Restoring TGFbeta function in microsatellite unstable (MSI-H) colorectal cancer reduces tumourigenicity but increases metastasis formation.
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.
Warusavitarne
Janindra
J
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
McDougall
Fiona
F
de Silva
Keshani
K
Barnetson
Rebecca
R
Messina
Marinella
M
Robinson
Bruce G
BG
Schnitzler
Margaret
M
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*
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