Abstract
Aberrant signaling of the hepatocyte growth factor (HGF)/c-Met pathway has been identified as a promoter of tumorigenesis in several tumor types including head and neck squamous cell carcinoma (HNSCC). Despite a relatively low c-Met mutation frequency, overexpression of HGF and its receptor c-Met has been observed in more than 80% of HNSCC tumors, with preclinical and clinical studies linking overexpression with cellular proliferation, invasion, migration, and poor prognosis. c-Met is activated by HGF through a paracrine mechanism to promote cellular morphogenesis enabling cells to acquire mesenchymal phenotypes in part through the epithelial-mesenchymal transition, contributing to metastasis. The HGF/c-Met pathway may also act as a resistance mechanism against epidermal growth factor receptor (EGFR) inhibition in advanced HNSCC. Furthermore, with the identification of a biologically distinct subset of HNSCC tumors acquired from human papillomavirus (HPV) infection that generally portends a good prognosis, high expression of HGF or c-Met in HPV-negative tumors has been associated with worse prognosis. Dysregulated HGF/c-Met signaling results in an aggressive HNSCC phenotype which has led to clinical investigations for targeted inhibition of this pathway. In this review, HGF/c-Met signaling, pathway alterations, associations with clinical outcomes, and preclinical and clinical therapeutic strategies for targeting HGF/c-Met signaling in HNSCC are discussed.
Highlights
Carcinomas of the head and neck account for an increasing number of cancer cases worldwide with an incidence of more than 500,000 new cases and 380,000 deaths annually [1]
While analyses of epidermal growth factor receptor (EGFR) gene copy number and protein expression in patient tumors have not been found to be predictive of cetuximab response [92,93], a well-established intrinsic or acquired resistance mechanism to anti-EGFR therapy in Head and neck cancers (HNC) are squamous cell carcinomas (HNSCC) is the compensatory activation of alternate receptor tyrosine kinases (RTKs) including c-Met
Candidate biomarkers include serum Veristat classification and tumor expression of phosphorylated c-Met (p-Met). The results of these ongoing trials will determine whether further testing of hepatocyte growth factor (HGF)/c-Met targeting agents is justified in HNSCC
Summary
Carcinomas of the head and neck account for an increasing number of cancer cases worldwide with an incidence of more than 500,000 new cases and 380,000 deaths annually [1]. In vitro studies show that HGF stimulation leads to significantly increased IL-8, VEGF, and PDGF expression in HNSCC tumor cells through MEK-dependent activation of EGR-1 [23,67,68].
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