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Genetic deficiency in plasma protein HRG enhances tumor growth and metastasis by exacerbating immune escape and vessel abnormalization
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
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2012 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445Article in journal (Refereed) Published
Abstract [en]

Histidine-rich glycoprotein (HRG) is a 75 kDa heparin-binding plasma protein implicated in the regulation of tumor growth and vascularization. In this study, we show that hrg-/- mice challenged with fibrosarcoma or pancreatic carcinomas grow larger tumors with increased metastatic properties. Compared with wild type mice, fibrosarcomas in hrg-/- mice were more hypoxic, necrotic and less perfused, indicating enhanced vessel abnormalization. HRG-deficiency was associated with a suppressed anti-tumor immune response, with both increased infiltration of M2-marker-expressing macrophages and decreased infiltration of dendritic cells and cytotoxic T cells. Analysis of transcript expression in tumor-associated as well as peritoneal macrophages from hrg-/- mice revealed an increased expression of genes associated with a pro-angiogenic and immunoinhibitory phenotype. In accordance, expression arrays performed on HRG-treated peritoneal macrophages showed induction of genes involved in extracellular matrix biology and immune responsiveness. In conclusion, our findings demonstrate that macrophages are a direct target of HRG. HRG loss influences macrophage gene regulation, leading to excess stimulation of tumor angiogenesis, suppression of tumor immune response, and increased tumor growth and metastatic spread.

Place, publisher, year, edition, pages
2012.
National Category
Clinical Laboratory Medicine
Research subject
Pathology
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URN: urn:nbn:se:uu:diva-170988DOI: 10.1158/0008-5472.CAN-11-2194ISI: 000302905700007PubMedID: 22374984OAI: oai:DiVA.org:uu-170988DiVA: diva2:510002
Available from: 2012-03-14 Created: 2012-03-14 Last updated: 2017-12-07Bibliographically approved

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Tugues, SòniaHonjo, SatoshiNoguer, OriolHedlund, MarieBotling, JohanClaesson-Welsh, Lena

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Tugues, SòniaHonjo, SatoshiNoguer, OriolHedlund, MarieBotling, JohanClaesson-Welsh, Lena
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Cancer and Vascular BiologyDepartment of Immunology, Genetics and PathologyMolecular and Morphological Pathology
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Cancer Research
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