HGF and c-Met Participate in Paracrine Tumorigenic Pathways in Head and Neck Squamous Cell Cancer
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: E...
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Published in | Clinical cancer research Vol. 15; no. 11; pp. 3740 - 3750 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Philadelphia, PA
American Association for Cancer Research
01.06.2009
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | L.M. Knowles and L.P. Stabile contributed equally to this study. |
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-08-3252 |