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  • 1.
    Bendahl, Par-Ola
    et al.
    Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Radiophys & Oncol, Lasarettsgatan 23A, SE-22185 Lund, Sweden.
    Gezelius, Emelie
    Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Lund Univ Hosp, Dept Resp Med, Entregatan 7, SE-22185 Lund, Sweden.
    Longitudinal Assessment of Circulating Tumor Cells and Outcome in Small Cell Lung Cancer: A Sub-Study of RASTEN-A Randomized Trial with Low Molecular Weight Heparin2023In: Cancers, ISSN 2072-6694, Vol. 15, no 12, article id 3176Article in journal (Refereed)
    Abstract [en]

    Simple Summary Small cell lung cancer (SCLC) is an aggressive lung cancer subtype associated with an overall poor prognosis but a variable response rate to chemotherapy. The measurement of circulating tumor cells (CTCs) offers a non-invasive method to monitor the disease and may provide prognostic information as potential guidance to clinicians in the management of SCLC. However, the value of CTCs during and after chemotherapy appears inconclusive. Here, we show that the detection of CTCs at baseline correlates to overall survival in SCLC, and that persistently detectable CTCs after completion of treatment adds further prognostic value. This suggests that repetitive analysis of CTCs during and after the course of treatment may have a role in the management of SCLC, warranting further studies. Circulating tumor cells (CTCs) may provide a liquid biopsy approach to disease monitoring in small cell lung cancer (SCLC), a particularly aggressive tumor subtype. Yet, the prognostic role of CTCs during and after treatment in relation to baseline remains ill-defined. Here, we assessed the value of longitudinal CTC analysis and the potential of low-molecular-weight heparin (LMWH) to reduce CTC abundance in SCLC patients from a randomized trial (RASTEN). Blood samples were collected at baseline, before chemotherapy Cycle 3, and at 2-month follow-up from 42 patients in total, and CTCs were quantified using the FDA-approved CellSearch system. We found a gradual decline in CTC count during and after treatment, independently of the addition of LMWH to standard therapy. Detectable CTCs at baseline correlated significantly to reduced survival compared to undetectable CTCs (unadjusted hazard ratio (HR) of 2.75 (95% CI 1.05-7.20; p = 0.040)). Furthermore, a persistent CTC count at 2-month follow-up was associated with a HR of 4.22 (95% CI 1.20-14.91; p = 0.025). Our findings indicate that persistently detectable CTCs during and after completion of therapy offer further prognostic information in addition to baseline CTC, suggesting a role for CTC in the individualized management of SCLC.

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  • 2.
    Berg, Tracy J.
    et al.
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden..
    Marques, Carolina
    CNIO, Sevc Ballesteros Fdn Brain Tumor Grp, Madrid, Spain..
    Pantazopoulou, Vasiliki
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden..
    Johansson, Elinn
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden..
    von Stedingk, Kristoffer
    Lund Univ, Dept Pediat, Clin Sci Lund, Lund, Sweden.;Univ Amsterdam, Dept Oncogen, Acad Med Ctr, M1-131, Amsterdam, Netherlands..
    Lindgren, David
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden..
    Jeannot, Pauline
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden..
    Pietras, Elin J.
    Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
    Bergström, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Governa, Valeria
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden..
    Bengzon, Johan
    Lund Univ, Lund Stem Cell Ctr, Dept Clin Sci, Div Neurosurg, Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden..
    Axelson, Hakan
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden..
    Squatrito, Massimo
    CNIO, Sevc Ballesteros Fdn Brain Tumor Grp, Madrid, Spain..
    Pietras, Alexander
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden..
    The Irradiated Brain Microenvironment Supports Glioma Stemness and Survival via Astrocyte-Derived Transglutaminase 22021In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 81, no 8, p. 2101-2115Article in journal (Refereed)
    Abstract [en]

    The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance. Following radiotherapy, recurrent gliomas form in an irradiated microenvironment. Here we report that astrocytes, when pre-irradiated, increase stemness and survival of cocultured glioma cells. Tumor-naive brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. Extracellular matrix derived from irradiated astrocytes were found to be a major driver of this phenotype and astrocyte-derived transglutaminase 2 (TGM2) was identified as a promoter of glioma stemness and radioresistance. TGM2 levels increased after radiation in vivo and in recurrent human glioma, and TGM2 inhibitors abrogated glioma stemness and survival. These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard-of-care radiotherapy by reducing stemness in glioma. Significance: These findings presented here indicate that radiotherapy can result in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence.

  • 3.
    Cerezo-Magana, M.
    et al.
    Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Barngatan 4, SE-22185 Lund, Sweden.
    Bang-Rudenstam, A.
    Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Barngatan 4, SE-22185 Lund, Sweden.
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Barngatan 4, SE-22185 Lund, Sweden;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden.
    The pleiotropic role of proteoglycans in extracellular vesicle mediated communication in the tumor microenvironment2020In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 62, p. 99-107Article, review/survey (Refereed)
    Abstract [en]

    Compartmental exchange between cells through extracellular vesicles (EVs), including exosomes and microvesicles, has emerged as a central mechanism that coordinates the complex communication between malignant and stromal cells during tumor initiation and evolution. Some of the most critical processes of EV-mediated communication, including EV biogenesis and EV uptake, can be mediated by heparan sulfate proteoglycans (HSPGs) that reside on the surface of producer and recipient cells as well as on EVs. With interestingly similar, HSPG-dependent, pathways as the ones exploited by some viruses, EVs may, in an evolutionary perspective, be viewed as endogenous counterparts of viral particles. Cancer cell-derived EVs exert their protumorigenic effects by direct interactions of biologically active surface molecules, by transfer of proteins and nucleic acids into recipient cells or by transfer of metabolites that can be utilized as an energy source by the recipient cell. Here, we discuss the pleiotropic role of the HSPG family in these different contexts of EV communication with a specific focus on tumor development. We propose EV-associated PGs as dynamic reservoirs and chaperones of signaling molecules with potential implications in ligand exchange between EVs and tumor target cells. The protumorigenic consequences of EV mediated communication through HSPG should motivate the development of therapeutic approaches targeting EV-HSPG interactions as a novel strategy in cancer treatment.

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  • 4.
    Cerezo-Magana, Myriam
    et al.
    Lund Univ, Dept Clin Sci Lund, Oncol, Lund, Sweden..
    Bång-Rudenstam, Anna
    Lund Univ, Dept Clin Sci Lund, Oncol, Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci Lund, Oncol, Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden..
    Proteoglycans: a common portal for SARS-CoV-2 and extracellular vesicle uptake2023In: American Journal of Physiology - Cell Physiology, ISSN 0363-6143, E-ISSN 1522-1563, Vol. 324, no 1, p. C76-C84Article, review/survey (Refereed)
    Abstract [en]

    As structural components of the glycocalyx, heparan sulfate proteoglycans (HSPGs) are involved in multiple pathophysiological processes at the apex of cell signaling cascades, and as endocytosis receptors for particle structures, such as lipoproteins, extracellular vesicles, and enveloped viruses, including SARS-CoV-2. Given their diversity and complex biogenesis regulation, HSPGs remain understudied. Here we compile some of the latest studies focusing on HSPGs as internalizing receptors of extracellular vesicles ("endogenous virus") and SARS-CoV-2 lipid-enclosed particles and highlight similarities in their biophysical and structural characteristics. Specifically, the similarities in their biogenesis, size, and lipid composition may explain a common dependence on HSPGs for efficient cell-surface attachment and uptake. We further discuss the relative complexity of extracellular vesicle composition and the viral mechanisms that evolve towards increased infectivity that complicate therapeutic strategies addressing blockade of their uptake.

  • 5.
    Cerezo-Magana, Myriam
    et al.
    Lund Univ, Dept Clin Sci, Sect Oncol, Lund, Sweden..
    Christianson, Helena C.
    Lund Univ, Dept Clin Sci, Sect Oncol, Lund, Sweden..
    van Kuppevelt, Toin H.
    Radboud Inst Mol Life Sci, Dept Biochem, Nijmegen, Netherlands..
    Forsberg Nilsson, 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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Lund Univ, Dept Clin Sci, Sect Oncol, Lund, Sweden.;Uppsala Univ, Sci Life Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden.;Skane Univ Hosp, Lund, Sweden..
    Hypoxic Induction of Exosome Uptake through Proteoglycan-Dependent Endocytosis Fuels the Lipid Droplet Phenotype in Glioma2021In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 19, no 3, p. 528-540Article in journal (Refereed)
    Abstract [en]

    As an adaptive response to hypoxic stress, aggressive tumors rewire their metabolic phenotype into increased malignant behavior through extracellular lipid scavenging and storage in lipid droplets (LD). However, the underlying mechanisms and potential lipid source retrieved in the hypoxic tumor microenvironment remain poorly understood. Here, we show that exosome-like extracellular vesicles (EV), known as influential messengers in the tumor microenvironment, may also serve anabolic functions by transforming hypoxic, patient-derived human glioblastoma cell lines into the LD+ phenotype. EVs were internalized via a hypoxia-sensitive, endocytic mechanism that fueled LD formation through direct lipid transfer, and independently of fatty acid synthase activity. EVs can enter cells through multiple and yet ill-defined pathways. On a mechanistic level, we found that hypoxia-mediated EV uptake depends on increased heparan sulfate proteoglycan (HSPG) endocytosis that preferentially followed the lipid raft pathway. The functional relevance of HSPG was evidenced by the reversal of EV-mediated LD loading by targeting of HSPG receptor function.

  • 6.
    Chandran, Vineesh Indira
    et al.
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden.;Fred Hutchinson Canc Res Ctr, Program Immunol, Div Clin Res, Seattle, WA 98109 USA..
    Mansson, Ann-Sofie
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden..
    Barbachowska, Magdalena
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden..
    Cerezo-Magana, Myriam
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden..
    Nodin, Bjorn
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden..
    Joshi, Bharat
    Univ British Columbia, Dept Cellular & Physiol Sci, Inst Life Sci, Vancouver, BC, Canada..
    Koppada, Neelima
    Genentech Inc, BioAnalyt Sci ADT, GRED, San Francisco, CA USA..
    Saad, Ola M.
    Genentech Inc, BioAnalyt Sci ADT, GRED, San Francisco, CA USA..
    Gluz, Oleg
    West German Study Grp, Monchengladbach, Germany..
    Isaksson, Karolin
    Lund Univ, Div Surg, Skane Univ Hosp, Cent Hosp, Kristianstad, Sweden..
    Borgquist, Signe
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden.;Aarhus Univ, Dept Oncol, Aarhus Univ Hosp, Aarhus, Denmark..
    Jirstrom, Karin
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden..
    Nabi, Ivan Robert
    Univ British Columbia, Dept Cellular & Physiol Sci, Inst Life Sci, Vancouver, BC, Canada..
    Jernstrom, Helena
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden.
    Hypoxia Attenuates Trastuzumab Uptake and Trastuzumab-Emtansine (T-DM1) Cytotoxicity through Redistribution of Phosphorylated Caveolin-12020In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 18, no 4, p. 644-656Article in journal (Refereed)
    Abstract [en]

    The antibody-drug conjugate trastuzumab-emtansine (T-DM1) offers an additional treatment option for patients with HER2-amplified tumors. However, primary and acquired resistance is a limiting factor in a significant subset of patients. Hypoxia, a hallmark of cancer, regulates the trafficking of several receptor proteins with potential implications for tumor targeting. Here, we have investigated how hypoxic conditions may regulate T-DM1 treatment efficacy in breast cancer. The therapeutic effect of T-DM1 and its metabolites was evaluated in conjunction with biochemical, flow cytometry, and high-resolution imaging studies to elucidate the functional and mechanistic aspects of hypoxic regulation. HER2 and caveolin-1 expression was investigated in a well-annotated breast cancer cohort. Wefind that hypoxia fosters relative resistance to T-DM1 in HER2(+) cells (SKBR3 and BT474). This effect was not a result of deregulated HER2 expression or resistance to emtansine and its metabolites. Instead, we show that hypoxia-induced translocation of caveolin-1 from cytoplasmic vesicles to the plasma membrane contributes to deficient trastuzumab internalization and T-DM1 chemosensitivity. Caveolin-1 depletion mimicked the hypoxic situation, indicating that vesicular caveolin-1 is indispensable for trastuzumab uptake and T-DM1 cytotoxicity. In vitro studies suggested that HER2 and caveolin-1 are not coregulated, which was supported by IHC analysis in patient tumors. We find that phosphorylation-deficient caveolin-1 inhibits trastuzumab internalization and T-DM1 cytotoxicity, suggesting a specific role for caveolin-1 phosphorylation in HER2 trafficking.

  • 7.
    Chandran, Vineesh Indira
    et al.
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Welinder, Charlotte
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    de Oliveira, Kelin Goncalves
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Cerezo-Magana, Myriam
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Mansson, Ann-Sofie
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Johansson, Maria C.
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Marko-Varga, Gyorgy
    Lund Univ, Biomed Ctr, Clin Prot Sci & Imaging, Dept Biomed Engn, Lund, Sweden.
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden.
    Global extracellular vesicle proteomic signature defines U87-MG glioma cell hypoxic status with potential implications for non-invasive diagnostics2019In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 144, no 3, p. 477-488Article in journal (Refereed)
    Abstract [en]

    Purpose Glioblastoma multiforme (GBM) is the most common and lethal of primary malignant brain tumors. Hypoxia constitutes a major determining factor for the poor prognosis of high-grade glioma patients, and is known to contribute to the development of treatment resistance. Therefore, new strategies to comprehensively profile and monitor the hypoxic status of gliomas are of high clinical relevance. Here, we have explored how the proteome of secreted extracellular vesicles (EVs) at the global level may reflect hypoxic glioma cells. Methods We have employed shotgun proteomics and label free quantification to profile EVs isolated from human high-grade glioma U87-MG cells cultured at normoxia or hypoxia. Parallel reaction monitoring was used to quantify the identified, hypoxia-associated EV proteins. To determine the potential biological significance of hypoxia-associated proteins, the cumulative Z score of identified EV proteins was compared with GBM subtypes from HGCC and TCGA databases. Results In total, 2928 proteins were identified in EVs, out of which 1654 proteins overlapped with the ExoCarta EV-specific database. We found 1034 proteins in EVs that were unique to the hypoxic status of U87-MG cells. We subsequently identified an EV protein signature, "HYPSIGNATURE", encompassing nine proteins that strongly represented the hypoxic situation and exhibited close proximity to the mesenchymal GBM subtype. Conclusions We propose, for the first time, an EV protein signature that could comprehensively reflect the hypoxic status of high-grade glioma cells. The presented data provide proof-of-concept for targeted proteomic profiling of glioma derived EVs, which should motivate future studies exploring its utility in non-invasive diagnosis and monitoring of brain tumor patients.

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  • 8.
    Chandran, Vineesh Indira
    et al.
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Welinder, Charlotte
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden;Lund Univ, CEBMMS, Lund, Sweden.
    Mansson, Ann-Sofie
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Offer, Svenja
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Freyhult, Eva
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pernemalm, Maria
    Karolinska Inst, Dept Oncol & Pathol, Solna, Sweden.
    Lund, Sigrid M.
    Aalborg Univ Hosp, Dept Clin Biochem, Aalborg, Denmark.
    Pedersen, Shona
    Aalborg Univ Hosp, Dept Clin Biochem, Aalborg, Denmark;Aalborg Univ, Fac Clin Med, Aalborg, Denmark.
    Lehtio, Janne
    Karolinska Inst, Dept Oncol & Pathol, Solna, Sweden.
    Marko-Varga, Gyorgy
    Lund Univ, CEBMMS, Lund, Sweden;Lund Univ, Dept Biomed Engn, Biomed Ctr, Clin Prot Sci & Imaging, Lund, Sweden.
    Johansson, Maria C.
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Englund, Elisabet
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Sundgren, Pia C.
    Lund Univ, Sect Diagnost Radiol, Dept Clin Sci, Lund, Sweden;Lund Univ, Lund BioImaging Ctr, Lund, Sweden;Skane Univ Hosp, Dept Med Imaging & Funct, Lund, Sweden.
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden.
    Ultrasensitive Immunoprofiling of Plasma Extracellular Vesicles Identifies Syndecan-1 as a Potential Tool for Minimally Invasive Diagnosis of Glioma2019In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 25, no 10, p. 3115-3127Article in journal (Refereed)
    Abstract [en]

    Purpose: Liquid biopsy has great potential to improve the management of brain tumor patients at high risk of surgery-associated complications. Here, the aim was to explore plasma extracellular vesicle (plEV) immunoprofiling as a tool for noninvasive diagnosis of glioma. Experimental Design: PlEV isolation and analysis were optimized using advanced mass spectrometry, nanoparticle tracking analysis, and electron microscopy. We then established a new procedure that combines size exclusion chromatography isolation and proximity extension assay-based ultrasensitive immunoprofiling of plEV proteins that was applied on a well-defined glioma study cohort (n = 82). Results: Among potential candidates, we for the first time identify syndecan-1 (SDC1) as a plEV constituent that can discriminate between high-grade glioblastoma multiforme (GBM, WHO grade IV) and low-grade glioma [LGG, WHO grade II; area under the ROC curve (AUC): 0.81; sensitivity: 71%; specificity: 91%]. These findings were independently validated by ELISA. Tumor SDC1 mRNA expression similarly discriminated between GBM and LGG in an independent glioma patient population from The Cancer Genome Atlas cohort (AUC: 0.91; sensitivity: 79%; specificity: 91%). In experimental studies with GBM cells, we show that SDC1 is efficiently sorted to secreted EVs. Importantly, we found strong support of plEV(SDC1) originating from GBM tumors, as plEVSDC1 correlated with SDC1 protein expression in matched patient tumors, and plEV(SDC1) was decreased postoperatively depending on the extent of surgery. Conclusions: Our studies support the concept of circulating plEVs as a tool for noninvasive diagnosis and monitoring of gliomas and should move this field closer to the goal of improving the management of cancer patients.

  • 9.
    Ehinger, Erik
    et al.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Neurosurg, Lund, Sweden.;Lund Univ, Dept Clin Sci, Glioma Immunotherapy Grp, Neurosurg, Lund, Sweden..
    Kopecky, Jan
    Lund Univ, Dept Clin Sci, Glioma Immunotherapy Grp, Neurosurg, Lund, Sweden..
    Darabi, Anna
    Lund Univ, Dept Clin Sci, Glioma Immunotherapy Grp, Neurosurg, Lund, Sweden..
    Visse, Edward
    Lund Univ, Dept Clin Sci, Glioma Immunotherapy Grp, Neurosurg, Lund, Sweden..
    Edvardsson, Charlotte
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Neurosurg, Lund, Sweden..
    Tomasevic, Gregor
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Neurosurg, Lund, Sweden..
    Cederberg, David
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Neurosurg, Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Skåne Univ Hosp, Dept Clin Sci, Oncol, Lund, Sweden; Skåne Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden.
    Bengzon, Johan
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Neurosurg, Lund, Sweden.;Lund Univ, Lund Stem Cell Ctr, Dept Clin Sci, Lund, Sweden..
    Siesjö, Peter
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Neurosurg, Lund, Sweden.;Lund Univ, Dept Clin Sci, Glioma Immunotherapy Grp, Neurosurg, Lund, Sweden..
    Antisecretory factor is safe to use as add-on treatment in newly diagnosed glioblastoma2023In: BMC Neurology, E-ISSN 1471-2377, Vol. 23, no 1, article id 76Article in journal (Refereed)
    Abstract [en]

    Purpose

    Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite the best available treatment, prognosis remains poor. Current standard therapy consists of surgical removal of the tumor followed by radiotherapy and chemotherapy with the alkylating agent temozolomide (TMZ). Experimental studies suggest that antisecretory factor (AF), an endogenous protein with proposed antisecretory and anti-inflammatory properties, may potentiate the effect of TMZ and alleviate cerebral edema. Salovum is an egg yolk powder enriched for AF and is classified as a medical food in the European Union. In this pilot study, we evaluate the safety and feasibility of add-on Salovum in GBM patients.

    Methods

    Eight patients with newly diagnosed, histologically confirmed GBM were prescribed Salovum during concomitant radiochemotherapy. Safety was determined by the number of treatment-related adverse events. Feasibility was determined by the number of patients who completed the full prescribed Salovum treatment.

    Results

    No serious treatment-related adverse events were observed. Out of 8 included patients, 2 did not complete the full treatment. Only one of the dropouts was due to issues directly related to Salovum, which were nausea and loss of appetite. Median survival was 23 months.

    Conclusions

    We conclude that Salovum is safe to use as an add-on treatment for GBM. In terms of feasibility, adherence to the treatment regimen requires a determined and independent patient as the large doses prescribed may cause nausea and loss of appetite.

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    FULLTEXT01
  • 10.
    Feldt, Maria
    et al.
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden.;Skane Univ Hosp, Dept Oncol, Lund, Sweden..
    Menard, Julien
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden..
    Rosendahl, Ann H.
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden.;Skane Univ Hosp, Dept Oncol, Lund, Sweden..
    Lettiero, Barbara
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden..
    Bendahl, Pär-Ola
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden.;Skane Univ Hosp, Dept Oncol, Lund, Sweden..
    Borgquist, Signe
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden.;Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark..
    The effect of statin treatment on intratumoral cholesterol levels and LDL receptor expression: a window-of-opportunity breast cancer trial2020In: Cancer & Metabolism, E-ISSN 2049-3002, Vol. 8, article id 25Article in journal (Refereed)
    Abstract [en]

    Background: Deregulated lipid metabolism is common in cancer cells and the mevalonate pathway, which synthesizes cholesterol, is central in lipid metabolism. This study aimed to assess statin-induced changes of the intratumoral levels of cholesterol and the expression of the low-density lipoprotein receptor (LDLR) to enhance our understanding of the role of the mevalonate pathway in cancer cholesterol metabolism.

    Methods: This study is based on a phase II clinical trial designed as a window-of-opportunity trial including 50 breast cancer patients treated with 80 mg of atorvastatin/day for 2 weeks, between the time of diagnosis and breast surgery. Lipids were extracted from frozen tumor tissue sampled pre- and post-atorvastatin treatment. Intratumoral cholesterol levels were measured using a fluorometric quantitation assay. LDLR expression was evaluated by immunohistochemistry on formalin-fixed paraffin-embedded tumor tissue. Paired blood samples pre- and post-atorvastatin were analyzed for circulating low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A1, and apolipoprotein B. In vitro experiments on MCF-7 breast cancer cells treated with atorvastatin were performed for comparison on the cellular level.

    Results: In the trial, 42 patients completed all study parts. From the paired tumor tissue samples, assessment of the cholesterol levels was achievable for 14 tumors, and for the LDLR expression in 24 tumors. Following atorvastatin treatment, the expression of LDLR was significantly increased (P = 0.004), while the intratumoral levels of total cholesterol remained stable. A positive association between intratumoral cholesterol levels and tumor proliferation measured by Ki-67 expression was found. In agreement with the clinical findings, results from in vitro experiments showed no significant changes of the intracellular cholesterol levels after atorvastatin treatment while increased expression of the LDLR was found, although not reaching statistical significance.

    Conclusions: This study shows an upregulation of LDLR and preserved intratumoral cholesterol levels in breast cancer patients treated with statins. Together with previous findings on the anti-proliferative effect of statins in breast cancer, the present data suggest a potential role for LDLR in the statin-induced regulation of breast cancer cell proliferation.

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  • 11.
    Gezelius, E.
    et al.
    Lund Univ, Div Oncol, Dept Clin Sci, Barngatan 4, SE-22185 Lund, Sweden;Skane Univ Hosp, Dept Resp Med, Entregatan 7, SE-22185 Lund, Sweden.
    Bendahl, P. O.
    Lund Univ, Div Oncol, Dept Clin Sci, Barngatan 4, SE-22185 Lund, Sweden.
    de Oliveira, K. Goncalves
    Lund Univ, Div Oncol, Dept Clin Sci, Barngatan 4, SE-22185 Lund, Sweden.
    Ek, L.
    Skane Univ Hosp, Dept Resp Med, Entregatan 7, SE-22185 Lund, Sweden.
    Bergman, B.
    Sahlgrens Univ Hosp, Dept Resp Med, SE-41345 Gothenburg, Sweden.
    Sundberg, J.
    Skane Univ Hosp, Dept Hematol Radiophys & Oncol, Lasarettsgatan 23A, SE-22185 Lund, Sweden.
    Strandberg, K.
    Lund Univ, Inst Lab Med, Dept Clin Chem, Inga Marie Nilssons Gata 53, SE-21428 Malmo, Sweden.
    Kraemer, R.
    Heidelberg Univ, Inorgan Chem Inst, Neuenheimer Feld 270, D-60129 Heidelberg, Germany.
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Lund Univ, Div Oncol, Dept Clin Sci, Barngatan 4, SE-22185 Lund, Sweden;Skane Univ Hosp, Dept Hematol Radiophys & Oncol, Lasarettsgatan 23A, SE-22185 Lund, Sweden.
    Low-molecular-weight heparin adherence and effects on survival within a randomised phase III lung cancer trial (RASTEN)2019In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 118, p. 82-90Article in journal (Refereed)
    Abstract [en]

    Background: Coagulation activation is a hallmark of cancer, and anticoagulants have shown tumour-inhibiting properties. However, recent trials have failed to demonstrate improved survival with low-molecular-weight heparin (LMWH) in cancer populations. This has raised the question of suboptimal adherence as a possible explanation for the lack of benefit. Still, there is no standardised method to directly monitor LMWH in patient plasma. Here, we directly determine LMWH levels in patients using the Heparin Red assay to objectively assess adherence and how this associates with the patient outcome in the RASTEN trial. Methods: RASTEN is a multicentre, randomised phase III trial investigating if the addition of LMWH to standard therapy can improve survival in small-cell lung cancer. LMWH was measured in plasma (N = 258) by the Heparin Red assay and compared with the anti-factor Xa (anti-FXa) activity assay. Results: Both methods could differentiate patients in the LMWH arm from the control arm and patients receiving therapeutic LMWH owing to thrombosis. Receiver Operating Characteristic (ROC) analysis yielded adherence rates of 85% for anti-FXa and 68% for Heparin Red. No survival benefits were found in the adherent subgroup compared with the control arm (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 0.95-1.67; P = 0.105 and HR: 1.19; 95% CI: 0.89-1.60; P = 0.248 for anti-FXa and Heparin Red, respectively). Heparin Red could define patients with high probability of adherence to LMWH treatment, which warrants prospective studies for further validation. Our finding that the LMWH-adherent subpopulation did not show improved survival excludes that the negative outcome of RASTEN was due to poor adherence. (C) 2019 The Authors. Published by Elsevier Ltd.

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  • 12.
    Gezelius, Emelie
    et al.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Oncol, Barngatan 4, SE-22185 Lund, Sweden.
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Lund Univ, Skane Univ Hosp, Dept Clin Sci, Oncol, Barngatan 4, SE-22185 Lund, Sweden.
    Biomarkers of venous thromboembolism in cancer: a silent echo from local events?2019In: Biomarkers in Medicine, ISSN 1752-0363, E-ISSN 1752-0371, Vol. 13, no 7, p. 507-509Article in journal (Other academic)
  • 13.
    Gezelius, Emelie
    et al.
    Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Lund Univ Hosp, Dept Resp Med, Entregatan 7, SE-22185 Lund, Sweden..
    Bendahl, Paer-Ola
    Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden..
    Gallo, Widet
    Lund Univ, Clin Res Ctr, Hypertens & Cardiovasc Dis Grp, Dept Clin Sci,Skane Univ Hosp, Jan Waldenstroms Gata 35, SE-21428 Malmö, Sweden..
    de Oliveira, Kelin Goncalves
    Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden..
    Ek, Lars
    Lund Univ Hosp, Dept Resp Med, Entregatan 7, SE-22185 Lund, Sweden..
    Bergman, Bengt
    Sahlgrens Univ Hosp, Dept Resp Med, SE-41345 Gothenburg, Sweden..
    Sundberg, Jan
    Skane Univ Hosp, Dept Hematol Radiophys & Oncol, Lasarettsgatan 23A, SE-22185 Lund, Sweden..
    Melander, Olle
    Lund Univ, Clin Res Ctr, Hypertens & Cardiovasc Dis Grp, Dept Clin Sci,Skane Univ Hosp, Jan Waldenstroms Gata 35, SE-21428 Malmö, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Radiophys & Oncol, Lasarettsgatan 23A, SE-22185 Lund, Sweden..
    Circulating Levels of the Cardiovascular Biomarkers ST2 and Adrenomedullin Predict Outcome within a Randomized Phase III Lung Cancer Trial (RASTEN)2022In: Cancers, ISSN 2072-6694, Vol. 14, no 5, article id 1307Article in journal (Refereed)
    Abstract [en]

    Simple Summary Cardiovascular disease is common in patients with small cell lung cancer, partly reflecting its high correlation with smoking. Cardiovascular comorbidities may limit patient tolerance to cytotoxic drugs, thereby influencing the choice and intensity of treatment and, ultimately, patient survival. In light of the challenges relating to assessing cardiovascular status clinically in newly diagnosed lung cancer, objective biomarkers of cardiovascular vulnerability are warranted. Here, we show that circulating levels of ST2, an established biomarker in heart failure, and adrenomedullin, a vasodilator peptide known to reflect several aspects of cardiovascular status, strongly correlate with survival in small cell lung cancer. Our data, which are based on a large, randomized trial cohort, suggest the potential use of cardiovascular biomarkers in guiding clinicians in making individualized treatment decisions. Cardiovascular comorbidity is common in small cell lung cancer (SCLC) and may significantly affect treatment tolerability and patient outcome. Still, there are no established biomarkers for objective and dynamic assessment as a tool for improved treatment decisions. We have investigated circulating levels of midregional-pro-adrenomedullin (MR-proADM), midregional-pro-atrial-natriuretic peptide (MR-proANP), copeptin (surrogate for vasopressin) and suppression-of-tumorigenicity-2 (ST2), all known to correlate with various aspects of cardiovascular function, in a SCLC cohort (N = 252) from a randomized, controlled trial (RASTEN). For all measured biomarkers, protein levels were inversely associated with survival, particularly with ST2 and MR-proADM, where the top versus bottom quartile was associated with an adjusted hazard ratio of 2.40 (95% CI 1.44-3.98; p = 0.001) and 2.18 (95% CI 1.35-3.51; p = 0.001), respectively, in the entire cohort, and 3.43 (95% CI 1.73-6.79; p < 0.001) and 3.49 (95% CI 1.84-6.60; p < 0.001), respectively, in extensive disease patients. A high combined score of MR-proADM and ST2 was associated with a significantly reduced median OS of 7.0 months vs. 14.9 months for patients with a low combined score. We conclude that the cardiovascular biomarkers MR-proADM and ST2 strongly correlate with survival in SCLC, warranting prospective studies on the clinical utility of MR-proADM and ST2 for improved, individualized treatment decisions.

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  • 14.
    Godina, Christopher
    et al.
    Lund Univ, Dept Clin Sci Lund Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci Lund Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Skane, Sweden..
    Vallon-Christersson, Johan
    Lund Univ, Dept Clin Sci Lund Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden..
    Isaksson, Karolin
    Lund Univ, Dept Clin Sci Lund Surg, Kristianstad, Sweden.;Kristianstad Hosp, Kristianstad, Sweden..
    Bosch, Ana
    Lund Univ, Dept Clin Sci Lund Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Skane, Sweden..
    Jernström, Helena
    Lund Univ, Dept Clin Sci Lund Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden..
    Caveolin-1 gene expression provides additional prognostic information combined with PAM50 risk of recurrence (ROR) score in breast cancer2024In: Scientific Reports, E-ISSN 2045-2322, Vol. 14, article id 6675Article in journal (Refereed)
    Abstract [en]

    Combining information from the tumor microenvironment (TME) with PAM50 Risk of Recurrence (ROR) score could improve breast cancer prognostication. Caveolin-1 (CAV1) is a marker of an active TME. CAV1 is a membrane protein involved in cell signaling, extracellular matrix organization, and tumor-stroma interactions. We sought to investigate CAV1 gene expression in relation to PAM50 subtypes, ROR score, and their joint prognostic impact. CAV1 expression was compared between PAM50 subtypes and ROR categories in two cohorts (SCAN-B, n = 5326 and METABRIC, n = 1980). CAV1 expression was assessed in relation to clinical outcomes using Cox regression and adjusted for clinicopathological predictors. Effect modifications between CAV1 expression and ROR categories on clinical outcome were investigated using multiplicative and additive two-way interaction analyses. Differential gene expression and gene set enrichment analyses were applied to compare high and low expressing CAV1 tumors. All samples expressed CAV1 with the highest expression in the Normal-like subtype. Gene modules consistent with epithelial-mesenchymal transition (EMT), hypoxia, and stromal activation were associated with high CAV1 expression. CAV1 expression was inversely associated with ROR category. Interactions between CAV1 expression and ROR categories were observed in both cohorts. High expressing CAV1 tumors conferred worse prognosis only within the group classified as ROR high. ROR gave markedly different prognostic information depending on the underlying CAV1 expression. CAV1, a potential mediator between the malignant cells and TME, could be a useful biomarker that enhances and further refines PAM50 ROR risk stratification in patients with ROR high tumors and a potential therapeutic target.

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  • 15.
    Godina, Christopher
    et al.
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, SE-22185 Lund, Sweden..
    Chandran, Vineesh Indira
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, SE-22185 Lund, Sweden..
    Barbachowska, Magdalena
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, SE-22185 Lund, Sweden..
    Tryggvadottir, Helga
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Malmö, Sweden.;Skane Univ Hosp, Barngatan 4, SE-22185 Lund, Sweden..
    Nodin, Björn
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, Lund, Sweden.;Skane Univ Hosp, Lund, Sweden..
    Visse, Edward
    Lund Univ, Dept Clin Sci Lund, Div Neurosurg, Lund, Sweden.;Skane Univ Hosp, Lund, Sweden..
    Borgquist, Signe
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Aarhus Univ, Dept Oncol, Aarhus, Denmark.;Skane Univ Hosp, Barngatan 4, SE-22185 Lund, Sweden.;Aarhus Univ Hosp, Aarhus, Denmark..
    Jirström, Karin
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, Lund, Sweden.;Skane Univ Hosp, Lund, Sweden..
    Isaksson, Karolin
    Lund Univ, Dept Clin Sci Lund, Div Surg, Kristianstad, Sweden.;Kristianstad Hosp, Kristianstad, Sweden..
    Bosch, Ana
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Malmö, Sweden.;Skane Univ Hosp, Barngatan 4, SE-22185 Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Malmö, Sweden.;Skane Univ Hosp, Barngatan 4, SE-22185 Lund, Sweden..
    Jernström, Helena
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, SE-22185 Lund, Sweden..
    Interplay between Caveolin-1 and body and tumor size affects clinical outcomes in breast cancer2022In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 22, article id 101464Article in journal (Refereed)
    Abstract [en]

    Background: Caveolin-1 (CAV1) is associated with cholesterol-rich membrane raft domains and is a master regulator of cell signaling and membrane transport. Here, we investigated CAV1's role in cellular compartments of breast cancer in relation to signaling pathways, clinicopathological features, and clinical outcomes.

    Methods: CAV1 levels were evaluated with immunohistochemistry in cytoplasm of invasive tumor cells and stromal cells in tumor tissue microarrays from a cohort of 1018 breast cancer patients (inclusion 2002-2012, Sweden). Cytoplasmic and stromal CAV1 were categorized as positive/negative and strong/not strong, respectively. CAV1 expression in relation to clinical outcomes was assessed with Cox regression. Investigations into CAV1 functional pathways was conducted in the STRING, GOBO, and TCGA databases.

    Results: CAV1 expression was associated with non-luminal subtypes, cell cycle control, inflammation, epithelialmesenchymal transition, and the IGF/Insulin system. Generally, CAV1 was not associated with recurrence risk. Stromal CAV1's impact on recurrence risk was modified by BMI > 25 kg/m(2) (P-interaction = 0.002), waist > 80 cm (P-interaction = 0.005), and invasive tumor size (pT2/3/4) (P-interaction = 0.028). In low-risk patients only, strong stromal CAV1 significantly increased recurrence risk (HRs(adj) > 1.61). In all patients, positive cytoplasmic CAV1 conferred > 2-fold risk for contralateral disease HRadj 2.63 (95% CI 1.36-5.10). Strong stromal CAV1 conferred nearly 2-fold risk for locoregional recurrence HRadj 1.88 (95% CI 1.09-3.24).

    Conclusions: CAV1's prognostic impact depended on its localization, anthropometric, and tumor factors. Stromal CAV1 predicted high recurrence risk in a group of supposedly "low-risk' patients. Cytoplasmic CAV1 predicted metachronous contralateral disease. If confirmed, CAV1 could be used as treatment target and for risk stratification.

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  • 16.
    Godina, Christopher
    et al.
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden..
    Tryggvadottir, Helga
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Malmö, Sweden..
    Bosch, Ana
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Malmö, Sweden..
    Borgquist, Signe
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden.;Aarhus Univ, Dept Oncol, Aarhus, Denmark.;Aarhus Univ Hosp, Aarhus, Denmark..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Division of Oncology, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Barngatan 4, 221 85, Lund, Sweden; Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund and Malmö, Sweden.
    Isaksson, Karolin
    Lund Univ, Dept Clin Sci Lund, Div Surg, Lund, Sweden.;Kristianstad Hosp, Kristianstad, Sweden..
    Jernström, Helena
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden..
    Caveolin-1 genotypes as predictor for locoregional recurrence and contralateral disease in breast cancer2023In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 199, no 2, p. 335-347Article in journal (Refereed)
    Abstract [en]

    Purpose

    Caveolin-1 (CAV1) has been implicated in breast cancer oncogenesis and metastasis and may be a potential prognosticator, especially for non-distant events. CAV1 functions as a master regulator of membrane transport and cell signaling. Several CAV1 SNPs have been linked to multiple cancers, but the prognostic impact of CAV1 SNPs in breast cancer remains unclear. Here, we investigated CAV1 polymorphisms in relation to clinical outcomes in breast cancer.

    Methods

    A cohort of 1017 breast cancer patients (inclusion 2002–2012, Sweden) were genotyped using Oncoarray by Ilumina. Patients were followed for up to 15 years. Five out of six CAV1 SNPs (rs10256914, rs959173, rs3807989, rs3815412, and rs8713) passed quality control and were used for haplotype construction. CAV1 genotypes and haplotypes in relation to clinical outcomes were assessed with Cox regression and adjusted for potential confounders (age, tumor characteristics, and adjuvant treatments).

    Results

    Only one SNP was associated with lymph node status, no other SNPs or haplotypes were associated with tumor characteristics. The CAV1 rs3815412 CC genotype (5.8% of patients) was associated with increased risk of contralateral breast cancer, adjusted hazard ratio (HRadj) 4.26 (95% CI 1.86–9.73). Moreover, the TTACA haplotype (13% of patients) conferred an increased risk for locoregional recurrence HRadj 2.24 (95% CI 1.24–4.04). No other genotypes or haplotypes were associated with clinical outcome.

    Conclusion

    CAV1 polymorphisms were associated with increased risk for locoregional recurrence and contralateral breast cancer. These findings may identify patients that could derive benefit from more tailored treatment to prevent non-distant events, if confirmed.

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  • 17.
    Governa, Valeria
    et al.
    Lund Univ, Dept Clin Sci Lund, Sect Oncol, S-22185 Lund, Sweden..
    Talbot, Hugo
    Lund Univ, Dept Clin Sci Lund, Sect Oncol, S-22185 Lund, Sweden..
    de Oliveira, Kelin Goncalves
    Lund Univ, Dept Clin Sci Lund, Sect Oncol, S-22185 Lund, Sweden..
    Cerezo-Magana, Myriam
    Lund Univ, Dept Clin Sci Lund, Sect Oncol, S-22185 Lund, Sweden..
    Bång-Rudenstam, Anna
    Lund Univ, Dept Clin Sci Lund, Sect Oncol, S-22185 Lund, Sweden..
    Johansson, Maria C.
    Lund Univ, Dept Clin Sci Lund, Sect Oncol, S-22185 Lund, Sweden..
    Månsson, Ann-Sofie
    Lund Univ, Dept Clin Sci Lund, Sect Oncol, S-22185 Lund, Sweden..
    Forsberg Nilsson, Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Marko-Varga, György
    Lund Univ, Biomed Ctr, Dept Biomed Engn, Clin Prot Sci & Imaging, S-22185 Lund, Sweden.;Yonsei Univ, Coll Life Sci & Biotechnol, Dept Biotechnol, Chem Genom Global Res Lab, Seoul 03722, South Korea.;Tokyo Med Univ, Dept Surg 1, Tokyo 1608402, Japan..
    Perez, Julio Enriquez
    Lund Univ, Dept Clin Sci Lund, Sect Neurosurg, S-22185 Lund, Sweden..
    Darabi, Anna
    Lund Univ, Dept Clin Sci Lund, Sect Neurosurg, S-22185 Lund, Sweden..
    Malmström, Johan
    Lund Univ, Dept Clin Sci Lund, Div Infect Med, S-22185 Lund, Sweden..
    Bengzon, Johan
    Lund Univ, Dept Clin Sci Lund, Sect Neurosurg, S-22185 Lund, Sweden.;Lund Univ, Lund Stem Cell Ctr, Dept Clin Sci, S-22185 Lund, Sweden..
    Welinder, Charlotte
    Lund Univ, Dept Clin Sci Lund, Sect Oncol, S-22185 Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci Lund, Sect Oncol, S-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, S-22185 Lund, Sweden..
    Landscape of surfaceome and endocytome in human glioma is divergent and depends on cellular spatial organization2022In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, no 9, article id e2114456119Article in journal (Refereed)
    Abstract [en]

    Therapeutic strategies directed at the tumor surfaceome (TS), including checkpoint inhibitor blocking antibodies, antibody drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cells, provide a new armament to fight cancer. However, a remaining bottleneck is the lack of strategies to comprehensively interrogate patient tumors for potential TS targets. Here, we have developed a platform (tumor surfaceome mapping [TS-MAP]) integrated with a newly curated TS classifier (SURFME) that allows profiling of primary 3D cultures and intact patient glioma tumors with preserved tissue architecture. Moreover, TS-MAP specifically identifies proteins capable of endocytosis as tractable targets for ADCs and other modalities requiring toxic payload internalization. In high-grade gliomas that remain among the most aggressive forms of cancer, we show that cellular spatial organization (2D vs. 3D) fundamentally transforms the surfaceome and endocytome (e.g., integrins, proteoglycans, semaphorins, and cancer stem cell markers) with general implications for target screening approaches, as exemplified by an ADC targeting EGFR. The TS-MAP platform was further applied to profile the surfaceome and endocytome landscape in a cohort of freshly resected gliomas. We found a highly diverse TS repertoire between patient tumors, not directly associated with grade and histology, which highlights the need for individualized approaches. Our data provide additional layers of understanding fundamental to the future development of immunotherapy strategies, as well as procedures for proteomics-based target identification and selection. The TS-MAP platform should be widely applicable in efforts aiming at a better understanding of how to harness the TS for personalized immunotherapy.

  • 18.
    Jujic, Amra
    et al.
    Lund Univ, Dept Clin Sci Malmö, Malmö, Sweden.;Skane Univ Hosp, Dept Cardiol, Malmö, Sweden.;Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ, Clin Res Ctr, Box 50332, S-20213 Malmö, Sweden..
    Godina, Christopher
    Lund Univ, Dept Clin Sci Lund, Oncol, Lund, Sweden.;Skane Univ Hosp, Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci Lund, Oncol, Lund, Sweden.;Skane Univ Hosp, Lund, Sweden..
    Melander, Olle
    Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmö, Sweden..
    Holst, Jens Juul
    Panum Inst, Dept Biomed Sci, Copenhagen, Denmark.;NNF Ctr Basal Metab Res, Panum Inst, Copenhagen, Denmark.;Univ Copenhagen, NNF Ctr Basal Metab Res, Copenhagen, Denmark..
    Ahlqvist, Emma
    Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmö, Sweden..
    Gomez, Maria F.
    Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmö, Sweden..
    Nilsson, Peter M.
    Lund Univ, Dept Clin Sci Malmö, Malmö, Sweden..
    Jernström, Helena
    Lund Univ, Dept Clin Sci Lund, Oncol, Lund, Sweden.;Skane Univ Hosp, Lund, Sweden..
    Magnusson, Martin
    Lund Univ, Dept Clin Sci Malmö, Malmö, Sweden.;Skane Univ Hosp, Dept Cardiol, Malmö, Sweden.;Lund Univ, Wallenberg Ctr Mol Med, Malmö, Sweden.;Northwest Univ Potchefstroom, Hypertens Afr Res Team HART, Potchefstroom, South Africa..
    Endogenous incretin levels and risk of first incident cancer: a prospective cohort study2023In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, article id 382Article in journal (Refereed)
    Abstract [en]

    Concerns have been raised regarding a potentially increased risk of cancer associated with treatment with glucagon-like peptide-1 (GLP-1) receptor agonists. Here, we explored whether fasting and oral glucose tolerance test post-challenge glucose-dependent insulinotropic peptide (GIP) and GLP-1 levels were associated with incident first cancer. Within the cardiovascular re-examination arm of the population-based Malmo Diet Cancer study (n = 3734), 685 participants with a previous cancer diagnosis were excluded, resulting in 3049 participants (mean age 72.2 +/- 5.6 years, 59.5% women), of whom 485 were diagnosed with incident first cancer (median follow-up time 9.9 years). Multivariable Cox-regression and competing risk regression (death as competing risk) were used to explore associations between incretin levels and incident first cancer. Higher levels of fasting GLP-1 (462 incident first cancer cases/2417 controls) showed lower risk of incident first cancer in competing risk regression (sub-hazard ratio 0.90; 95% confidence interval 0.82-0.99; p = 0.022). No association was seen for fasting GIP, post-challenge GIP, or post-challenge GLP-1 and incident first cancer. In this prospective study, none of the fasting and post-challenge levels of GIP and GLP-1 were associated with higher risk of incident first cancer; by contrast, higher levels of fasting GLP-1 were associated with lower risk of incident first cancer.

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  • 19.
    Li, Jiaxin
    et al.
    Lund Univ, Stem Cell Ctr, Lund, Sweden.;Lund Univ, Dept Clin Sci, Div Neurosurg, Lund, Sweden..
    Ek, Fredrik
    Lund Univ, Dept Expt Med Sci, Chem Biol & Therapeut, Lund, Sweden..
    Olsson, Roger
    Lund Univ, Dept Expt Med Sci, Chem Biol & Therapeut, Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Sect Oncol, Dept Clin Sci, Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden..
    Bengzon, Johan
    Lund Univ, Stem Cell Ctr, Lund, Sweden.;Lund Univ, Dept Clin Sci, Div Neurosurg, Lund, Sweden.;Skane Univ Hosp, Dept Neurosurg, Lund, Sweden..
    Glioblastoma CD105(+) cells define a SOX2(-) cancer stem cell-like subpopulation in the pre-invasive niche2022In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 10, article id 126Article in journal (Refereed)
    Abstract [en]

    Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. Glioma stem like cells (GSC) represent the highest cellular hierarchy in GBM and have a determining role in tumor growth, recurrence and patient prognosis. However, a better definition of GSC subpopulations, especially at the surgical resection margin, is warranted for improved oncological treatment options. The present study interrogated cells expressing CD105 (CD105(+)) specifically within the tumor front and the pre-invasive niche as a potential GSC subpopulation. GBM primary cell lines were generated from patients (n = 18) and CD105(+) cells were isolated and assessed for stem-like characteristics. In vitro, CD105(+) cells proliferated and enriched in serum-containing medium but not in serum-free conditions. CD105(+) cells were characterized by Nestin(+), Vimentin(+) and SOX2(-), clearly distinguishing them from SOX2(+) GCS. GBM CD105(+) cells differentiated into osteocytes and adipocytes but not chondrocytes. Exome sequencing revealed that GBM CD105(+) cells matched 83% of somatic mutations in the Cancer cell line encyclopedia, indicating a malignant phenotype and in vivo xenotransplantation assays verified their tumorigenic potential. Cytokine assays showed that immunosuppressive and protumorigenic cytokines such as IL6, IL8, CCL2, CXCL-1 were produced by CD105(+) cells. Finally, screening for 88 clinical drugs revealed that GBM CD105(+) cells are resistant to most chemotherapeutics except Doxorubicin, Idarubicin, Fludarabine and ABT-751. Our study provides a rationale for targeting tumoral CD105(+) cells in order to reshape the tumor microenvironment and block GBM progression.

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  • 20.
    Pocas, Juliana
    et al.
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal.;Univ Porto, ICBAS Inst Ciencias Biomed Abel Salazar, P-4050313 Porto, Portugal..
    Marques, Catarina
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal.;Univ Porto, ICBAS Inst Ciencias Biomed Abel Salazar, P-4050313 Porto, Portugal..
    Gomes, Catarina
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal..
    Otake, Andreia Hanada
    Univ Sao Paulo, Hosp Clin HCFMUSP, Fac Med, Inst Canc Estado Sao Paulo, BR-01246000 Sao Paulo, Brazil.;Champalimaud Fdn, Champalimaud Physiol & Canc Programme, P-1400038 Lisbon, Portugal..
    Pinto, Filipe
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal..
    Ferreira, Mariana
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal..
    Silva, Tiago
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal..
    Faria-Ramos, Isabel
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal..
    Matos, Rita
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal..
    Ribeiro, Ana Raquel
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal..
    Senra, Emanuel
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal..
    Cavadas, Bruno
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal..
    Batista, Silvia
    Champalimaud Fdn, Champalimaud Physiol & Canc Programme, P-1400038 Lisbon, Portugal..
    Maia, Joana
    Champalimaud Fdn, Champalimaud Physiol & Canc Programme, P-1400038 Lisbon, Portugal..
    Macedo, Joana A.
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal..
    Lima, Luis
    Portuguese Oncol Inst Porto IPO Porto, Res Ctr IPO Porto CI IPOP RISE CI IPOP, Hlth Res Network, Expt Pathol & Therapeut Grp, P-4200072 Porto, Portugal..
    Afonso, Luis Pedro
    Portuguese Oncol Inst Porto IPO Porto, Res Ctr IPO Porto CI IPOP RISE CI IPOP, Hlth Res Network, Expt Pathol & Therapeut Grp, P-4200072 Porto, Portugal..
    Ferreira, José Alexandre
    Portuguese Oncol Inst Porto IPO Porto, Res Ctr IPO Porto CI IPOP RISE CI IPOP, Hlth Res Network, Expt Pathol & Therapeut Grp, P-4200072 Porto, Portugal..
    Santos, Lúcio Lara
    Portuguese Oncol Inst Porto IPO Porto, Res Ctr IPO Porto CI IPOP RISE CI IPOP, Hlth Res Network, Expt Pathol & Therapeut Grp, P-4200072 Porto, Portugal..
    Polónia, António
    Osório, Hugo
    Univ Porto, FMUP Fac Med, P-4200319 Porto, Portugal..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci, Sect Oncol, S-22184 Lund, Sweden; Skane Univ Hosp, S-22185 Lund, Sweden.
    Reis, Celso A.
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal.;Univ Porto, ICBAS Inst Ciencias Biomed Abel Salazar, P-4050313 Porto, Portugal.;Univ Porto, FMUP Fac Med, P-4200319 Porto, Portugal..
    Costa-Silva, Bruno
    Champalimaud Fdn, Champalimaud Physiol & Canc Programme, P-1400038 Lisbon, Portugal..
    Magalhães, Ana
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal.;Univ Porto, ICBAS Inst Ciencias Biomed Abel Salazar, P-4050313 Porto, Portugal..
    Syndecan-4 is a maestro of gastric cancer cell invasion and communication that underscores poor survival2023In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, no 20, article id e2214853120Article in journal (Refereed)
    Abstract [en]

    Gastric cancer is a dominating cause of cancer-associated mortality with limited therapeutic options. Here, we show that syndecan-4 (SDC4), a transmembrane pro-teoglycan, is highly expressed in intestinal subtype gastric tumors and that this sig -nature associates with patient poor survival. Further, we mechanistically demonstrate that SDC4 is a master regulator of gastric cancer cell motility and invasion. We also find that SDC4 decorated with heparan sulfate is efficiently sorted in extracellular vesicles (EVs). Interestingly, SDC4 in EVs regulates gastric cancer cell-derived EV organ distribution, uptake, and functional effects in recipient cells. Specifically, we show that SDC4 knockout disrupts the tropism of EVs for the common gastric cancer metastatic sites. Our findings set the basis for the molecular implications of SDC4 expression in gastric cancer cells and provide broader perspectives on the development of therapeutic strategies targeting the glycan-EV axis to limit tumor progression.

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    fulltext
  • 21.
    Slipsager, Anna
    et al.
    Aalborg Univ Hosp, Dept Oncol, Aalborg, Denmark.;Aalborg Univ Hosp, Clin Canc Res Ctr, Aalborg, Denmark.;Aalborg Univ, Dept Clin Med, Aalborg, Denmark.;Dept Oncol, Hobrovej 18-22, DK-9000 Aalborg, Denmark..
    Henrichsen, Sofie N.
    Aalborg Univ Hosp, Clin Canc Res Ctr, Aalborg, Denmark.;Aalborg Univ, Dept Clin Med, Aalborg, Denmark..
    Falkmer, Ursula G.
    Aalborg Univ Hosp, Dept Oncol, Aalborg, Denmark.;Aalborg Univ Hosp, Clin Canc Res Ctr, Aalborg, Denmark.;Aalborg Univ, Dept Clin Med, Aalborg, Denmark..
    Dybkaer, Karen
    Aalborg Univ, Dept Clin Med, Aalborg, Denmark.;Aalborg Univ Hosp, Dept Hematol, Aalborg, Denmark..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Lund Univ, Dept Clin Sci, Lund, Sweden.
    Poulsen, Laurids Ø.
    Aalborg Univ Hosp, Dept Oncol, Aalborg, Denmark.;Aalborg Univ Hosp, Clin Canc Res Ctr, Aalborg, Denmark.;Aalborg Univ, Dept Clin Med, Aalborg, Denmark..
    Predictive biomarkers in radioresistant rectal cancer: A systematic review2023In: Critical reviews in oncology/hematology, ISSN 1040-8428, E-ISSN 1879-0461, Vol. 186, article id 103991Article, review/survey (Refereed)
    Abstract [en]

    Background and aims

    The treatment of locally advanced rectal cancer often consists of neoadjuvant chemoradiotherapy followed by surgery. However, approximately 15% of patients show no response to this neoadjuvant chemoradiotherapy. This systematic review aimed to identify biomarkers of innate radioresistant rectal cancer.

    Method

    Through a systematic literature search, 125 papers were included and analyzed using ROBINS-I, a Cochrane risk of bias tool for non-randomized studies of interventions. Both statistically significant and nonsignificant biomarkers were identified. Biomarkers mentioned more than once in the results or biomarkers with a low or moderate risk of bias were included as the final results.

    Results

    Thirteen unique biomarkers, three genetic signatures, one specific pathway, and two combinations of two or four biomarkers were identified. In particular, the connection between HMGCS2, COASY, and PI3K-pathway seems promising. Future scientific research should focus on further validating these genetic resistance markers.

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    fulltext
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