Expression of the c-Met oncogene by tumor cells predicts a favorable outcome in classical Hodgkin's lymphoma.

ABSTRACT

BACKGROUND: The c-Met signaling pathway regulates a variety of biological processes, including proliferation, survival and migration. Deregulated c-Met activation has been implicated in the pathogenesis and prognosis of many human malignancies. We studied the function and prognostic significance of c-Met and hepatocyte growth factor protein expression in patients with classical Hodgkin's lymphoma. DESIGN AND METHODS: Expression of c-Met and its ligand, hepatocyte growth factor, were determined by immunohistochemistry. Prognostic values were defined in cohorts of German and Dutch patients with classical Hodgkin's lymphoma. Functional studies were performed on Hodgkin's lymphoma cell lines. RESULTS: Expression of c-Met was detected in the tumor cells of 52% (80/153) of the patients and expression of its ligand, hepatocyte growth factor, in 8% (10/121) of the patients. c-Met expression correlated with a 5-year freedom from tumor progression of 94%, whereas lack of expression correlated with a 5-year freedom from tumor progression of 73% (P<0.001) in the combined cohort. In multivariate analysis both c-Met (hazard ratio 5.0, 95% confidence interval 1.9-13.3, P<0.001) and stage (hazard ratio 2.8, 95% confidence interval 1.2-6.4, P=0.014) were independent predictors for freedom from tumor progression. In functional studies activation with hepatocyte growth factor did not affect cell growth, while the c-Met inhibitor SU11274 suppressed cell growth by inducing G2/M cell cycle arrest. CONCLUSIONS: Although functional studies showed an oncogenic role of the hepatocyte growth factor/c-Met signaling pathway in cell cycle progression, expression of c-Met in tumor cells from patients with classical Hodgkin's lymphoma strongly correlated with a favorable prognosis in two independent cohorts.