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A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
Published on: July 6, 2017
Microsatellite unstable colorectal cancer cell lines with truncating TGFbetaRII mutations remain sensitive to
1Department of Pathology, McGill University, Montréal, Québec H3A 2B4, Canada. kristi.baker@mcgill.ca
Abstract:
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. 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.
Insights
Microsatellite unstable colorectal cancers (MSI-H CRCs) can still respond to transforming growth factor beta (TGF-beta) signaling through TGF-beta receptor I (TGFbetaRI), even without a functional TGFbeta receptor II (TGFbetaRII). This autocrine signaling promotes invasion but not proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling
Background:
- Transforming growth factor beta (TGF-beta) signaling disruptions are common in human adenocarcinomas.
- Cancer cells often develop resistance to TGF-beta's growth-suppressive effects while retaining sensitivity to its tumor-promoting roles.
- Microsatellite unstable colorectal cancers (MSI-H CRCs) typically have mutations in TGF-beta receptor II (TGFbetaRII), leading to the assumption of complete TGF-beta insensitivity.
Purpose of the Study:
- To investigate the actual extent of TGF-beta sensitivity in MSI-H CRCs.
- To clarify the consequences of TGFbetaRII loss and the independent function of TGFbetaRI in these cancers.
- To understand the selective nature of TGF-beta resistance in cancer progression.
Main Methods:
- Stimulation of MSI-H colorectal cancer (CRC) cell lines with exogenous TGF-beta.
- Assessment of TGF-beta signaling using a specific inhibitor of the type I TGF-beta receptor (TGFbetaRI).
- Analysis of Smad2 activation, Erk signaling repression, gene expression via real-time PCR, cell proliferation, and invasion assays.
Main Results:
- MSI-H CRCs can bind soluble TGF-beta, but most remain unresponsive to exogenous TGF-beta signaling due to non-functional TGFbetaRII.
- All examined MSI-H CRC cell lines exhibit sensitivity to endogenously produced TGF-beta via autocrine signaling through TGFbetaRI.
- Autocrine TGFbetaRI signaling leads to constitutive Smad2 activation, Erk signaling repression, altered expression of TGF-beta-modulated genes, and increased invasion capacity, similar to non-MSI-H CRCs.
- Independent TGFbetaRI signaling does not affect the proliferation rate of MSI-H CRC cells.
Conclusions:
- MSI-H CRC cell lines are not entirely refractory to TGF-beta signaling, demonstrating residual sensitivity via TGFbetaRI.
- Autocrine TGFbetaRI signaling plays a significant role in promoting invasion in MSI-H CRCs.
- The study highlights the selective development of TGF-beta resistance in cancers and the distinct roles of TGFbetaRII and TGFbetaRI.
