title: Restoring TGFbeta function in microsatellite unstable (MSI-H) colorectal cancer reduces tumourigenicity but increases metastasis formation.
abstract: BACKGROUND
  TGFbeta is an important cell growth regulator which may have a role in metastasis formation. Microsatellite unstable (MSI-H) colon cancer serves as a unique model to demonstrate this as most MSI-H colon cancers have a mutation in the transforming growth factor beta receptor II (TGFbetaRII) gene and a low metastatic rate.
  
  
  OBJECTIVE
  To demonstrate an increase in invasion and metastasis in a MSI-H colorectal cancer cell line with a known mutation in TGFbetaRII.
  
  
  METHODS
  By restoring the wild-type TGFbetaRII gene in the KM12C MSI-H colorectal carcinoma cell line with a known mutation in TGFbetaRII, we have demonstrated that both invasion and metastasis in this cell line was significantly increased. A mouse metastatic model have shown that liver metastases were increased in mice inoculated with cells containing a wild-type TGFbetaRII gene (42% for the transfected group compared with 15% for the control group; p = 0.0379), despite a reduction in the size of primary tumours.
  
  
  CONCLUSIONS
  This study highlights an important mechanism which may contribute to the low metastatic rate of MSI-H colon cancers and demonstrates the importance of TGFbeta signalling in metastasis formation. Previous studies involving breast cancer cell lines have shown that blocking TGFbeta signalling results in a reduction in metastasis formation. This study is the first study to use a cell line with a low metastatic rate and TGFbetaRII mutations to demonstrate that restoring TGFbeta signalling increases the metastatic rate.
authors.affiliation: Department of Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St. Leonards, NSW, 2065, Australia. j.warusavitarne@garvan.org.au
authors.forename: Janindra
authors.initials: J
authors.lastname: Warusavitarne
authors.forename: Fiona
authors.initials: F
authors.lastname: McDougall
authors.forename: Keshani
authors.initials: K
authors.lastname: de Silva
authors.forename: Rebecca
authors.initials: R
authors.lastname: Barnetson
authors.forename: Marinella
authors.initials: M
authors.lastname: Messina
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Robinson
authors.forename: Margaret
authors.initials: M
authors.lastname: Schnitzler
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003094:Collagen; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004338:Drug Combinations; D006801:Humans; D007797:Laminin; D051379:Mice; D053842:Microsatellite Instability; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011509:Proteoglycans; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C059485:matrigel; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II