c-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion

Cancer Res. 2007 Feb 15;67(4):1670-9. doi: 10.1158/0008-5472.CAN-06-1147.


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 alpha(5) and beta(1) 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 alpha(5)beta(1) integrin-dependent mechanism. Therefore, c-Met should be explored further as a therapeutic target in ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Cell Adhesion / physiology
  • Cell Growth Processes / physiology
  • Female
  • Humans
  • Integrin alpha5beta1 / metabolism
  • Mice
  • Mice, Nude
  • Middle Aged
  • Neoplasm Invasiveness
  • Ovarian Neoplasms / enzymology*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology*
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / secondary*
  • Prognosis
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / biosynthesis*
  • Proto-Oncogene Proteins c-met / genetics
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics


  • Integrin alpha5beta1
  • RNA, Messenger
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-met