title: Overexpression of Ephrin A2 receptors in cancer stromal cells is a prognostic factor for the relapse of gastric cancer.
abstract: BACKGROUND
  Microenvironments control cancer growth and progression. We explored the prognostic impact of stromal reaction and cancer stromal cells on relapse risk and survival after curative gastrectomy in gastric cancer patients.
  
  
  METHODS
  Tissue samples were obtained from 107 patients with gastric adenocarcinoma who underwent curative (R0) gastrectomy. Primary stromal cells isolated from gastric cancer tissue (GCSC) and normal gastric tissue (Gastric stromal cell: GSC) in each patient were cultured and subjected to comprehensive proteome (LC-MS/MS) and real-time RT-PCR analysis. Expression of Ephrin A2 receptors (EphA2) in cancers and GCSC was evaluated immunohistochemically. Intermingling of EphA2-positive cancer cells and GCSC (IC/A2+) and overexpression of EphA2 in cancer cells (Ca/A2+) in invasive parts of tumors were assessed, as were relationships of IC/A2+, Ca/A2+, and clinicopathological factors with relapse-free survival and overall survival.
  
  
  RESULTS
  Proteome analysis showed that EphA2 expression was significantly higher in GCSC than GSC. Real-time RT-PCR analysis showed that levels of EphA1/A2/A3/A5 and EphB2/B4 were ≥2.0-fold higher in GCSC than GSC. Ca/A2 and IC/A2 were positive in 65 (60.7 %) and 26 (24.3 %) patients, respectively. Relapse was significantly more frequent in IC/A2-positive than in IC/A2-negative (HR, 2.12; 95 % CI, 1.16-5.41; p = 0.0207) patients. Among the 54 patients who received S-1 adjuvant chemotherapy, relapse-free survival (RFS) was significantly shorter in those who were IC/A2-positive than in those who were IC/A2-negative and Ca/A2-negative (HR, 2.83; 95 % CI, 1.12-12.12; p = 0.0339). Multivariable analysis indicated that pathological stage (p = 0.010) and IC/A2+ (p = 0.008) were independent risk factors for recurrence.
  
  
  CONCLUSIONS
  IC/A2+ was predictive of relapse after curative (R0) gastrectomy.
authors.affiliation: Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan, skikuchi@hyo-med.ac.jp.
authors.forename: Shojiro
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Kaibe
authors.forename: Koji
authors.initials: K
authors.lastname: Morimoto
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Fukui
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Niwa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Maeyama
authors.forename: Masashi
authors.initials: M
authors.lastname: Takemura
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Shoji
authors.initials: S
authors.lastname: Nakamori
authors.forename: Hiroto
authors.initials: H
authors.lastname: Miwa
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hirota
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sasako
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D004338:Drug Combinations; D006801:Humans; D007150:Immunohistochemistry; D010094:Oxonic Acid / Q000627:therapeutic use; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*; D036121:Receptor, EphA3; D036123:Receptor, EphA5 / Q000235:genetics / Q000378:metabolism; D036183:Receptor, EphB2 / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D005641:Tegafur / Q000627:therapeutic use; D059016:Tumor Microenvironment
chemical_list: D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; C491718:EPHA3 protein, human; C484173:EPHA5 protein, human; C586310:EPHB2 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D036104:Receptor, EphA2; D036121:Receptor, EphA3; D036123:Receptor, EphA5; D036183:Receptor, EphB2