Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation
2012
Details
- Autor(en) / Beteiligte
- Titel
- Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation
- Ist Teil von
- Cancer cell, 2012-11, Vol.22 (5), p.571-584
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2012
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] ► TGF-β pathway mutant cells require a stromal TGF-β program for metastasis ► CRC patients with low levels of stromal TGF-β program do not relapse ► Pharmacological blockade of TGF-β stromal signaling prevents metastasis initiation ► A TGF-β/IL-11/GP130 signaling cycle confers metastatic organ colonization capacity
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1535-6108eISSN: 1878-3686DOI: 10.1016/j.ccr.2012.08.013Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3512565
- Format
- –
- Schlagworte
- Animals, Colorectal Neoplasms - drug therapy, Colorectal Neoplasms - pathology, Cytokine Receptor gp130 - genetics, Cytokine Receptor gp130 - metabolism, Cytokine Receptor gp130 - physiology, HT29 Cells, Humans, Interleukin-11 - genetics, Interleukin-11 - metabolism, Interleukin-11 - physiology, Mice, Neoplasm Metastasis - drug therapy, Protein-Serine-Threonine Kinases - antagonists & inhibitors, Receptors, Transforming Growth Factor beta - antagonists & inhibitors, Recurrence, Signal Transduction, STAT3 Transcription Factor - genetics, STAT3 Transcription Factor - metabolism, STAT3 Transcription Factor - physiology, Stromal Cells - metabolism, Stromal Cells - pathology, Transforming Growth Factor beta - genetics, Transforming Growth Factor beta - metabolism, Transforming Growth Factor beta - physiology, Tumor Cells, Cultured, Tumor Microenvironment