View : 21 Download: 0

Effective inhibition of c-MET-mediated signaling, growth and migration of ovarian cancer cells is influenced by the ovarian tissue microenvironment

Title
Effective inhibition of c-MET-mediated signaling, growth and migration of ovarian cancer cells is influenced by the ovarian tissue microenvironment
Authors
Kwon Y.Smith B.D.Zhou Y.Kaufman M.D.Godwin A.K.
Ewha Authors
권영주
SCOPUS Author ID
권영주scopus
Issue Date
2015
Journal Title
Oncogene
ISSN
0950-9232JCR Link
Citation
vol. 34, no. 2, pp. 144 - 153
Keywords
c-METDCC-2701hepatocyte growth factorhuman ovarian fibroblastovarian cancer
Publisher
Nature Publishing Group
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
The signaling mediated by c-MET and its ligand, hepatocyte growth factor (HGF), has been implicated in malignant progression of cancer involving stimulation of proliferation, invasion and metastasis. We studied the c-MET/HGF axis as a mediator of tumor-stromal interaction in ovarian cancer and the value of targeting c-MET for the treatment of ovarian cancer. To assess c-MET signaling, we established in vitro models of the microenvironment using primary and immortalized human fibroblasts from normal ovary and tumor samples and epithelial ovarian cancer cell lines. We found that fibroblast from normal ovaries secreted high levels of HGF (1500-3800 pg/ml) as compared with tumor-derived fibroblasts (undetectable level) and could elicit cellular biological responses on c-MET-expressing ovarian cancer cells including increase of cell proliferation and migration (2-to 140-fold increase). HGF secreted by fibroblasts was also found sequestered within extracellular matrices (ECMs) and when degraded this ECM-derived HGF stimulated cancer cell migration (1.5-to 24-fold). In cells containing constitutive c-MET phosphorylation, recombinant HGF and fibroblast-derived HGF negligibly affect c-MET phosphorylation on Tyr 1234 and Tyr 1003. However, both sources of HGF increased the phosphorylation of c-MET on Tyr 1349, the multi-substrate docking site, by more than sixfold and led to activation of downstream signaling transducers. DCC-2701 (Deciphera Pharmaceuticals, LLC), a novel c-MET/TIE-2/VEGFR inhibitor was able to effectively reduce tumor burden in vivo and block c-MET pTyr 1349-mediated signaling, cell growth and migration as compared with a HGF antagonist in vitro. Importantly, DCC-2701's anti-proliferative activity was dependent on c-MET activation induced by stromal human fibroblasts and to a lesser extent exogenous HGF. Our data suggest for the first time that DCC-2701 may be superior to HGF antagonists that are in clinical trials and that pTyr 1349 levels might be a good indicator of c-MET activation and likely response to targeted therapy as a result of signals from the microenvironment. © 2015 Macmillan Publishers Limited.
DOI
10.1038/onc.2013.539
Appears in Collections:
엘텍공과대학 > 식품공학전공 > Journal papers
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML


qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE