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Endostatin Binding to Ovarian Cancer Cells Inhibits Peritoneal Attachment and Dissemination

Departments of ¹ Pharmacology, ² Biomedical Image Processing Laboratory, ³ Obstetrics and Gynecology, and ⁴ Cancer Center, University of Minnesota, Minneapolis, Minnesota

Requests for reprints: S. Ramakrishnan, Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street Southeast, Minneapolis, MN 55455. Phone: 612-624-1461; Fax: 612-625-8408; E-mail: sunda001{at}umn.edu.

Ovarian cancer cells use integrins to attach to the peritoneal wall. Integrin ₅ß₁ 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 ₅ß₁ 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 ₅ and ß₁ 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. [Cancer Res 2007;67(22):10813–22]