Warusavitarne Janindra, McDougall Fiona, de Silva Keshani, Barnetson Rebecca, Messina Marinella, Robinson Bruce G, Schnitzler Margaret
Department of Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St. Leonards, NSW, 2065, Australia.
Int J Colorectal Dis. 2009 Feb;24(2):139-44. doi: 10.1007/s00384-008-0606-x. Epub 2008 Nov 5.
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.
To demonstrate an increase in invasion and metastasis in a MSI-H colorectal cancer cell line with a known mutation in TGFbetaRII.
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.
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.
转化生长因子β（TGFβ）是一种重要的细胞生长调节因子，可能在转移形成中发挥作用。微卫星不稳定（MSI-H）结肠癌是一个独特的模型，可用于证明这一点，因为大多数MSI-H结肠癌在转化生长因子β受体II（TGFβRII）基因中存在突变，且转移率较低。
在具有已知TGFβRII突变的MSI-H结直肠癌细胞系中证明侵袭和转移增加。
通过在具有已知TGFβRII突变的KM12C MSI-H结直肠癌细胞系中恢复野生型TGFβRII基因，我们证明该细胞系中的侵袭和转移均显著增加。一个小鼠转移模型显示，接种含有野生型TGFβRII基因细胞的小鼠肝转移增加（转染组为42%，而对照组为15%；p = 0.0379），尽管原发肿瘤大小有所减小。
本研究突出了一个可能导致MSI-H结肠癌低转移率的重要机制，并证明了TGFβ信号传导在转移形成中的重要性。先前涉及乳腺癌细胞系的研究表明，阻断TGFβ信号传导会导致转移形成减少。本研究是首次使用具有低转移率和TGFβRII突变的细胞系来证明恢复TGFβ信号传导会增加转移率。
