, Spain.
    Bertran, Esther
    Univ Barcelona, Barcelona, Spain.
    Iglesias-Serret, Daniel
    Univ Barcelona, Barcelona, Spain.
    Gil, Joan
    Univ Barcelona, Barcelona, Spain.
    Fabregat, Isabel
    Univ Barcelona, Barcelona, Spain.
    Overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-{beta}-induced cell death through impairing up-regulation of the NADPH oxidase NOX4.2009In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 69, no 19, p. 7595-7602Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-beta (TGF-beta) induces apoptosis in hepatocytes, being considered a liver tumor suppressor. However, many human hepatocellular carcinoma (HCC) cells escape from its proapoptotic effects, gaining response to this cytokine in terms of malignancy. We have recently reported that the apoptosis induced by TGF-beta in hepatocytes requires up-regulation of the NADPH oxidase NOX4, which mediates reactive oxygen species (ROS) production. TGF-beta-induced NOX4 expression is inhibited by antiapoptotic signals, such as the phosphatydilinositol-3-phosphate kinase or the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways. The aim of the present work was to analyze whether resistance to TGF-beta-induced apoptosis in HCC cells is related to the impairment of NOX4 up-regulation due to overactivation of survival signals. Results indicate that inhibition of the MAPK/ERK kinase (MEK)/ERK pathway in HepG2 cells, which are refractory to the proapoptotic effects of TGF-beta, sensitizes them to cell death through a mitochondrial-dependent mechanism, coincident with increased levels of BIM and BMF, decreased levels of BCL-XL and MCL1, and BAX/BAK activation. Regulation of BMF, BCL-XL, and MCL1 occurs at the mRNA level, whereas BIM regulation occurs post-transcriptionally. ROS production and glutathione depletion are only observed in cells treated with TGF-beta and PD98059, which correlates with NOX4 up-regulation. Targeting knockdown of NOX4 impairs ROS increase and all the mitochondrial-dependent apoptotic features by a mechanism that is upstream from the regulation of BIM, BMF, BCL-XL, and MCL1 levels. In conclusion, overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-beta-induced cell death through impairing NOX4 up-regulation, which is required for an efficient mitochondrial-dependent apoptosis.

  • 15. Cedervall, Jessica
    et al.
    Jamil, Seema
    Prasmickaite, Lina
    Cheng, YenFu
    Eskandarpour, Malihe
    Hansson, Johan
    Maelandsmo, Gunhild M.
    Ringborg, Ulrik
    Gulyas, Miklos
    Department of pathology and cytology, central hospital, Gävle, Sweden.
    Zhen, He Suo
    Kanter, Lena
    Ahrlund-Richter, Lars
    Species-specific in vivo engraftment of the human BL melanoma cell line results in an invasive dedifferentiated phenotype not present in xenografts2009In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 69, no 9, p. 3746-3754Article in journal (Refereed)
    Abstract [en]

    For clinically relevant studies on melanoma progression and invasiveness, in vivo experimental systems with a human cellular microenvironment would be advantageous. We have compared tumor formation from a human cutaneous malignant melanoma cell line (BL), after injection as conventional xenografts in the mouse, or when injected into a predominantly species-specific environment of human embryonic stem cell-derived teratoma induced in the mouse (the hEST model). The resulting melanoma histology was generally analogous, both systems showing delimited densely packed areas with pleomorphic cells of malignant appearance. A specificity of the integration process into the human embryonic teratoma tissues was indicated by the melanoma exclusively being found in areas compatible with condensed mesenchyme, similar to neural crest development. Here, also enhanced neovascularization was seen within the human mesenchymal tissues facing the BL melanoma growth. Furthermore, in the hEST model an additional melanoma cell phenotype occurred, located at the border of, or infiltrating into, the surrounding human loose mesenchymal fibrous stroma. This BL population had a desmoplastic spindle-like appearance, with markers indicative of dedifferentiation and migration. The appearance of this apparently more aggressive phenotype, as well as the induction of human angiogenesis, shows specific interactions with the human embryonic microenvironment in the hEST model. In conclusion, these data provide exciting options for using the hEST model in molecular in vivo studies on differentiation, invasiveness, and malignancy of human melanoma, while analyzing species-specific reactions in vivo.

  • 16.
    Cedervall, Jessica
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Yanyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Huang, Hua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Femel, Julia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Olsson, Anna-Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 13, p. 2653-2662Article in journal (Refereed)
    Abstract [en]

    Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1 beta, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites.

  • 17.
    Cedervall, Jessica
    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.
    Zhang, Yanyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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.
    Tumor-Induced NETosis as a Risk Factor for Metastasis and Organ Failure2016In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76, no 15, p. 4311-4315Article, review/survey (Refereed)
    Abstract [en]

    A large proportion of cancer-related deaths are caused by thrombosis and general organ failure. One example is acute renal failure, a major cause of morbidity and mortality in cancer patients. Surprisingly, however, little is known about the situation in organs that are not targets for metastasis or affected by the primary tumor. Recently, neutrophil extracellular traps (NET) were implicated in tumor-induced effects on distant organs unaffected by the actual tumor cells. Formation of NETs (NETosis) was identified a decade ago as amechanismby which the innate immune system protects us from infections, especially in situations with sepsis. NETs are formed when neutrophils externalize their nuclear DNA together with antimicrobial granule proteins and form a web-like structure that can trap and kill microbes. It is now becoming increasingly clear that NETs also form under noninfectious inflammatory conditions like cancer, thrombosis, autoimmunity, and diabetes and significantly contribute to disease development. The existence of NET-dissolving drugs like heparin and DNase I, already in clinical use, and recent development of specific inhibitors of proteinarginine deiminase 4 (PAD4), an enzyme required for NET formation, should enable clinical targeting of NETosis. Preventing NETosis in cancer could provide a strategy to counteract tumor-induced thrombosis and organ failure as well as to suppress metastasis.

  • 18.
    Chaudhry, Arvind
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Gobl, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Different splice variants of CD44 are expressed in gastrinomas but not in other subtypes of endocrine pancreatic tumors1994In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 54, no 4, p. 981-986Article in journal (Refereed)
    Abstract [en]

    Endocrine pancreatic tumors are neuroendocrine neoplasms with malignant potential and give rise to varied clinical syndromes due to excessive secretion of multiple hormones. In this study 22 endocrine pancreatic tumors and 11 carcinoid tumors were examined for the expression of CD44 using a monoclonal antibody. CD44 gene activity of 11 endocrine pancreatic tumor tissues and five carcinoid tumor tissues was also studied by amplifying messenger RNA with the polymerase chain reaction followed by electrophoresis and blot hybridization. Strong immunoreactivity was detected on all gastrinomas examined (P < 0.001), and in two non-functioning endocrine pancreatic tumors. Such immunoreactivity was not observed in other subtypes of endocrine pancreatic tumors. In the normal human pancreas, the acinar portion and ductal epithelial cells stained strongly positive but pancreatic islet cells did not show any significant immunostaining. Furthermore, in endocrine pancreatic tumors with metastatic disease, CD44-positive tumors had a tendency to metastasize to lymph nodes (P = 0.005), as compared with CD44-negative tumors which were locally invasive or metastasized to the liver. Although, in this limited material and short follow-up, we were not able to show any statistical significance, patients with CD44-negative endocrine pancreatic tumors had prolonged survival time compared with patients with CD44-positive tumors (73% versus 59% at 5 years; P = 0.7). Of 10 carcinoid tumors examined, all three foregut carcinoids and one midgut carcinoid stained strongly positive, whereas all other midgut carcinoids were negative. Analysis of CD44 splice variants showed that in all five gastrinomas there was overproduction of alternatively spliced larger molecular variants as compared with other types of endocrine pancreatic tumors and carcinoid tumors. The band pattern from one case of carcinoid tumor with a fulminant clinical course was similar to that of gastrinomas, whereas other carcinoid tumors expressed the epithelial form of CD44. The earlier identified splice variants which confer metastatic behavior on a pancreatic tumor cell line were not expressed in neuroendocrine tumors. Our data indicate that CD44 expression in endocrine pancreatic tumors correlates with the ability to give rise to lymph node metastases and may play a vital role in determining the fate of metastasizing cells. Moreover, because gastrin is not detectable in the normal human pancreas, the pancreatic ductal cell positivity for CD44 strengthened the ductal origin concept of gastrinomas. The band pattern of CD44 splice variants suggests that the previously described splice variants conferring metastatic behavior do not accompany metastatic activity of neuroendocrine tumors.

  • 19.
    Cunha, Sara I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Bocci, Matteo
    Lovrot, John
    Eleftheriou, Nikolas
    Roswall, Pernilla
    Cordero, Eugenia
    Lindstrom, Linda
    Bartoschek, Michael
    Haller, B. Kristian
    Pearsall, R. Scott
    Mulivor, Aaron W.
    Kumar, Ravindra
    Larsson, Christer
    Bergh, Jonas
    Pietras, Kristian
    Endothelial ALK1 Is a Therapeutic Target to Block Metastatic Dissemination of Breast Cancer2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 12, p. 2445-2456Article in journal (Refereed)
    Abstract [en]

    Exploration of new strategies for the prevention of breast cancer metastasis is justifiably at the center of clinical attention. In this study, we combined a computational biology approach with mechanism-based preclinical trials to identify inhibitors of activin-like receptor kinase (ALK) 1 as effective agents for blocking angiogenesis and metastasis in breast cancer. Pharmacologic targeting of ALK1 provided long-term therapeutic benefit in mouse models of mammary carcinoma, accompanied by strikingly reduced metastatic colonization as a monotherapy or part of combinations with chemotherapy. Gene-expression analysis of breast cancer specimens from a population-based nested case-control study encompassing 768 subjects defined endothelial expression of ALK1 as an independent and highly specific prognostic factor for metastatic manifestation, a finding that was corroborated in an independent clinical cohort. Overall, our results suggest that pharmacologic inhibition of endothelial ALK1 constitutes a tractable strategy for interfering with metastatic dissemination of breast cancer.

  • 20.
    Diaconu, Iulia
    et al.
    University of Helsinki.
    Cerullo, Vincenzo
    University of Helsinki.
    Hirvinen, Mari L M
    University of Helsinki.
    Escutenaire, Sophie
    University of Helsinki.
    Ugolini, Matteo
    University of Helsinki.
    Pesonen, Saila K
    University of Helsinki.
    Bramante, Simona
    University of Helsinki.
    Parviainen, Suvi
    University of Helsinki.
    Kanerva, Anna
    University of Helsinki.
    Loskog, Angelica S I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eliopoulos, Aristides G
    Hellas FORTH.
    Pesonen, Sari
    University of Helsinki.
    Hemminki, Akseli
    University of Helsinki.
    Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus2012In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 72, no 9, p. 2327-2338Article in journal (Refereed)
    Abstract [en]

    Oncolytic adenovirus is an attractive platform for immunotherapy because virus replication is highly immunogenic and not subject to tolerance. Although oncolysis releases tumor epitopes and provides costimulatory danger signals, arming the virus with immunostimulatory molecules can further improve efficacy. CD40 ligand (CD40L, CD154) induces apoptosis of tumor cells and triggers several immune mechanisms, including a T-helper type 1 (TH1) response, which leads to activation of cytotoxic T cells and reduction of immunosuppression. In this study, we constructed a novel oncolytic adenovirus, Ad5/3-hTERT-E1A-hCD40L, which features a chimeric Ad5/3 capsid for enhanced tumor transduction, a human telomerase reverse transcriptase (hTERT) promoter for tumor selectivity, and human CD40L for increased efficacy. Ad5/3-hTERT-E1A-hCD40L significantly inhibited tumor growth in vivo via oncolytic and apoptotic effects, and (Ad5/3-hTERT-E1A-hCD40L)–mediated oncolysis resulted in enhanced calreticulin exposure and HMGB1 and ATP release, which were suggestive of immunogenicity. In two syngeneic mouse models, murine CD40L induced recruitment and activation of antigen-presenting cells, leading to increased interleukin-12 production in splenocytes. This effect was associated with induction of the TH1 cytokines IFN-γ, RANTES, and TNF-α. Tumors treated with Ad5/3-CMV-mCD40L also displayed an enhanced presence of macrophages and cytotoxic CD8+ T cells but not B cells. Together, our findings show that adenoviruses coding for CD40L mediate multiple antitumor effects including oncolysis, apoptosis, induction of T-cell responses, and upregulation of TH1 cytokines.

  • 21.
    Dixelius, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Thulin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lee, Chunsik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Johansson, Irja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein2006In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, no 4, p. 2089-97Article in journal (Refereed)
    Abstract [en]

    Histidine-rich glycoprotein (HRGP) is an abundant heparin-binding plasma protein that efficiently arrests growth and vascularization of mouse tumor models. We have shown that the antiangiogenic effect of HRGP is dependent on its histidine/proline-rich domain, which needs to be released from the mother protein to exert its effects. Here we identify a 35-amino-acid peptide, HRGP330, derived from the histidine/proline-rich domain as endowed with antiangiogenic properties in vitro and in vivo. The mechanism of action of HRGP330 involves subversion of focal adhesion function by disruption of integrin-linked kinase (ILK) and focal adhesion kinase (FAK) functions, inhibition of vascular endothelial growth factor (VEGF)-induced tyrosine phosphorylation of the FAK substrate alpha-actinin, and, as a consequence, an arrest in endothelial cell motility. The disturbed focal adhesion function is reflected in the ability of HRGP as well as of HRGP330 to prevent endothelial cell adhesion to vitronectin in a manner involving alpha(v)beta3 integrin. In conclusion, HRGP330, which we define as the minimal antiangiogenic domain of HRGP, exerts its effects through signal transduction targeting focal adhesions, thereby interrupting VEGF-induced endothelial cell motility.

  • 22.
    Edfeldt, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ahmad, Tanvver
    Åkerstrom, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Stalberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    TCEB3C (Elongin A3) on chromosome 18 presents a putative tumor suppressor gene of small intestine neuroendocrine tumors.2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8Article in journal (Other academic)
  • 23. Ekström Smedby, Karin
    et al.
    Hjalgrim, Henrik
    Chang, Ellen T.
    Rostgaard, Klaus
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Adami, Hans-Olov
    Melbye, Mads
    Childhood social environment and risk of non-Hodgkin lymphoma in adults2007In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 67, no 22, p. 11074-11082Article in journal (Refereed)
    Abstract [en]

    Better hygiene and sanitation and decreasing family size parallel the increasing incidence of non-Hodgkin lymphoma (NHL) in many populations around the world. However, whether sibship size, birth order, and crowding are related to adult NHL risk is not clear. We investigated how family structure and childhood social environment were related to the risk of NHL and NHL subtypes in a large Scandinavian population-based case control study with 6,242 participants aged 18 to 74 years. Detailed exposure information was obtained through telephone interviews. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using logistic regression, and all statistical tests were two-sided. Having four or more siblings was associated with a moderately increased risk of NHL, compared with having no siblings (OR 1.34, 95% CI 1.11-1.62, P(trend) < 0.001). Having four or more older siblings was associated with a similar risk increase (OR 1.33, 95% CI 1.12-1.59, P(trend) = 0.003) compared with being the oldest, whereas number of younger siblings was unrelated overall. The associations were independent of other environmental exposures and did not vary by country, age, or sex. High household crowding was also positively associated with risk of NHL. Results were slightly stronger for diffuse large B-cell and T-cell lymphomas than for other major NHL subtypes. Our findings add to the evidence that large sibship size, late birth order, and childhood crowding are associated with an elevated risk of NHL. Effect mechanisms may be related to early age at onset and high frequency of specific infections or total microbial exposure in childhood.

  • 24.
    Erlandsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Brännvall, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gustafsdottir, Sigrun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Autocrine/Paracrine platelet-derived growth factor regulates proliferation of neural progenitor cells2006In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, no 16, p. 8042-8048Article in journal (Refereed)
    Abstract [en]

    Growth factors play an important role in regulating neural stem cell proliferation and differentiation. This study shows that platelet-derived growth factor (PDGF) induces a partial differentiation of neural stem/progenitor cells (NSPCs) in the absence of other mitogens in vitro. NSPCs thus acquire an immature morphology and display markers for both neurons and glia. In addition, these cells do not readily mature in the absence of further stimuli. When NSPC cultures treated with PDGF were exposed to additional differentiation factors, however, the differentiation proceeded into neurons, astrocytes, and oligodendrocytes. We find that NSPC cultures are endowed with an endogenous PDGF-BB production. The PDGF-BB expression peaks during early differentiation and is present both in cell lysates and in conditioned medium, allowing for autocrine as well as paracrine signaling. When the NSPC-derived PDGF was inhibited, progenitor cell numbers decreased, showing that PDGF is involved in NSPC expansion. Addition of a PDGF receptor (PDGFR) inhibitor resulted in a more rapid differentiation. Neurons and oligodendrocytes appeared earlier and had more elaborate processes than in control cultures where endogenous PDGFR signaling was not blocked. Our observations point to PDGF as an inducer of partial differentiation of NSPC that also sustains progenitor cell division. Such an intermediate stage in stem cell differentiation is of relevance for the understanding of brain tumor development because autocrine PDGF stimulation is believed to drive malignant conversion of central nervous system progenitor cells.

  • 25. Falk, Ingrid Jakobsen
    et al.
    Fyrberg, Anna
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Nahi, Hareth
    Palmqvist, Lars
    Paul, Christer
    Paul, Esbjorn
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Stockelberg, Dick
    Wei, Yuan
    Green, Henrik
    Lotfi, Kourosh
    Correlation between cytidine deaminase single nucleotide polymorphisms and in vitro drug sensitivity, DNA methylation and outcome in normal karyotype acute myelogenous leukemia2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8Article in journal (Other academic)
  • 26. Falk, Ingrid Jakobsen
    et al.
    Willander, Kerstin
    Chaireti, Roza
    Lund, Johan
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Green, Henrik
    Soderkvist, Peter
    Lotfi, Kourosh
    TP53 mutations and MDM2 single nucleotide polymorphism 309T-G predicts outcome and treatment resistance in acute myeloid leukemia2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 27. Fiorentino, Michelangelo
    et al.
    Judson, Gregory
    Penney, Kathryn
    Flavin, Richard
    Stark, Jennifer
    Fiore, Christopher
    Fall, Katja
    Uppsala University Hospital.
    Martin, Neil
    Ma, Jing
    Sinnott, Jennifer
    Giovannucci, Edward
    Stampfer, Meir
    Sesso, Howard D.
    Kantoff, Philip W.
    Finn, Stephen
    Loda, Massimo
    Mucci, Lorelei
    Immunohistochemical Expression of BRCA1 and Lethal Prostate Cancer2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 8, p. 3136-3139Article in journal (Refereed)
    Abstract [en]

    BRCA1 functions as a tumor suppressor; recent work suggests that BRCA1 may also induce cell cycle arrest to allow for DNA repair. We hypothesized that BRCA1 expression in prostate tumor tissue may be associated with prostate cancer progression through regulation of the cell cycle. We used immunohistochemistry to evaluate BRCA1 protein expression in archival tumor samples from 393 prostate cancer cases in the Physicians' Health Study. The men were followed prospectively from diagnosis to development of metastases and mortality. Fifteen percent of tumors stained positive for BRCA1. BRCA1-positive tumors had substantially increased tumor proliferation index compared with negative tumors (47.0 Ki67-positive nuclei versus 10.3, P = 0.0016) and were more likely to develop lethal cancer compared with BRCA1-negative tumors (hazard ratio, 4.6; 95% confidence interval, 2.4-8.7). These findings strengthen the hypothesis that BRCA1 plays a role in cell cycle control and show that BRCA1 is a marker of clinical prostate cancer prognosis. Cancer Res; 70(8); 3136-9. (C) 2010 AACR.

  • 28. Fischer, Silvia
    et al.
    Gesierich, Sabine
    Griemert, Barbara
    Schaenzer, Anne
    Acker, Till
    Augustin, Hellmut G.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Preissner, Klaus T.
    Extracellular RNA Liberates Tumor Necrosis Factor-alpha to Promote Tumor Cell Trafficking and Progression2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 16, p. 5080-5089Article in journal (Refereed)
    Abstract [en]

    Extracellular RNA (eRNA) released from injured cells promotes tissue permeability, thrombosis, and inflammation in vitro and in vivo, and RNase1 pretreatment can reduce all these effects. In this study, we investigated the role of the eRNA/RNase1 system in tumor progression and metastasis. Under quiescent and stimulatory conditions, tumor cells released much higher levels of endogenous extracellular RNA (eRNA) than nontumor cells. In glioblastomas, eRNA was detected at higher levels in tumors than nontumor tissue. eRNA induced tumor cells to adhere to and migrate through human cerebral microvascular endothelial cells (HCMEC/D3), in a manner requiring activation of VEGF signaling. In addition, eRNA liberated TNF-alpha from macrophages in a manner requiring activation of the TNF-alpha-converting enzyme TACE. Accordingly, supernatants derived from eRNA-treated macrophages enhanced tumor cell adhesion to HCMEC/D3. TNF-alpha release evoked by eRNA relied upon signaling activation of mitogen-activated protein kinases and the NF-kappa B pathway. In subcutaneous xenograft models of human cancer, administration of RNase1 but not DNase decreased tumor volume and weight. Taken together, these results suggest that eRNA released from tumor cells has the capacity to promote tumor cell invasion through endothelial barriers by both direct and indirect mechanisms, including through a mechanism involving TNF-alpha release from tumor-infiltrating monocytes/macrophages. Our findings establish a crucial role for eRNA in driving tumor progression, and they suggest applications for extracellular RNase1 as an antiinvasive regimen for cancer treatment. 

  • 29. Frisch, Morten
    et al.
    Fenger, Claus
    van den Brule, Adriaan J. C.
    Sorensen, Per
    Meijer, Chris J. L. M.
    Walboomers, Jan M. M.
    Adami, Hans-Olov
    Melbye, Mads
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Variants of squamous cell carcinoma of the anal canal and perianal skin and their relation to human papillomaviruses1999In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 59, no 3, p. 753-757Article in journal (Refereed)
    Abstract [en]

    High-risk types of human papillomaviruses (hrHPVs) may be a necessary cause in cervical cancer and in some subtype of anal, vulvar, and penile cancers. Large studies aimed at characterizing hrHPV-associated and non-hrHPV-associated subtypes of anal carcinomas are, however, lacking. We searched for human papillomavirus type 16 and 13 other hrHPVs in tumor tissue by PCR and performed a systematic histological evaluation of specimens from 386 patients with anal cancer (86% invasive; 302 women and 84 men). Cancers in women and homosexual men were more often hrHPV positive (P < 0.01) and located in the anal canal (P < or = 0.01) than were cancers in heterosexual men. In both women and men, anal canal cancers contained hrHPV clearly more often than did perianal skin cancers, and increasing hrHPV positivity was seen with higher localization in the anal canal. Indeed, 95 and 83% of cancers involving the anal canal in women and men, respectively, were hrHPV positive versus 80 and 28% of perianal skin cancers (P-trend < 0.001). Basaloid feature, adjacent anal intraepithelial neoplasia, poor or absent keratinization, and a predominance of small or medium neoplastic cells were all strongly positively associated with hrHPV status. Like cancer of the uterine cervix, the development of cancer of the anal canal may require infection with hrHPV, whereas a dual etiology of perianal skin cancers bears parallels to vulvar and penile cancers.

  • 30.
    Funa, Nina S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kriz, Vitezslav
    Zang, Guangxiang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Calounova, Gabriela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Åkerblom, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mares, Jaroslav
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sun, Ying
    Betsholtz, Christer
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Dysfunctional microvasculature as a consequence of shb gene inactivation causes impaired tumor growth2009In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 69, no 5, p. 2141-2148Article in journal (Refereed)
    Abstract [en]

    Shb (Src homology 2 protein B) is an adapter protein downstream of the vascular endothelial growth factor receptor receptor-2 (VEGFR-2). Previous experiments have suggested a role for Shb in endothelial cell function. Recently, the Shb gene was inactivated and Shb null mice were obtained on a mixed genetic background, but not on C57Bl6 mice. The present study was performed to address endothelial function in the Shb knockout mouse and its relevance for tumor angiogenesis. Tumor growth was retarded in Shb mutant mice, and this correlated with decreased angiogenesis both in tumors and in Matrigel plugs. Shb null mice display an abnormal endothelial ultrastructure in liver sinusoids and heart capillaries with cytoplasmic extensions projecting toward the lumen. Shb null heart VE-cadherin staining was less distinct than that of control heart, exhibiting in the former case a wavy and punctuate pattern. Experiments on isolated endothelial cells suggest that these changes could partly reflect cytoskeletal abnormalities. Vascular permeability was increased in Shb null mice in heart, kidney, and skin, whereas VEGF-stimulated vascular permeability was reduced in Shb null mice. It is concluded that Shb plays an important role in maintaining a functional vasculature in adult mice, and that interference with Shb signaling may provide novel means to regulate tumor angiogenesis.

  • 31.
    Furuhashi, Masao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Abramsson, Alexandra
    Ellingsen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Li, Hong
    Bergsten-Folestad, Erika
    Eriksson, Ulf
    Heuchel, Rainer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Östman, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate2004In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 64, no 8, p. 2725-2733Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) receptor signaling participates in different processes in solid tumors, including autocrine stimulation of tumor cell growth, recruitment of tumor stroma fibroblasts, and stimulation of tumor angiogenesis. In the present study, the B16 mouse melanoma tumor model was used to investigate the functional consequences of paracrine PDGF stimulation of host-derived cells. Production of PDGF-BB or PDGF-DD by tumor cells was associated with an increased tumor growth rate. Characterization of tumors revealed an increase in pericyte abundance in tumors derived from B16 cells producing PDGF-BB or PDGF-DD. The increased tumor growth rate associated with PDGF-DD production was not seen in mice expressing an attenuated PDGF beta-receptor and was thus dependent on host PDGF beta-receptor signaling. The increased pericyte abundance was not associated with an increased tumor vessel density. However, tumor cell apoptosis, but not proliferation, was reduced in tumors displaying PDGF-induced increased pericyte coverage. Our findings thus demonstrate that paracrine PDGF production stimulates pericyte recruitment to tumor vessels and suggest that pericyte abundance influences tumor cell apoptosis and tumor growth.

  • 32.
    Furuta, Eiji
    et al.
    Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
    Pai, Sudha K
    Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
    Zhan, Rui
    Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
    Bandyopadhyay, Sucharita
    Department of Developmental Biology, Stanford University, School of Medicine, Stanford, California.
    Watabe, Misako
    Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
    Mo, Yin-Yuan
    Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
    Hirota, Shigeru
    Akita Red Cross Hospital, Akita, Japan.
    Hosobe, Sadahiro
    Akita Red Cross Hospital, Akita, Japan.
    Tsukada, Taisei
    Akita Red Cross Hospital, Akita, Japan.
    Miura, Kunio
    Akita Red Cross Hospital, Akita, Japan.
    Kamada, Shuichi
    Akita Red Cross Hospital, Akita, Japan.
    Saito, Ken
    Akita Red Cross Hospital, Akita, Japan.
    Iiizumi, Megumi
    Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
    Liu, Wen
    Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
    Ericsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Watabe, Kounosuke
    Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
    Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-12008In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 68, no 4, p. 1003-1011Article in journal (Refereed)
    Abstract [en]

    The fatty acid synthase (FAS) gene is significantly up-regulated in various types of cancers, and blocking the FAS expression results in apoptosis of tumor cells. Therefore, FAS is considered to be an attractive target for anticancer therapy. However, the molecular mechanism by which the FAS gene is up-regulated in tumor cells is poorly understood. We found that FAS was significantly up-regulated by hypoxia, which was also accompanied by reactive oxygen species (ROS) generation in human breast cancer cell lines. The FAS expression was also activated by H(2)O(2), whereas N-acetyl-L-cystein, a ROS inhibitor, suppressed the expression. We also found that the hypoxia significantly up-regulated sterol regulatory-element binding protein (SREBP)-1, the major transcriptional regulator of the FAS gene, via phosphorylation of Akt followed by activation of hypoxia-inducible factor 1 (HIF1). Moreover, our results of reporter assay and chromatin immunoprecipitation analysis indicate that SREBP-1 strongly bound to the SREBP binding site/E-box sequence on the FAS promoter under hypoxia. In our xenograft mouse model, FAS was strongly expressed in the hypoxic regions of the tumor. In addition, our results of immunohistochemical analysis for human breast tumor specimens indicate that the expressions of both FAS and SREBP-1 were colocalized with hypoxic regions in the tumors. Furthermore, we found that hypoxia-induced chemoresistance to cyclophosphamide was partially blocked by a combination of FAS inhibitor and cyclophosphamide. Taken together, our results indicate that FAS gene is up-regulated by hypoxia via activation of the Akt and HIF1 followed by the induction of the SREBP-1 gene, and that hypoxia-induced chemoresistance is partly due to the up-regulation of FAS.

  • 33.
    Garousi, Javad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Lindbo, Sarah
    Nilvebrant, Johan
    Åstrand, Mikael
    Buijs, Jos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Hober, Sophia
    ADAPT, a novel scaffold protein-based probe for radionuclide imaging of molecular targets that are expressed in disseminated cancers2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 20, p. 4364-4371Article in journal (Refereed)
    Abstract [en]

    Small engineered scaffold proteins have attracted attention as probes for radionuclide-based molecular imaging. One class of these imaging probes, termed ABD-Derived Affinity ProTeins (ADAPT), have been created using the albumin-binding domain (ABD) of streptococcal protein G as a stable protein scaffold. In this study, we report the development of a clinical lead probe termed ADAPT6 that binds HER2, an oncoprotein overexpressed in many breast cancers that serves as a theranostic biomarker for several approved targeting therapies. Surface-exposed amino acids of ABD were randomized to create a combinatorial library enabling selection of high affinity binders to various proteins. Further, ABD was engineered to rapidly purify ADAPT6, eradicate its binding to albumin and enable rapid blood clearance. Incorporation of a unique cysteine allowed site-specific conjugation to a maleimido derivative of a DOTA chelator, enabling radionuclide labeling, 111In for SPECT imaging and 68Ga for PET imaging. Pharmacological studies in mice demonstrated that the fully engineered molecule 111In/68Ga-DOTA-(HE)3-ADAPT6 was specifically bound and taken up by HER2-expressing tumors, with a high tumor-to-normal tissue ratio in xenograft models of human cancer. Unbound tracer underwent rapid renal clearance followed by high renal reabsorption. HER2-expressing xenografts were visualized by gamma-camera or PET by one hour post-infusion. PET experiments demonstrated feasibility for discrimination of xenografts with high or low HER2 expression. Our results offer a preclinical proof of concept for the use of ADAPT probes for non-invasive in vivo imaging.

  • 34. Gaudet, Mia M
    et al.
    Gierach, Gretchen L
    Carter, Brian D
    Luo, Juhua
    Milne, Roger L
    Weiderpass, Elisabete
    Giles, Graham G
    Tamimi, Rulla M
    Eliassen, A Heather
    Rosner, Bernard
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Adami, Hans-Olov
    Margolis, Karen L
    Gapstur, Susan M
    Garcia-Closas, Montserrat
    Brinton, Louise A
    Pooled Analysis of Nine Cohorts Reveals Breast Cancer Risk Factors by Tumor Molecular Subtype.2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 20, p. 6011-6021Article in journal (Refereed)
    Abstract [en]

    Various subtypes of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR), and HER2 exhibit etiologic differences in reproductive factors, but associations with other risk factors are inconsistent. To clarify etiologic heterogeneity, we pooled data from nine cohort studies. Multivariable, joint Cox proportional hazards regression models were used to estimate HRs and 95% confidence intervals (CI) for molecular subtypes. Of 606,025 women, 11,741 invasive breast cancers with complete tissue markers developed during follow-up: 8,700 luminal A–like (ER+ or PR+/HER2), 1,368 luminal B–like (ER+ or PR+/HER2+), 521 HER2-enriched (ER/PR/HER2+), and 1,152 triple-negative (ER/PR/HER2) disease. Ever parous compared with never was associated with lower risk of luminal A–like (HR, 0.78; 95% CI, 0.73–0.83) and luminal B–like (HR, 0.74; 95% CI, 0.64–0.87) as well as a higher risk of triple-negative disease (HR, 1.23; 95% CI, 1.02–1.50; P value for overall tumor heterogeneity < 0.001). Direct associations with luminal-like, but not HER2-enriched or triple-negative, tumors were found for age at first birth, years between menarche and first birth, and age at menopause (P value for overall tumor heterogeneity < 0.001). Age-specific associations with baseline body mass index differed for risk of luminal A–like and triple-negative breast cancer (P value for tumor heterogeneity = 0.02). These results provide the strongest evidence for etiologic heterogeneity of breast cancer to date from prospective studies.

    Significance: These findings comprise the largest study of prospective data to date and contribute to the accumulating evidence that etiological heterogeneity exists in breast carcinogenesis. Cancer Res; 78(20); 6011–21. ©2018 AACR.

    .

  • 35.
    Goodwin, Richard
    et al.
    AstraZeneca, Global DMPK, Cambridge, England..
    Swales, John
    AstraZeneca, Global DMPK, Cambridge, England..
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andrén, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Strittmatter, Nicola
    Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London, England..
    Takats, Zoltan
    Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London, England..
    Howes, Colin
    AstraZeneca, Oncol iMED, Macclesfield, Cheshire, England..
    Taylor, Paula
    AstraZeneca, Oncol iMED, Macclesfield, Cheshire, England..
    Ashton, Susan
    AstraZeneca, Oncol iMED, Macclesfield, Cheshire, England..
    Jewsbury, Philip
    AstraZeneca, Oncol iMED, Macclesfield, Cheshire, England..
    Barry, Simon T.
    AstraZeneca, Oncol iMED, Macclesfield, Cheshire, England..
    Imaging AZD1152HQPA Accurin (TM) nanoparticle accumulation in preclinical tumors2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75Article in journal (Other academic)
  • 36. Hatschek, Thomas
    et al.
    Bjoehle, Judith
    Lidbrink, Elisabet
    Lekberg, Tobias
    Loman, Niklas
    Vaeppling, Anna von Wachenfeldt
    Soederberg, Martin
    Einbeigi, Zakaria
    Carlsson, Lena
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Fredriksson, Irma
    Frisell, Jan
    Loefgren, Lars
    Ryden, Lisa
    Hellstroem, Mats
    Fernoe, Marten
    Bergh, Jonas
    Is pathologic complete response (pCR) a valid marker of outcome even in large breast cancer?: Clinical results from a neoadjuvant trial using a combination of epirubicin, docetaxel and bevacizumab (PROMIX)2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 9, article id P3-11-14Article in journal (Other academic)
  • 37. He, Yulong
    et al.
    Rajantie, Iiro
    Ilmonen, Maritta
    Makinen, Taija
    Karkkainen, Marika J
    Haiko, Paula
    Salven, Petri
    Alitalo, Kari
    Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis.2004In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 64, no 11Article in journal (Refereed)
    Abstract [en]

    Endothelial progenitor cells have been shown to contribute to angiogenesis in various tumor models. Here, we have studied the relative contributions of bone marrow (BM)-derived endothelial progenitors and pre-existing lymphatic vessels to tumor lymphangiogenesis. We did not find significant incorporation of genetically marked BM-derived cells in lymphatic vessels during tumor- or vascular endothelial growth factor C-induced lymphangiogenesis. The degree of tumor lymphangiogenesis correlated with lymphatic vessel density in the peritumoral area, and despite tumor lymphangiogenesis, lymphatic metastasis failed to occur in gene-targeted vascular endothelial growth factor C(+/-) mice that have hypoplasia of the lymphatic network. Our data demonstrate that during tumor lymphangiogenesis and cancer cell dissemination via the lymphatics, the newly formed lymphatic vessels sprout from the pre-existing local lymphatic network with little if any incorporation of BM-derived endothelial progenitor cells.

  • 38.
    Heesch, Sandra
    et al.
    BioNTech AG, Mainz, Germany..
    Britten, Cedrik M.
    BioNTech RNA Pharmaceut GmbH, Mainz, Germany..
    Bukur, Valesca
    BioNTech AG, Mainz, Germany..
    Buck, Janina
    BioNTech RNA Pharmaceut GmbH, Mainz, Germany..
    Castle, John
    TRON, Mainz, Germany..
    Diekmann, Jan
    BioNTech RNA Pharmaceut GmbH, Mainz, Germany..
    Diken, Mustafa
    TRON, Mainz, Germany..
    Frenzel, Katrin
    BioNTech AG, Mainz, Germany..
    Kreiter, Sebastian
    TRON, Mainz, Germany..
    Kuhn, Andreas N.
    BioNTech RNA Pharmaceut GmbH, Mainz, Germany..
    Kuehlcke, Klaus
    EUFETS GmbH, Idar Oberstein, Germany..
    Loewer, Martin
    TRON, Mainz, Germany..
    Haas, Heinrich
    BioNTech RNA Pharmaceut GmbH, Mainz, Germany..
    Kemmer-Brueck, Alexandra
    BioNTech AG, Mainz, Germany..
    Kloke, Bjoern-Philipp
    BioNTech RNA Pharmaceut GmbH, Mainz, Germany..
    Otte, Burkhard
    BioNTech RNA Pharmaceut GmbH, Mainz, Germany..
    Paruzynski, Anna
    BioNTech AG, Mainz, Germany..
    Petri, Sebastian
    BioNTech RNA Pharmaceut GmbH, Mainz, Germany..
    Schwarck-Kokarakis, Doreen
    BioNTech AG, Mainz, Germany..
    Schmidt, Marcus
    Univ Hosp, Mainz, Germany..
    Andre, Fabrice
    Gustave Roussy, Villejuif, France..
    De Greve, Jacques
    Vrije Univ Brussel, Brussels, Belgium..
    Kuendig, Thomas
    Univ Zurich Hosp, CH-8091 Zurich, Switzerland..
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Pascolo, Steve
    Univ Zurich Hosp, CH-8091 Zurich, Switzerland..
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Thielemans, Kris
    Vrije Univ Brussel, Brussels, Belgium..
    Zitvogel, Laurence
    Gustave Roussy Comprehens Canc Ctr, Villejuif, France..
    Tuereci, Oezlem
    Johannes Gutenberg Univ Mainz, Univ Med Ctr, D-55122 Mainz, Germany..
    Sahin, Ugur
    BioNTech AG, Mainz, Germany..
    The Mutanome Engineered RNA Immuno-Therapy (MERIT) project2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75Article in journal (Other academic)
  • 39.
    Hermano, Esther
    et al.
    Hadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Jerusalem, Israel.
    Goldberg, Rachel
    Hadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Jerusalem, Israel.
    Rubinstein, Ariel M.
    Hadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Jerusalem, Israel.
    Sonnenblick, Amir
    Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Oncol Div, Tel Aviv, Israel; Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel.
    Maly, Bella
    Hadassah Hebrew Univ, Med Ctr, Dept Pathol, Jerusalem, Israel.
    Nahmias, Daniela
    Hadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Jerusalem, Israel.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bakker, Marinka A. H.
    Radboud Univ Nijmegen, Nijmegen Ctr Mol Life Sci, Dept Nephrol, Nephrol Res Lab,Med Ctr, Nijmegen, Netherlands.
    van der Vlag, Johan
    Radboud Univ Nijmegen, Nijmegen Ctr Mol Life Sci, Dept Nephrol, Nephrol Res Lab,Med Ctr, Nijmegen, Netherlands.
    Vlodavsky, Israel
    Technion, Rappaport Fac Med, Canc & Vasc Biol Res Ctr, Haifa, Israel.
    Peretz, Tamar
    Hadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Jerusalem, Israel; Hebrew Univ Jerusalem, Med Sch, Jerusalem, Israel.
    Elkin, Michael
    Hadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Jerusalem, Israel; Hebrew Univ Jerusalem, Med Sch, Jerusalem, Israel.
    Heparanase Accelerates Obesity-Associated Breast Cancer Progression2019In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 79, no 20, p. 5342-5354Article in journal (Refereed)
    Abstract [en]

    Obese women have higher risk of bearing breast tumors that are highly aggressive and resistant to therapies. Tumor-promoting effects of obesity occur locally via adipose inflammation and related alterations to the extracellular matrix (ECM) as well as systemically via circulating metabolic mediators (e.g., free fatty acids, FFA) associated with excess adiposity and implicated in toll-like receptor-mediated activation of macrophages-key cellular players in obesity-related cancer progression. Although the contribution of macrophages to proneoplastic effects of obesity is well documented, the role of ECM components and their enzymatic degradation is less appreciated. We show that heparanase, the sole mammalian endoglucuronidase that cleaves heparan sulfate in ECM, is preferentially expressed in clinical/experimental obesity-associated breast tumors. Heparanase deficiency abolished obesity-accelerated tumor progression in vivo. Heparanase orchestrated a complex molecular program that occurred concurrently in adipose and tumor tissue and sustained the cancer-promoting action of obesity. Heparanase was required for adipose tissue macrophages to produce inflammatory mediators responsible for local induction of aromatase, a rate-limiting enzyme in estrogen biosynthesis. Estrogen upregulated heparanase in hormone-responsive breast tumors. In subsequent stages, elevated levels of heparanase induced acquisition of procancerous phenotype by tumor-associated macrophages, resulting in activation of tumor-promoting signaling and acceleration of breast tumor growth under obese conditions. As techniques to screen for heparanase expression in tumors become available, these findings provide rational and a mechanistic basis for designing antiheparanase approaches to uncouple obesity and breast cancer in a rapidly growing population of obese patients. Significance: This study reveals the role of heparanase in promoting obesity-associated breast cancer and provides a mechanistically informed approach to uncouple obesity and breast cancer in a rapidly growing population of obese patients.

  • 40.
    Hessman, Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lindberg, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Carling, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Mutation of the Multiple Endocrine Neoplasia Type 1 gene in nonfamilial, malignant tumors of the endocrine pancreas1998In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 58, no 3, p. 377-379Article in journal (Refereed)
    Abstract [en]

    Endocrine pancreatic tumors are rare neoplasms that occur sporadically or as part of a multiple endocrine neoplasia type 1 (MEN1) syndrome. Germ-line mutations of the MEN1 gene, located at 11q13, have been demonstrated in MEN1 kindreds, and loss of heterozygosity (LOH) on 11q13 together with somatic MEN1 mutations have been detected in 20% of nonfamilial parathyroid tumors. Here, we examine 11 non-MEN1 malignant tumors of the endocrine pancreas, 9 nonfunctioning tumors, and 2 glucagonomas. LOH of at least one informative locus on 11q13 was found in 70% of the tumors. Three tumors displayed somatic mutations of the MEN1 gene together with LOH on 11q13, whereas the corresponding germ-line DNA was normal. These findings support the hypothesis that MEN1 gene mutations contribute to the tumorigenesis of nonfamilial, malignant endocrine pancreatic tumors.

  • 41. Hill, Rebecca M.
    et al.
    Kuijper, Sanne
    Lindsey, Janet
    Schwalbe, Ed C.
    Barker, Karen
    Boult, Jessica
    Williamson, Daniel
    Ahmad, Zai
    Hallsworth, Albert
    Ryan, Sarra
    Poon, Evon
    Robinson, Simon
    Ruddle, Ruth
    Raynaud, Florence
    Howell, Louise
    Kwok, Colin
    Joshi, Abhijit
    Nicholson, Sarah
    Crosier, Stephen
    Wharton, Stephen
    Jacques, Tom
    Robson, Keith
    Michalski, Antony
    Hargrave, Darren
    Pizer, Barry
    Bailey, Simon
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Petrie, Kevin
    Weiss, William A.
    Chesler, Louis
    Clifford, Steve
    MYC and TP53 defects interact at medulloblastoma relapse to define rapidly progressive disease and can be targeted therapeutically2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 42.
    Hirsch, Jan M
    et al.
    Department of Oral Surgery, University of Göteborg, Sweden.
    Svennerholm, B
    Vahlne, A
    Inhibition of herpes simplex virus replication by tobacco extracts1984In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 44, no 5, p. 1991-1997Article in journal (Refereed)
    Abstract [en]

    Herpes simplex virus type 1 (HSV-1) has been associated with the genesis of leukoplakias, epithelial atypia, and oral cancer. Tobacco habits, such as snuff dipping, are also definitely correlated with this type of lesion. The normal cytolytic HSV-1 infection can, after in vitro inactivation, transform cells. Extracts of snuff were prepared and assayed for their ability to inhibit HSV-1 replication. Plaque formation assays of HSV-1 in the presence of snuff extract showed that a reduced number of plaques was formed. Different batches of one brand of snuff were tested for inhibition of herpes simplex virus (HSV) production. More than 99% inhibition of 24-hr HSV production was obtained with undiluted batches. The 1:5 dilutions of snuff had an inhibitory effect of 85% and 1:25 dilutions, 39%. In agreement, the attachment of the virus to the host cell and penetration of the virus to the cell nuclei were found to be inhibited as was the synthesis of viral DNA. Nicotine had an inhibitory effect, while aromatic additions to snuff were found to have no major inhibitory effect on HSV replication. Snuff extracts were prepared from different brands of snuff reported to contain high and low quantities of tobacco-specific N-nitrosamines. Brands with reported high levels of tobacco-specific N-nitrosamines had significantly greater ability to inhibit HSV replication. In conclusion, this study has shown that extracts of snuff have inhibitory effects on the production of cytolytic HSV-1 infections. A chronic snuff dipper keeps tobacco in the mouth for the major part of the day. Thus, virus shed in the oral cavity in connection with a reactivated latent HSV-1 infection has great possibilities of being affected by snuff or derivatives of snuff. It is suggested that an interaction between tobacco products and HSV-1 might be involved in the development of dysplastic lesions in the oral cavity.

  • 43. Hjalgrim, Henrik
    et al.
    Smedby, Karin Ekström
    Rostgaard, Klaus
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hamilton-Dutoit, Stephen
    Chang, Ellen T.
    Ralfkiaer, Elisabeth
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Adami, Hans-Olov
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Melbye, Mads
    Infectious mononucleosis, childhood social environment, and risk of Hodgkin lymphoma2007In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 67, no 5, p. 2382-2388Article in journal (Refereed)
    Abstract [en]

    Infectious mononucleosis (IM) has been associated with an increased risk of Hodgkin lymphoma (HL), implicating a role for Epstein-Barr virus (EBV) in HL development. Although essential to the understanding of the association, it has remained uncertain if the relationship is restricted to the EBV-positive subset of HL. We collected information on mononucleosis history and childhood socioenvironmental characteristics in a population-based study of 586 patients with classic HL and 3,187 controls in Denmark and Sweden. Tumor EBV status was established for 499 cases by immunohistochemistry and in situ hybridization techniques. Odds ratios (OR) for the relationship between HL risk and mononucleosis and other risk factors were estimated by logistic regression for HL in younger (18-44 years) and older (45-74 years) adults, overall and by tumor EBV status. All analyses were adjusted for country-specific measures of maternal education and mononucleosis history. IM was associated with an increased risk of EBV-positive [OR, 3.23; 95% confidence interval (95% CI) 1.89-5.55] but not EBV-negative HL (OR, 1.35; 95% CI, 0.86-2.14). Risk of EBV-positive HL varied with time since IM and was particularly pronounced in younger adults (OR, 3.96; 95% CI, 2.19-7.18). IM-associated lymphomas occurred with a median of 2.9 years (1.8-4.9 years) after infection. The EBV specificity of the IM association was corroborated by a case-case comparison of IM history between younger adult EBV-positive and EBV-negative HL patients (OR(IM EBV+ HL versus EBV- HL), 2.68; 95% CI, 1.40-5.12). We found further evidence that IM is associated only with EBV-positive HL. This finding is compatible with the notion that EBV-positive and EBV-negative HL may have different etiologies.

  • 44. Ivshina, Anna V.
    et al.
    George, Joshy
    Senko, Oleg
    Mow, Benjamin
    Putti, Thomas C.
    Smeds, Johanna
    Lindahl, Thomas
    Pawitan, Yudi
    Hall, Per
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wong, John E. L.
    Liu, Edison T.
    Bergh, Jonas
    Kuznetsov, Vladimir A.
    Miller, Lance D.
    Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer2006In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, no 21, p. 10292-10301Article in journal (Refereed)
    Abstract [en]

    Histologic grading of breast cancer defines morphologic subtypes informative of metastatic potential, although not without considerable interobserver disagreement and clinical heterogeneity particularly among the moderately differentiated grade 2 (G2) tumors. We posited that a gene expression signature capable of discerning tumors of grade 1 (G1) and grade 3 (W) histology might provide a more objective measure of grade with prognostic benefit for patients with G2 disease. To this end, we studied the expression profiles of 347 primary invasive breast tumors analyzed on Affymetrix microarrays. Using class prediction algorithms, we identified 264 robust grade-associated markers, six of which could accurately classify G1 and G3 tumors, and separate G2 tumors into two highly discriminant classes (termed G2a and G2b genetic grades) with patient survival outcomes highly similar to those with G1 and G3 histology, respectively. Statistical analysis of conventional clinical variables further distinguished G2a and G2b subtypes from each other, but also from histologic G1 and G3 tumors. In multivariate analyses, genetic grade was consistently found to be an independent prognostic indicator of disease recurrence comparable with that of lymph node status and tumor size. When incorporated into the Nottingham prognostic index, genetic grade enhanced detection of patients with less harmful tumors, likely to benefit little from adjuvant therapy. Our findings show that a genetic grade signature can improve prognosis and therapeutic planning for breast cancer patients, and support the view that low- and high-grade disease, as defined genetically, reflect independent pathobiological entities rather than a continuum of cancer progression.

  • 45.
    Jerhammar, Fredrik
    et al.
    Karolinska Inst, Stockholm, Sweden..
    Bersani, Cinzia
    Karolinska Inst, Stockholm, Sweden..
    Djureinovic, Dijana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wiman, Klas G.
    Karolinska Inst, Stockholm, Sweden..
    The role of the p53 target Wig-1 in senescence and cancer2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 15, p. 110-Article in journal (Other academic)
  • 46. Joensuu, Heikki
    et al.
    Fraser, Judith
    Wildiers, Hans
    Huovinen, Riikka
    Auvinen, Paivi
    Utriainen, Meri
    Nyandoto, Paul
    Villman, Kenneth K.
    Halonen, Paivi
    Granstam Björneklett, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Västerås Central Hospital, Västerås, Sweden.
    Lundgren, Lotta
    Yachnin, Jeffrey
    Turpeenniemi-Hujanen, Taina
    Ritchie, Diana
    Huttunen, Teppo
    Neven, Patric
    Canney, Peter
    Harvey, Vernon J.
    Kellokumpu-Lehtinen, Pirkko-Liisa
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Abstract GS3-04: A randomized phase III study of adjuvant trastuzumab for a duration of 9 weeks versus 1 year, combined with adjuvant taxane-anthracycline chemotherapy, for early HER2-positive breast cancer (the SOLD study)2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 4Article in journal (Other academic)
  • 47. Johansson, S L
    et al.
    Hirsch, Jan M
    Department of Oral Surgery, University of Göteborg, Sweden.
    Larsson, P A
    Saidi, J
    Österdahl, B G
    Snuff-induced carcinogenesis: effect of snuff in rats initiated with 4-nitroquinoline N-oxide1989In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 49, no 11, p. 3063-3069Article in journal (Refereed)
    Abstract [en]

    A canal in the lower lip to function as a reservoir for snuff was surgically created in 150 male Sprague-Dawley rats. The animals were randomized into five groups of 30 each: Group I received snuff twice a day, 5 days a wk; Group II was painted with propylene glycol (solvent control) on the hard palate 3 times a wk during 4 wk; Group III underwent painting on the hard palate with 4-nitroquinoline N-oxide (4-NQO) dissolved in propylene glycol, 3 times a wk for 4 wk; Group IV received 4-NQO as in Group III followed by snuff application as in Group I; and Group V received a cotton pellet dipped in saline twice a day, 5 days a wk. Treatment continued for up to 108 wk. There was no significant difference in mean survival time between the groups. Squamous cell tumors of the lip, oral and nasal cavities, esophagus, and forestomach were seen only in Groups I, III, and IV. Nine tumors of these organs were found in Group I (six carcinomas and three papillomas), nine in Group III (seven carcinomas and two papillomas), and ten in Group IV (eight carcinomas and two papillomas). The difference between each of these groups and the control groups (II and V) with regard to tumor incidence is statistically significant (P less than 0.05). In Group I, four oral cavity or lip carcinomas were found in 29 rats, a significant difference in relation to control rats (P less than 0.05). In addition, hyperplastic lesions of the lip, palate, and forestomach were significantly more common in Groups I and IV compared with Groups II, III, and V. The study has shown that snuff and 4-NQO by themselves have the potential to induce malignant tumors. Initiation with 4-NQO followed by snuff did not significantly enhance tumor formation.

  • 48. Julin, Bettina
    et al.
    Wolk, Alicja
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Bottai, Matteo
    Akesson, Agneta
    Dietary Cadmium Exposure and Risk of Postmenopausal Breast Cancer: A Population-Based Prospective Cohort Study2012In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 72, no 6, p. 1459-1466Article in journal (Refereed)
    Abstract [en]

    The ubiquitous food contaminant cadmium has features of an estrogen mimetic that may promote the development of estrogen-dependent malignancies, such as breast cancer. However, no prospective studies of cadmium exposure and breast cancer risk have been reported. , We examined the association between dietary cadmium exposure (at baseline, 1987) and the risk of overall and estrogen receptor (ER)-defined (ER+ or ER-) breast cancer within a population-based prospective cohort of 55,987 postmenopausal women. During an average of 12.2 years of follow-up, 2,112 incident cases of invasive breast cancer were ascertained (1,626 ER+ and 290 ER-). After adjusting for confounders, including consumption of whole grains and vegetables (which account for 40% of the dietary exposure, but also contain putative anticarcinogenic phytochemicals), dietary cadmium intake was positively associated with overall breast cancer tumors, comparing the highest tertile with the lowest [rate ratio (RR), 1.21; 95% confidence interval (CI), 1.07-1.36; P-trend = 0.02]. Among lean and normal weight women, statistically significant associations were observed for all tumors (RR, 1.27; 95% CI, 1.07-1.50) and for ER+ tumors (RR, 125; 95% CI, 1.03-1.52) and similar, but not statistically significant associations were found for ER- tumors (RR, 1.22; 95% CI, 0.76-1.93). The risk of breast cancer increased with increasing cadmium exposure similarly within each textile of whole grain/vegetable consumption and decreased with increasing consumption of whole grain/vegetables within each tertile of cadmium exposure (P-interaction = 0.73). Overall, these results suggest a role for dietary cadmium in postmenopausal breast cancer development.

  • 49.
    Karakatsanis, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Olofsson, H. M.
    Eriksson, S.
    Andersson, Y.
    Bergkvist, Leif A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Mohammed, I.
    Sundqvist, M.
    Abdsaleh, Shahin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Bagge, R. Olofsson
    Sund, M.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    SentiNot: A way to avoid sentinel node biopsy (SNB) in patients with a preoperative diagnosis of ductal cancer in situ (DCIS)2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77Article in journal (Refereed)
  • 50. Karlsson, Terese
    et al.
    Kvarnbrink, Samuel
    Holmlund, Camilla
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Johansson, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Henriksson, Roger
    Hedman, Hakan
    Interactions between LRIG proteins and LMO7 and the expression of LMO7 in human lung cancer.2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8, p. S1-Article in journal (Other academic)
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