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Two different PDGF beta-receptor cohorts in human pericytes mediate distinct biological endpoints
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. 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 Medical Biochemistry and Microbiology.
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2009 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 175, no 1, 171-189 p.Article in journal (Refereed) Published
Abstract [en]

How activation of a specific growth factor receptor selectively results in either cell proliferation or cytoskeletal reorganization is of central importance to the field of pathophysiology. In this study, we report on a novel mechanism that explains how this process is accomplished. Our current investigation demonstrates that soluble platelet derived growth factor- (PDGF)-BB activates a cohort of PDGF-beta receptors primarily confined to the lipid raft component of the cell membrane, specifically caveolae. In contrast, cell-bound PDGF-BB delivered via cell-cell contact results in activation and the subsequent up-regulation of a cohort of PDGF beta-receptors primarily confined to the non-lipid raft component of the cell membrane. Individual activation of these two receptor cohorts results in distinct biological endpoints, cytoskeletal reorganization or cell proliferation. Mechanistically, our evidence suggests that PDGF-BB-bearing cells preferentially stimulate the non-lipid raft receptor cohort through interleukin 1beta-mediated inhibition of the lipid raft cohort of receptors, leaving the non-raft receptor cohort operational and preferentially stimulated. In human skin injected with PDGF-BB and in tissue reparative processes PDGF beta-receptors colocalize with the caveolae/lipid raft marker caveolin-1. In contrast, in human skin injected with PDGF-BB-bearing tumor cells and in colorectal adenocarcinoma, activated PDGF beta-receptors do not colocalize with caveolin-1. Thus, growth factor receptors are segregated into specific cell membrane compartments that are preferentially activated through different mechanisms of ligand delivery, resulting in distinct biological endpoints.

Place, publisher, year, edition, pages
2009. Vol. 175, no 1, 171-189 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-119729DOI: 10.2353/ajpath.2009.080769ISI: 000267508600016PubMedID: 19497991OAI: oai:DiVA.org:uu-119729DiVA: diva2:300750
Available from: 2010-03-01 Created: 2010-03-01 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Extracellular Matrix and Connective Tissue Cells of the Tumor Microenvironment
Open this publication in new window or tab >>Extracellular Matrix and Connective Tissue Cells of the Tumor Microenvironment
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In addition to malignant cells, solid tumors comprise supporting stromal tissue that consists of extra cellular matrix (ECM), connective tissue cells, inflammatory cells and blood vessels. The stromal compartment and the malignant cells together shape the tumor microenvironment that in turn determines tumor progression and efficacy of anti-tumor treatments. In this thesis, studies that investigate the roles of different kinds of interactions between tumor cells and stromal cells were undertaken. Further, growth factors that have important roles in interactions between tumor cells and stromal cells were investigated in a non-tumor environment. Tumor cells were found to modulate the response to the platelet derived growth factor  (PDGF) by microvascular pericytes, a cell type found in the vasculature of solid tumors. The importance of this growth factor in biology of tumors has earlier been shown, but here it was shown that PDGF also modulate the ECM phenotype of solid tumors. The ECM of tumors treated with an inhibitor of PDGF receptor (PDGFR) signaling induced a less fibrotic collagen scaffold, which could explain how PDGFR inhibition in earlier reports lowered tumor interstitial fluid pressure (IFP). Lowering the normally high IFP in tumors increases efficacy of chemotherapy. The integrin αVβ3 is activated downstream of PDGF-B in acute inflammations, and this integrin is important for raising IFP in loose connective tissue in such conditions. However, in tumors we found that lack of the β3 subunit lead to an increased IFP, which were attributed to a more fibrotic ECM phenotype. In addition to PDGF-B, transforming growth factor β (TGFβ) is an important growth factor in the biology of tumors. These two growth factors were separately overexpressed in mouse skin and they both induced an inflammatory response. Expressed in a tumor free context, they evoked a response that was in many ways reminiscent of what can be observed in the tumor microenvironment. This thesis contributes further understanding of how the complex tumor microenvironment affects the phenotype of solid tumors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 89 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 613
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell and Molecular Biology Cell and Molecular Biology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-132855 (URN)978-91-554-7927-5 (ISBN)
Public defence
2010-12-09, B21, BMC, Husargatan 3, Uppsala, 10:00 (English)
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Available from: 2010-11-17 Created: 2010-10-27 Last updated: 2011-01-13Bibliographically approved

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