HGF and c-Met participate in paracrine tumorigenic pathways in head and neck squamous cell cancer

Lynn M. Knowles, Laura P. Stabile, Ann Marie Egloff, Mary E. Rothstein, Sufi M. Thomas, Christopher T. Gubish, Edwina C. Lerner, Raja R. Seethala, Shinsuke Suzuki, Kelly M. Quesnelle, Sarah Morgan, Robert L. Ferris, Jennifer R. Grandis, Jill M. Siegfried

Research output: Contribution to journalArticlepeer-review

148 Scopus citations

Abstract

Purpose: We determined hepatocyte growth factor (HGF) and c-Met expression and signaling in human head and neck squamous cell carcinoma (HNSCC) cells and primary tissues and tested the ability of c-Met tyrosine kinase inhibitors (TKI) to block HGF-induced biological signaling. Experimental Design: Expression and signaling were determined using immunoblotting, ELISA, and immunohistochemistry. Biological end points included wound healing, cell proliferation, and invasion. c-Met TKIs were tested for their ability to block HGF-induced signaling and biological effects in vitro and in xenografts established in nude mice. Results: c-Met was expressed and functional in HNSCC cells. HGF was secreted by HNSCC tumor-derived fibroblasts, but not by HNSCC cells. Activation of c-Met promoted phosphorylation of AKT and mitogen-activated protein kinase as well as release of the inflammatory cytokine interleukin-8. Cell growth and wound healing were also stimulated by HGF. c-Met TKIs blocked HGF-induced signaling, interleukin-8 release, and wound healing. Enhanced invasion of HNSCC cells induced by the presence of tumor-derived fibroblasts was completely blocked with a HGF-neutralizing antibody. PF-2341066, a c-Met TKI, caused a 50% inhibition of HNSCC tumor growth in vivo with decreased proliferation and increased apoptosis within the tumors. In HNSCC tumor tissues, both HGF and c-Met protein were increased compared with expression in normal mucosa. Conclusions: These results show that HGF acts mainly as a paracrine factor in HNSCC cells, the HGF/c-Met pathway is frequently up-regulated and functional in HNSCC, and a clinically relevant c-Met TKI shows antitumor activity in vivo. Blocking the HGF/c-Met pathway may be clinically useful for the treatment of HNSCC.

Original languageEnglish (US)
Pages (from-to)3740-3750
Number of pages11
JournalClinical Cancer Research
Volume15
Issue number11
DOIs
StatePublished - Jun 1 2009

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