Binding of endostatin to human ovarian cancer cells inhibits cell attachment.
Endostatin, a C-terminal fragment of collagen type XVIII, is one of the well-characterized endogenous inhibitors of angiogenesis. Endostatin is known to bind integrin alpha(5)beta(1), which is upregulated on tumor endothelium. Most of the ovarian cancer cells express significant amounts of alpha(5)beta(1) integrin, which is important for ovarian cancer cells to attach to the peritoneal wall. Therefore we investigated whether endostatin could directly bind ovarian cancer cells and inhibit tumor cell attachment to extracellular matrix. Binding of endostatin to ovarian cancer cells was characterized by preincubation with function blocking antibodies to integrin subunits. These studies showed that ovarian cancer cell attachment to fibronectin-coated wells can be inhibited by alpha(5)beta(1) integrin specific antibodies as well as endostatin. Downregulation of integrin alpha(5) and beta(1) by siRNA abrogated the binding of OVCAR5 and human umbilical vein endothelial cell to endostatin. Although endostatin treatment did not affect ovarian cancer cell migration, treated cells failed to attach mouse peritoneal wall preparations. These studies suggest an extra-antiangiogenic role for endostatin, which can be used prevent peritoneal attachment and dissemination of ovarian cancer cells.
Yokoyama
Yumi
Y
Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.
Ramakrishnan
S
S
D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D043169:Endostatins / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D039081:Integrin alpha5beta1 / Q000187:drug effects / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000517:prevention & control* / Q000556:secondary; D034741:RNA, Small Interfering / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D043169:Endostatins; D005353:Fibronectins; D039081:Integrin alpha5beta1; D016023:Integrins; D034741:RNA, Small Interfering