Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation.
Cancer Cell, 2012/11/13;22(5):571-84.
Calon A[1], Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Céspedes MV, Sevillano M, Nadal C, Jung P, Zhang XH, Byrom D, Riera A, Rossell D, Mangues R, Massagué J, Sancho E, Batlle E
Affiliations
PMID: 23153532
Impact factor: 38.585
Abstract
A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-β pathway, yet, paradoxically, they are characterized by elevated TGF-β production. Here, we unveil a prometastatic program induced by TGF-β in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-β 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-β-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-β stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC.
MeSH terms
Animals; Colorectal Neoplasms; Cytokine Receptor gp130; HT29 Cells; Humans; Interleukin-11; Mice; Neoplasm Metastasis; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Recurrence; STAT3 Transcription Factor; Signal Transduction; Stromal Cells; Transforming Growth Factor beta; Tumor Cells, Cultured; Tumor Microenvironment
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