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

Am J Pathol. 2001 Apr;158(4):1451-63. doi: 10.1016/S0002-9440(10)64096-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Autocrine Communication / physiology
  • Cell Line
  • Computer Systems
  • Dissection / methods
  • Fibroblasts / metabolism*
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / pharmacology
  • Humans
  • Lasers
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Muscle, Smooth / cytology
  • Muscle, Smooth / metabolism*
  • Phosphorylation / drug effects
  • Prognosis
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism*
  • Proto-Oncogene Proteins c-met / physiology
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tyrosine / metabolism


  • RNA, Messenger
  • Tyrosine
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met