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


METHODS
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.
Knowles
Lynn M
LM
Departments of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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
D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D004305:Dose-Response Relationship, Drug; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019899:Paracrine Communication / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013314:Stress, Mechanical; D013449:Sulfonamides / Q000494:pharmacology; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects
C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D007211:Indoles; D010879:Piperazines; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D013449:Sulfonamides; D000077547:Crizotinib; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met