title: Abnormality of the hepatocyte growth factor/MET pathway in pulmonary adenocarcinogenesis.
abstract: BACKGROUND
  Signaling mediated by hepatocyte growth factor (HGF)/MET promotes multiple biological activities, including cell proliferation, motility, invasion, angiogenesis, and morphogenesis. Overexpression of HGF and MET and an increase of the MET gene copy number have recently been found in various cancers that had a poor outcome. Here we investigated the copy number of the MET gene and expression of MET and HGF in small pulmonary adenocarcinomas.
  
  
  METHODS
  Tumor tissues were obtained from 106 pulmonary small adenocarcinomas 2 cm or less in diameter. MET gene copy number, and the expression of MET and HGF, were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry, respectively.
  
  
  RESULTS
  MET FISH-positive signals were observed in 11 (10.4%) of 106 cases. One case (0.9%) showed gene amplification and 10 (9.4%) exhibited high polysomy. High immunoreactivity for MET and HGF in tumor cells was found in 30 (28.3%) and 19 cases (17.9%), respectively. HGF was also expressed in stromal cells in 32 cases (30.2%). No cases of non-invasive adenocarcinoma (adenocarcinoma in situ, localized bronchioloalveolar carcinoma) showed MET FISH-positive signals or high expression of HGF in the tumor cells. Expression of both MET and stromal HGF was stronger in invasive than in non-invasive adenocarcinoma. MET FISH-positive signals and high immunoreactivity for MET and HGF in tumor cells were associated with factors indicative of poor prognosis such as pleural invasion, vascular invasion, lymphatic permeation, lymph node metastasis, and nuclear grading. Univariate and multivariate analyses that included these factors showed that all statuses except for MET and HGF immunoreactivity were significantly associated with an increased risk of death. However, multivariate analysis revealed no independent factors related to poor prognosis.
  
  
  CONCLUSIONS
  Our results suggest that abnormality of the HGF/MET pathway occurs during the course of progression from non-invasive to invasive pulmonary adenocarcinoma. An increased MET gene copy number is indicative of a poor outcome in patients with small pulmonary adenocarcinomas.
authors.affiliation: Department of Surgery, Institute of Medical Sciences, Kyorin University, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.
authors.forename: Keisei
authors.initials: K
authors.lastname: Tachibana
authors.forename: Yuko
authors.initials: Y
authors.lastname: Minami
authors.forename: Aya
authors.initials: A
authors.lastname: Shiba-Ishii
authors.forename: Junko
authors.initials: J
authors.lastname: Kano
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Nakazato
authors.forename: Yukio
authors.initials: Y
authors.lastname: Sato
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Goya
authors.forename: Masayuki
authors.initials: M
authors.lastname: Noguchi
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology* / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D017228:Hepatocyte Growth Factor / Q000032:analysis / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000209:etiology* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met