SEARCH

SEARCH BY CITATION

Keywords:

  • colorectal cancer;
  • microsatellite instability;
  • transforming growth factor β (TGFβ);
  • TGFβ receptors

Abstract

Disruptions to the TGFβ signalling pathway have been implicated in most human adenocarcinomas. As cancers progress, many acquire resistance to the growth-suppressing properties of TGFβ while retaining sensitivity to its tumour-promoting effects. Microsatellite unstable colorectal cancers (MSI-H CRCs) possess truncating mutations in the type II TGFβ receptor (TGFβRII) gene that have been assumed to render these tumours insensitive to TGFβ. However, numerous reports of TGFβRII bypass exist and this study was thus undertaken in order to clarify the true extent of TGFβ sensitivity in MSI-H CRCs. Using stimulation with exogenous TGFβ, we demonstrated that, while MSI-H CRCs are capable of binding soluble TGFβ, two out of three cell lines examined remain refractory to its signalling effects. In contrast, use of a specific inhibitor of the type I TGFβ receptor (TGFβRI) revealed that all remain sensitive to signalling by endogenously produced TGFβ. Specifically, autocrine signalling via TGFβRI 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 TGFβ-modulated genes. An invasion assay revealed that autocrine TGFβRI signalling also promotes the invasion capacity of MSI-H CRCs to an extent similar to that seen in their non-MSI-H counterparts. Independent TGFβRI 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 TGFβ, despite lacking functional TGFβRII. In addition to clarifying the true consequences of natural TGFβRII loss and the independent function of TGFβRI, our results highlight the selective nature of TGFβ resistance developed by cancers. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.