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

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...

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Published in:	Cancer research (Chicago, Ill.) Vol. 67; no. 4; pp. 1670 - 1679
Main Authors:	SAWADA, Kenjiro, REZA RADJABI, A, TRETIAKOVA, Maria S, LENGYEL, Ernst, SHINOMIYA, Nariyoshi, KISTNER, Emily, KENNY, Hilary, BECKER, Amy R, TURKYILMAZ, Muge A, SALGIA, Ravi, YAMADA, S. Diane, VANDE WOUDE, George F
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 15-02-2007
Subjects:	Abdomen Adenovirus Adult Aged Aged, 80 and over Animals Antineoplastic agents Biological and medical sciences Cell Adhesion - physiology Cell Growth Processes - physiology Female Female genital diseases Gastroenterology. Liver. Pancreas. Abdomen Gynecology. Andrology. Obstetrics Humans Integrin alpha5beta1 - metabolism Medical sciences Mice Mice, Nude Middle Aged Neoplasm Invasiveness Ovarian Neoplasms - enzymology Ovarian Neoplasms - genetics Ovarian Neoplasms - pathology Peritoneal Neoplasms - metabolism Peritoneal Neoplasms - secondary Pharmacology. Drug treatments 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 Tumors Prognosis Targeting Ovary cancer Gene overexpression Malignant tumor Invasion Female genital diseases Ovarian diseases Target Efficiency Abdominal disease C-Onc gene Peritoneal metastasis Inhibitor Protooncogene
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.can-06-1147