Endostatin binding to ovarian cancer cells inhibits peritoneal attachment and dissemination.
Ovarian cancer cells use integrins to attach to the peritoneal wall. Integrin alpha(5)beta(1) is also the target for the angiogenesis inhibitor, endostatin. Therefore, the ability of endostatin to competitively inhibit tumor cell seeding of the peritoneum was investigated. An imaging method was developed to determine early phases of peritoneal dissemination of ovarian cancer cells. Using this method, endostatin was found to bind ovarian cancer cells through integrin alpha(5)beta(1) and inhibit vessel cooption efficiently. Although both angiostatin and endostatin are potent inhibitors of tumor angiogenesis, peritoneal attachment and vessel cooption was blocked only by the endostatin. Knocking down the expression of integrins alpha(5) and beta(1) in ovarian cancer cells interfered with endostatin-mediated inhibition of peritoneal seeding. Furthermore, adenovirus-mediated in situ expression of endostatin either inside the peritoneum or by the ovarian tumor cells inhibited peritoneal seeding and dissemination in vivo. Endostatin treatment also prevented primary ovarian cancer cells from attaching to mouse peritoneal wall. These studies show a paraendothelial mechanism by which endostatin can inhibit peritoneal dissemination of ovarian cancer cells and raises the possibility of intraperitoneal expression of endostatin to reduce recurrence.
Yokoyama
Yumi
Y
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Sedgewick
Gerald
G
Ramakrishnan
S
S
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D043169:Endostatins / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D039482:Integrin alpha5 / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010537:Peritoneum / Q000378:metabolism*; D011485:Protein Binding
D043169:Endostatins; D039482:Integrin alpha5; D019012:Integrin beta1