Restoring TGFβ function in microsatellite unstable (MSI-H) colorectal cancer reduces tumourigenicity but increases metastasis formation

TGF beta 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 (TGF beta RII) gene and a low metastatic rate. To demonstrate an increase in invasion and metastasis in a MSI-H colorectal cancer cell line with a known mutation in TGF beta RII. By restoring the wild-type TGF beta RII gene in the KM12C MSI-H colorectal carcinoma cell line with a known mutation in TGF beta RII, 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 TGF beta RII 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. This study highlights an important mechanism which may contribute to the low metastatic rate of MSI-H colon cancers and demonstrates the importance of TGF beta signalling in metastasis formation. Previous studies involving breast cancer cell lines have shown that blocking TGF beta 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 TGF beta RII mutations to demonstrate that restoring TGF beta signalling increases the metastatic rate.