c-MET expression in myofibroblasts - Role in autocrine activation and prognostic significance in lung adenocarcinoma

Hepatocyte growth factor (HGF) plays important rots in tumor development an d progression. It is currently thought that the main action of HGF is of a paracrine nature: HGF produced by mesenchymal cells acts on epithelial cell s that express its receptor c-MET. In this investigation, we explored the s ignificance of c-MET expression in myofibroblasts, both in culture and in p atients with lung adenocarcinoma. We first showed that human myofibroblasts derived from primary lung cancer expressed c-MET mRNA and protein by rever se transcription-polymerase chain reaction and Western blot analysis. Proli feration of myofibroblasts was stimulated in a dose-dependent manner by exo genously added recombinant human HGF whereas it was inhibited in a dose-dep endent manner by neutralizing antibody to HGF. The addition of HGF in the c ulture medium stimulated tyrosine phosphorylation of c-MET. The c-MET prote in was immunohistochemically detected in myofibroblasts in the invasive are a of lung adenocarcinoma. Finally, the prognostic significance of c-MET exp ression in stromal myofibroblasts was explored in patients with small-sized lung adenocarcinomas. c-MET-positive myofibroblasts were observed in 69 of 131 cases (53%). A significant relationship between myofibroblast c-MET ex pression and shortened patient survival was observed in a whole cohort of p atients including ah pathological stages (two-sided P = 0.0089 by log-rank test) and in patients with stage IA disease (two-sided P = 0.0019 by log-ra nk test). These data suggest that the HGF/c-MET system constitutes an autoc rine activation loop in cancer-stromal myofibroblasts. This autocrine syste m may play a role in invasion and metastasis of lung adenocarcinoma.