Research results from McGill University, Department of Pathology update understanding of colon cancer
2007 NOV 19 -- Data detailed in 'Microsatellite unstable colorectal cancer cell lines with truncating TGFbetaRII mutations remain sensitive to endogenous TGFbeta' have been presented. According to recent research from Montreal, Canada, "Disruptions to the TGFbeta signalling pathway have been implicated in most human adenocarcinomas. As cancers progress, many acquire resistance to the growth-suppressing properties of TGFbeta while retaining sensitivity to its tumour-promoting effects." "Microsatellite unstable colorectal cancers (MSI-H CRCs) possess truncating mutations in the type II TGFbeta receptor (TGFbetaRII) gene that have been assumed to render these tumours insensitive to TGFbeta. However, numerous reports of TGFbetaRII bypass exist and this study was thus undertaken in order to clarify the true extent of TGFbeta sensitivity in MSI-H CRCs. Using stimulation with exogenous TGFbeta, we demonstrated that, while MSI-H CRCs are capable of binding soluble TGFbeta, two out of three cell lines examined remain refractory to its signalling effects. In contrast, use of a specific inhibitor of the type I TGFbeta receptor (TGFbetaRI) revealed that all remain sensitive to signalling by endogenously produced TGFbeta. Specifically, autocrine signalling via TGFbetaRI mediates constitutive activation of Smad2 as well as repression of Erk signalling. Real-time PCR confirmed that these effects are sufficient to affect the expression level of various TGFbeta-modulated genes. An invasion assay revealed that autocrine TGFbetaRI signalling also promotes the invasion capacity of MSI-H CRCs to an extent similar to that seen in their non-MSI-H counterparts. Independent TGFbetaRI signalling, however, has no effect on the rate of proliferation of MSI-H CRC cells. Together, these results demonstrate that MSI-H CRC cell lines are not completely refractory to TGFbeta, despite lacking functional TGFbetaRII," wrote K. Baker and colleagues, McGill University, Department of Pathology. The researchers concluded: "In addition to clarifying the true consequences of natural TGFbetaRII loss and the independent function of TGFbetaRI, our results highlight the selective nature of TGFbeta resistance developed by cancers." Baker and colleagues published their study in the Journal of Pathology (Microsatellite unstable colorectal cancer cell lines with truncating TGFbetaRII mutations remain sensitive to endogenous TGFbeta. Journal of Pathology, 2007;213(3):257-65). For additional information, contact K. Baker, McGill University, Dept. of Pathology, Montreal, Quebec H3A 2B4, Canada. Publisher contact information for the Journal of Pathology is: John Wiley & Sons Ltd., the Atrium, Southern Gate, Chichester PO19 8SQ, W Sussex, England. Keywords: Canada, Montreal, Colon Cancer, Colon Carcinoma, Colorectal, Gastroenterology, Oncology, Pathology. This article was prepared by Clinical Oncology Week editors from staff and other reports. Copyright 2007, Clinical Oncology Week via NewsRx.com.
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