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

Oncogene volume 34, pages 144–153 (2015)Cite this article

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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 Tyr1234 and Tyr1003. However, both sources of HGF increased the phosphorylation of c-MET on Tyr1349, 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 pTyr1349-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 pTyr1349 levels might be a good indicator of c-MET activation and likely response to targeted therapy as a result of signals from the microenvironment.

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Acknowledgements

We thank Dr Ziyan Pessetto for her expertise in the cell viability assays and Dr Daniel Flynn for his helpful comments and guidance in regards the biology and activity of DCC-2701. The study was supported in part by a program project grant from Ovarian Cancer Research Fund (http://www.ocrf.org) and a grant from the NCI (R01 CA140323) to AKG. We would also like to acknowledge support from the University of Kansas Cancer Center’s CCSG (P30 CA168524), the Kansas Bioscience Authority Eminent Scholar Program. AKG is the Chancellors Distinguished Chair in Biomedical Sciences endowed Professor.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA

    Y Kwon & A K Godwin

  2. Department of Food Science and Engineering, Ewha Womans University, Seoul, Korea

    Y Kwon

  3. Deciphera,Pharmaceuticals, LLC, Lawrence, KS, USA

    B D Smith & M D Kaufman

  4. Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA

    Y Zhou

  5. University of Kansas Cancer Center, Kansas City, KS, USA

    A K Godwin

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  1. Y Kwon
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Correspondence to A K Godwin.

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Competing interests

Dr AKG’s work has been funded by the NIH/NCI, the state of Kansas and non-profit organizations. BSD and MDK are employees of and receive compensation from Deciphera Pharmaceuticals, LLC. The remaining authors declare no conflict of interest.

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Kwon, Y., Smith, B., Zhou, Y. et al. Effective inhibition of c-MET-mediated signaling, growth and migration of ovarian cancer cells is influenced by the ovarian tissue microenvironment. Oncogene 34, 144–153 (2015). https://doi.org/10.1038/onc.2013.539

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