A fragment of histidine-rich glycoprotein is a potent inhibitor of tumor vascularization.
In this study, we show that recombinant human histidine-rich glycoprotein (HRGP) has potent antiangiogenic properties as judged from effects on a syngeneic tumor model in C57/bl6 mice. Growth of fibrosarcoma, a very aggressive tumor, was reduced by >60% by HRGP treatment, and tumor angiogenesis was dramatically decreased. Treatment with HRGP led to increased apoptosis and reduced proliferation in the tumors. In contrast, HRGP did not affect apoptosis or DNA synthesis in endothelial cells or tumor cells in vitro. The mechanism of action of HRGP involves rearrangement of focal adhesions and decreased attachment of endothelial cells to vitronectin and, as a consequence, reduced endothelial cell migration. By using truncated versions of HRGP, we demonstrate that the isolated 150 amino acid-residue His/Pro-rich domain, which is also released by spontaneous proteolysis from purified HRGP, mediates the inhibitory effect on chemotaxis. Moreover, the His/Pro-rich domain must be released from HRGP to exert its effect. This study shows for the first time inhibitory effects of HRGP on tumor vascularization in vivo, thus providing proof of concept that HRGP is an angiogenesis inhibitor.
Olsson
Anna-Karin
AK
Department of Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
Larsson
Helena
H
Dixelius
Johan
J
Johansson
Irja
I
Lee
Chunsik
C
Oellig
Cornelia
C
Björk
Ingemar
I
Claesson-Welsh
Lena
L
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta; D001859:Bone Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D002448:Cell Adhesion / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005354:Fibrosarcoma / Q000098:blood supply* / Q000188:drug therapy; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010446:Peptide Fragments / Q000494:pharmacology*; D011506:Proteins / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine; D000099053:Histidine-Rich Glycoprotein
D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D011506:Proteins; D011994:Recombinant Proteins; D000099053:Histidine-Rich Glycoprotein