Abstract
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.
Highlights
Ovarian cancer is estimated to occur in 22,430 women in the year 2007 and remains to be the leading cause of death among gynecologic cancers [1]
We have shown that human endostatin can bind to ovarian cancer cells and inhibit cell attachment to fibronectin-coated plates in vitro
To further understand which one of the integrin complex is involved in this process, a panel of ovarian cancer cell lines was compared for integrin expression and endostatin binding
Summary
Ovarian cancer is estimated to occur in 22,430 women in the year 2007 and remains to be the leading cause of death among gynecologic cancers [1]. The majority of ovarian tumors arise from the single epithelial layer covering the ovaries, which are contiguous with the mesothelium [2]. Tumor cells breach the ovarian capsule and reach the peritoneal cavity. 3) and disseminate throughout the peritoneal cavity, posing a major challenge in treating ovarian cancer patients. Preventing peritoneal dissemination can improve the survival of ovarian cancer patients. It has been observed that tumor cells that adhere closer to blood vessels (vessel cooption) have a survival advantage, and are selected for further growth [4]. Vessel cooption is followed by angiogenic switch and neovascularization, leading to invasive cancers [5]
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