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


ABSTRACT: 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.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.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.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.

SUBMITTER: Knowles LM 

PROVIDER: S-EPMC3159511 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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

Knowles Lynn M LM   Stabile Laura P LP   Egloff Ann Marie AM   Rothstein Mary E ME   Thomas Sufi M SM   Gubish Christopher T CT   Lerner Edwina C EC   Seethala Raja R RR   Suzuki Shinsuke S   Quesnelle Kelly M KM   Morgan Sarah S   Ferris Robert L RL   Grandis Jennifer R JR   Siegfried Jill M JM  

Clinical cancer research : an official journal of the American Association for Cancer Research 20090526 11


<h4>Purpose</h4>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.<h4>Experimental design</h4>Expression and signaling were determined using immunoblotting, ELISA, and immunohistochemistry. Biological end points included wound healing, cell proliferation, and invasion. c-Met TKIs w  ...[more]

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