Dependency of colorectal cancer on a TGF-?-driven program in stromal cells for metastasis initiation.

ABSTRACT: A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-? pathway, yet, paradoxically, they are characterized by elevated TGF-? production. Here, we unveil a prometastatic program induced by TGF-? in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-? on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-?-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-? stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC.

SUBMITTER: Calon A 

PROVIDER: S-EPMC3512565 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature