The Role of Hepatocyte Growth Factor Pathway Signaling in Renal Cell Carcinoma

The urgent need for effective therapies for patients with advanced renal cell carcinoma (RCC), fewer than twenty percent of whom will survive more than two years, has led to the identification of critical genetic determinants and associated molecular pathways contributing to RCC oncogenesis, progression and spread. Among the signaling pathways dysregulated in RCC is that of hepatocyte growth factor (HGF), which through the cell surface receptor tyrosine kinase, Met, stimulates proliferation, motility and morphogenesis. Germline missense mutations in the tyrosine kinase domain Met are associated with hereditary papillary renal carcinoma (HPRC), while somatic mutations and frequent trisomy of chromosome 7 implicate pathway involvement in sporadic papillary type 1 RCC. In addition, loss of the VHL tumor suppressor gene results in the derepression of an embryonic HGF-driven phenotype likely to contribute to tumor invasiveness and metastasis in clear cell RCC. Our knowledge of HGF/Met signaling has enabled rapid progress in characterizing its contributions to RCC and in laying the framework for the development of novel anti-cancer therapeutics. A better understanding of how HGF/Met signaling is integrated with other oncogenic pathways in RCC should aid the development of combinatorial treatment strategies, and help predict potential adverse effects of long-term pathway blockade.