Involvement of the hepatocyte growth factor/scatter factor receptor c-met and of Bcl-x(L) in the resistance of oropharyngeal cancer to ionizing radiation

The activation of cytoplasmic signal transduction pathways by a number of g rowth factors and their tyrosine-kinase receptors, including hepatocyte gro wth factor/scatter factor (HGF/SF) and its receptor c-met, exerts an inhibi tory influence on apoptosis induced by ionizing radiation in vitro. The cli nical relevance of the aforementioned ligand-receptor pair, of Bcl-x(L), wh ich is targeted by HGF/SF/c-met signaling, and of Bcl-2, was assessed by ev aluating their predictive and prognostic impact in a cohort of 97 patients with radically irradiated squamous cell cancers of the oropharynx. Immunohi stochemical expression of c-met and Bcl-x(L) was correlated with decreased rates of complete remission of the primary tumor in both the univariate (c- met: P = 0.01; Bcl-x(L): P = 0.001) and multivariate analyses. Expression o f c-met was, moreover, a significant and independent predictor of impaired local failure-free survival (P = 0.003), disease-free survival (P = 0.003) and overall survival (p = 0.001). Bcl-2 expression was, on the other hand, associated with a favorable outcome, in terms of both local failure-free su rvival (P = 0.01) and overall survival (P = 0.001). In accordance with in v itro data, c-met and Bcl-xL appear to be involved in the resistance of orop haryngeal cancers to ionizing radiation, and may therefore represent attrac tive targets for radiosensitization.(C) 2001 Wiley-Liss, Inc.