A Stromal TGF-β Response Promotes Colon Cancer Metastasis

TGF-β signaling exerts a tumor-suppressive function in colorectal cancer and is frequently inactivated by mutations in epithelial cancer cells. However, serum TGFB1 levels are paradoxically elevated in patients with colorectal cancer and are associated with poor outcome, suggesting that this pathway may promote metastasis, as in the case of breast and prostate cancer. Calon and colleagues hypothesized that activation of the tumor microenvironment by TGF-β may facilitate colorectal cancer progression. In support of this idea, both TGFB mRNA levels and TGF-β gene expression signatures derived from stromal cells, in particular cancer-associated fibroblasts (CAF), were predictive of tumor recurrence; high TGFB expression or enrichment of these stromal response programs was tightly correlated with relapse after therapy, whereas patients with low TGFB levels did not experience disease relapse. Furthermore, increased TGFB1 secretion by colorectal cancer cell lines harboring mutations in the TGF-β pathway activated a stromal TGF-β response that promoted the metastatic colonization of distant organs. This effect was dependent on TGF-β–driven induction of interleukin (IL)-11 in CAFs, which reduced cancer cell clearance during initial colonization and augmented the metastatic potential of colorectal cancer cells, suggesting that stromal TGF-β signaling enhances cancer cell survival. Indeed, IL-11–mediated activation of IL-6 signal transducer (also known as GP130) and STAT3 signaling in tumor epithelial cells promoted the survival of colorectal cancer cells during colonization and was required for efficient metastasis initiation. Importantly, pharmacologic blockade of TGF-β receptor 1 signaling in the tumor stroma decreased primary tumor formation and diminished the engraftment of colorectal cancer cells in the liver. These results identify stromal TGF-β signaling as a critical mediator of colon cancer metastasis and suggest that inhibition of this pathway may suppress tumor relapse.

Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Céspedes MV, et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell 2012;22:571–84.

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