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c-Met Overexpression Is a Prognostic Factor in Ovarian Cancer and an Effective Target for Inhibition of Peritoneal Dissemination and Invasion

Departments of ¹ Obstetrics and Gynecology/Section of Gynecologic Oncology, ² Health Studies, ³ Pathology, and ⁴ Medicine/Section of Hematology and Oncology and ⁵ Committee on Cancer Biology, University of Chicago, Chicago, Illinois; ⁶ Department of Microbiology, National Defense Medical College, Tokorozawa, Japan; and ⁷ Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, Michigan

Requests for reprints: Ernst Lengyel, Department of Obstetrics and Gynecology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637. Phone: 773-702-6722; Fax: 773-702-5411; E-mail: elengyel{at}uchicago.edu.

The hepatocyte growth factor receptor c-Met is a receptor tyrosine kinase that plays an important role in tumor growth by activating mitogenic signaling pathways. The goal of this study was to evaluate the role of c-Met in the biology of ovarian cancer and to determine its potential as a therapeutic target. c-Met protein expression was detected by immunohistochemistry in 138 advanced-stage ovarian cancers using a tissue microarray annotated with disease-specific patient follow-up. Fifteen of 138 (11%) tissues had c-Met overexpression. Median survival for patients with high c-Met levels was 17 months versus 32 months (P = 0.001) for patients with low c-Met expression. Infection of SKOV-3ip1 cells with an adenovirus expressing a small interfering RNA (siRNA) against c-Met efficiently inhibited c-Met protein and mRNA expression as well as extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling. It also inhibited adhesion to different extracellular matrix components, human primary mesothelial cells, and full-thickness human peritoneum and, in vivo, to mouse peritoneum. This was paralleled by a significant reduction in ₅ and ß₁ integrin protein and mRNA expression as well as a reduction of urokinase and matrix metalloproteinase (MMP)-2/MMP-9 activity. In SKOV-3ip1 ovarian cancer xenografts, i.p. treatment with the c-Met siRNA significantly reduced tumor burden, ascites formation, protease activity, and the number of peritoneal implants but not tumor size or angiogenesis. These results suggest that c-Met overexpression is a prognostic factor in ovarian cancer and that targeting c-Met in vivo inhibits peritoneal dissemination and invasion through an ₅ß₁ integrin-dependent mechanism. Therefore, c-Met should be explored further as a therapeutic target in ovarian cancer. [Cancer Res 2007;67(4):1670–9]

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