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

      Cancer Cell

      Tumor Microenvironment, Tumor Cells, Cultured, physiology, metabolism, genetics, Transforming Growth Factor beta, pathology, Stromal Cells, Signal Transduction, STAT3 Transcription Factor, Recurrence, antagonists & inhibitors, Receptors, Transforming Growth Factor beta, Protein-Serine-Threonine Kinases, drug therapy, Neoplasm Metastasis, Mice, Interleukin-11, Humans, HT29 Cells, Cytokine Receptor gp130, Colorectal Neoplasms, Animals

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          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. Copyright © 2012 Elsevier Inc. All rights reserved.

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          Author and article information

          Journal
          10.1016/j.ccr.2012.08.013
          3512565
          23153532

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