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Activated platelets provide a functional microenvironment for the antiangiogenic fragment of histidine-rich glycoprotein
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
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2009 (English)In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 7, no 11, 1792-1802 p.Article in journal (Refereed) Published
Abstract [en]

The angiogenesis inhibitor histidine-rich glycoprotein (HRG) constitutes one of several examples of molecules regulating both angiogenesis and hemostasis. The antiangiogenic properties of HRG are mediated via its proteolytically released histidine- and proline-rich (His/Pro-rich) domain.Using a combination of immunohistochemistry and massspectrometry, we here provide biochemical evidence for thepresence of a proteolytic peptide, corresponding to the antiangiogenic domain of HRG, in vivo in human tissue. This finding supports a role for HRG as an endogenous regulator of angiogenesis. Interestingly, the His/Pro-rich peptide bound to the vessel wall in tissue from cancer patients but not to the vasculature in tissue from healthy persons.Moreover, the His/Pro-rich peptide was found in close association with platelets. Relesate from in vitro–activated platelets promoted binding of the His/Pro-rich domain of HRG to endothelial cells, an effect mediated by Zn2+.Previous studies have shown that zinc-dependent bindingof the His/Pro-rich domain of HRG to heparan sulfate on endothelial cells is required for inhibition of angiogenesis.We describe a novel mechanism to increase the local concentration and activity of an angiogenesis inhibitor,which may reflect a host response to counteract angiogenesis during pathologic conditions. Our finding that tumor angiogenesis is elevated in HRG-deficient mice supports this conclusion.

Place, publisher, year, edition, pages
2009. Vol. 7, no 11, 1792-1802 p.
Keyword [en]
histidine-rich glycoprotein, angiogenesis, cancer, platelets
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-110827DOI: 10.1158/1541-7786.MCR-09-0094ISI: 000272006300005PubMedID: 19903770OAI: oai:DiVA.org:uu-110827DiVA: diva2:278488
Available from: 2009-11-26 Created: 2009-11-26 Last updated: 2017-12-12Bibliographically approved
In thesis
1. The Role of Histidine-rich Glycoprotein in Angiogenesis and Tumor Growth
Open this publication in new window or tab >>The Role of Histidine-rich Glycoprotein in Angiogenesis and Tumor Growth
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Histidine-rich glycoprotein (HRG) is a heparin-binding plasma protein modulating immune, hemostatic and vascular functions. I have studied the antiangiogenic functions of HRG in vitro and in vivo in order to understand the molecular mechanisms of action of HRG as an angiogenesis inhibitor.

Angiogenesis is the formation of new blood vessels from the pre-existing vasculature. It is a central rate-limiting step of tumor development and thus a possible target for cancer therapeutics. Previous studies have shown that HRG has antiangiogenic functions in vivo and that the antiangiogenic effects are mediated via the proteolytically released His/Pro-rich domain of HRG. In this thesis we demonstrate that HRG can inhibit endothelial cell migration by interfering with focal adhesion and cytoskeletal turnover. Moreover we have identified the minimal active domain of HRG, a 35 amino acid peptide derived from the histidine- and proline-rich domain of HRG.

Analyzing human tumor tissue samples, we have found that a His/Pro-rich fragment of HRG is bound to the vasculature from cancer patients but not to the vasculature from healthy individuals. The fragment is found in association with platelets, and we show that activated platelets can induce a functional microenvironment for the His/Pro-rich fragment. Cancer patients often display an increased coagulation and our data describe a new mechanism to confer specificity of an angiogenesis inhibitor for situations with enhanced platelet activation, as in the tumor.

We have further studied the role of HRG in tumor growth by crossing HRG-deficient mice with a transgenic mouse model of pancreatic insulinoma. We show that mice lacking HRG display an elevated “angiogenic switch” and that the total tumor volume is larger in these mice than in wild type mice. HRG is also involved in regulation of platelet function and platelets can stimulate angiogenesis in various ways. We have depleted mice of platelets to study the possible connection between the function of HRG in angiogenesis and platelet regulation. Our data suggest an involvement of platelets in the antiangiogenic activities of HRG.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 505
Keyword
Histidine-rich glycoprotein, HRG/HRGP/HPRG, angiogenesis inhibitor, cancer, VEGF, platelets
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:uu:diva-110829 (URN)978-91-554-7674-8 (ISBN)
Public defence
2010-01-16, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2009-12-22 Created: 2009-11-26 Last updated: 2011-02-28Bibliographically approved

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Thulin, ÅsaRingvall, MariaDimberg, AnnaSiegbahn, AgnetaOlsson, Anna-Karin

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Thulin, ÅsaRingvall, MariaDimberg, AnnaSiegbahn, AgnetaOlsson, Anna-Karin
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Department of Medical Biochemistry and MicrobiologyDepartment of Genetics and PathologyDepartment of Women's and Children's HealthDepartment of Oncology, Radiology and Clinical ImmunologyClinical ImmunologyDepartment of Medical Sciences
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