Inhibition of HGF/cMET expression prevents distant recurrence of rectal cancer after preoperative chemoradiotherapy

Abstract

Hepatocyte growth factor (HGF) and its receptor cMET play an important role in tumor proliferation, invasion and metastasis. In this study, we investigated the association of HGF/cMET signaling with distant recurrence in rectal cancer after preoperative chemoradiotherapy and whether inhibition of the HGF/cMET signaling pathway could suppress the re-growth of cancer cells after irradiation. We obtained total RNA from residual cancer cells and stromal tissue separately using microdissection from a total of 53 rectal cancer specimens from patients who underwent preoperative CRT, performed transcriptional analyses, and analyzed the association of HGF and cMET expression levels with clinical outcomes. We performed in vitro experiments to examine HGF and cMET expression and the re-growth of cancer cells after irradiation and treatment with a tyrosine kinase inhibitor specific for cMET (SU11274). We found significant correlations between cancer cell HGF and cMET gene expression, and stromal cell HGF and cancer cell cMET expression. Elevated cancer cell cMET and stromal HGF expression were significantly associated with a worse prognosis. In vitro experiments showed that the up-regulation of HGF expression and the re-growth of irradiated cancer cells were effectively suppressed by inhibiting cMET. Our results suggest that inhibition of radiation-induced HGF up-regulation and blockade of autocrine/paracrine HGF/cMET signaling are potential new strategies for controlling distant recurrence in rectal cancer patients after preoperative CRT.