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Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein
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 Genetics and Pathology.
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 Genetics and Pathology.
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2006 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, no 4, 2089-97 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
2006. Vol. 66, no 4, 2089-97 p.
Keyword [en]
Actinin/metabolism, Amino Acid Sequence, Animals, Cattle, Cell Movement/drug effects/physiology, Endothelial Cells/cytology/*drug effects, Focal Adhesion Protein-Tyrosine Kinases/metabolism, Integrin alphaVbeta3/metabolism, Molecular Sequence Data, Neovascularization; Physiologic/*drug effects, Paxillin/antagonists & inhibitors/biosynthesis, Peptide Fragments/chemistry/*pharmacology, Phosphorylation/drug effects, Protein Structure; Tertiary, Protein-Serine-Threonine Kinases/metabolism, Proteins/chemistry/*pharmacology, Research Support; Non-U.S. Gov't, Vascular Endothelial Growth Factor A/antagonists & inhibitors/metabolism/pharmacology, Vascular Endothelial Growth Factor Receptor-2/metabolism
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-80197DOI: 10.1158/0008-5472.CAN-05-2217PubMedID: 16489009OAI: oai:DiVA.org:uu-80197DiVA: diva2:108111
Available from: 2006-05-03 Created: 2006-05-03 Last updated: 2011-06-28Bibliographically 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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Olsson, Anna-KarinClaesson-Welsh, Lena

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