title: c-MET expression in myofibroblasts: role in autocrine activation and prognostic significance in lung adenocarcinoma.
abstract: Hepatocyte growth factor (HGF) plays important roles in tumor development and progression. It is currently thought that the main action of HGF is of a paracrine nature: HGF produced by mesenchymal cells acts on epithelial cells that express its receptor c-MET. In this investigation, we explored the significance of c-MET expression in myofibroblasts, both in culture and in patients with lung adenocarcinoma. We first showed that human myofibroblasts derived from primary lung cancer expressed c-MET mRNA and protein by reverse transcription-polymerase chain reaction and Western blot analysis. Proliferation of myofibroblasts was stimulated in a dose-dependent manner by exogenously added recombinant human HGF whereas it was inhibited in a dose-dependent manner by neutralizing antibody to HGF. The addition of HGF in the culture medium stimulated tyrosine phosphorylation of c-MET. The c-MET protein was immunohistochemically detected in myofibroblasts in the invasive area of lung adenocarcinoma. Finally, the prognostic significance of c-MET expression 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 expression and shortened patient survival was observed in a whole cohort of patients including all 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-rank test). These data suggest that the HGF/c-MET system constitutes an autocrine activation loop in cancer-stromal myofibroblasts. This autocrine system may play a role in invasion and metastasis of lung adenocarcinoma.
authors: Pathology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors: M
authors: M
authors: Tokunou
authors: T
authors: T
authors: Niki
authors: K
authors: K
authors: Eguchi
authors: S
authors: S
authors: Iba
authors: H
authors: H
authors: Tsuda
authors: T
authors: T
authors: Yamada
authors: Y
authors: Y
authors: Matsuno
authors: H
authors: H
authors: Kondo
authors: Y
authors: Y
authors: Saitoh
authors: H
authors: H
authors: Imamura
authors: S
authors: S
authors: Hirohashi
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D019898:Autocrine Communication / Q000502:physiology; D002460:Cell Line; D003199:Computer Systems; D004210:Dissection / Q000379:methods; D005347:Fibroblasts / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D007834:Lasers; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014443:Tyrosine / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met