title: Connective tissue growth factor inhibits gastric cancer peritoneal metastasis by blocking integrin α3β1-dependent adhesion.
abstract: BACKGROUND
  Connective tissue growth factor (CTGF) plays important roles in normal and pathological conditions. The aim of this study was to investigate the role of CTGF in peritoneal metastasis as well as the underlying mechanism in gastric cancer progression.
  
  
  METHODS
  CTGF expression levels for wild-type and stable overexpression clones were determined by Western blotting and quantitative polymerase chain reaction (Q-PCR). Univariate and multivariate analyses, immunohistochemistry, and survival probability analyses were performed on gastric cancer patients. The extracellular matrix components involved in CTGF-regulated adhesion were determined. Recombinant CTGF was added to cells or coinoculated with gastric cancer cells into mice to evaluate its therapeutic potential.
  
  
  RESULTS
  CTGF overexpression and treatment with the recombinant protein significantly inhibited cell adhesion. In vivo peritoneal metastasis demonstrated that CTGF-stable transfectants markedly decreased the number and size of tumor nodules in the mesentery. Statistical analysis of gastric cancer patient data showed that patients expressing higher CTGF levels had earlier TNM staging and a higher survival probability after the surgery. Integrin α3β1 was the cell adhesion molecule mediating gastric cancer cell adhesion to laminin, and blocking of integrin α3β1 prevented gastric cancer cell adhesion to recombinant CTGF. Coimmunoprecipitation results indicated that CTGF binds to integrin α3. Coinoculation of recombinant CTGF and gastric cancer cell lines in mice showed effective inhibition of peritoneal dissemination.
  
  
  CONCLUSIONS
  Our results suggested that gastric cancer peritoneal metastasis is mediated through integrin α3β1 binding to laminin, and CTGF effectively blocks the interaction by binding to integrin α3β1, thus demonstrating the therapeutic potential of recombinant CTGF in gastric cancer patients.
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan, cnchen@ntu.edu.tw.
authors.forename: Chiung-Nien
authors.initials: CN
authors.lastname: Chen
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chang
authors.forename: Hong-Shiee
authors.initials: HS
authors.lastname: Lai
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
authors.forename: Chia-I
authors.initials: CI
authors.lastname: Chen
authors.forename: King-Jeng
authors.initials: KJ
authors.lastname: Chang
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Lee
authors.forename: Hsinyu
authors.initials: H
authors.lastname: Lee
mesh_terms: D000368:Aged; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D039201:Integrin alpha3beta1 / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D008297:Male; D016513:Mice, SCID; D008875:Middle Aged; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D014407:Tumor Cells, Cultured
chemical_list: C526317:CCN2 protein, human; D039201:Integrin alpha3beta1; D007797:Laminin; D011994:Recombinant Proteins; D055513:Connective Tissue Growth Factor