2012
DOI: 10.1016/j.ccr.2012.08.013
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Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation

Abstract: SUMMARY A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-beta pathway yet paradoxically, they are characterized by elevated TGF-beta production. Here, we unveil a prometastatic programme induced by TGF-beta in the microenvironment that associates with a high-risk of CRC relapse upon treatment. The activity of TGF-beta on stromal cells increases the efficiency of organ colonization by CRC cells whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilien… Show more

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Cited by 930 publications
(939 citation statements)
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References 49 publications
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“…Our results indicate that the tumor-initiating Apc mutation increases the sensitivity to TGF-β-induced cell death, whereas the KRas progression mutation increases resistance to cell death both ex vivo and in vivo. This is consistent with the fact that stromal cellderived TGF-β promotes CRC progression only at later stages of the disease via a mesenchyme-dependent mechanism (29). Our results further support the view that oncogenic progression gradually converts proapoptotic TGF-β signals to mechanisms that fuel tumor growth and metastasis (30).…”
Section: Discussionsupporting
confidence: 78%
“…Our results indicate that the tumor-initiating Apc mutation increases the sensitivity to TGF-β-induced cell death, whereas the KRas progression mutation increases resistance to cell death both ex vivo and in vivo. This is consistent with the fact that stromal cellderived TGF-β promotes CRC progression only at later stages of the disease via a mesenchyme-dependent mechanism (29). Our results further support the view that oncogenic progression gradually converts proapoptotic TGF-β signals to mechanisms that fuel tumor growth and metastasis (30).…”
Section: Discussionsupporting
confidence: 78%
“…HT29 M6 cells do not express Smad4, rendering this cell line unresponsive to TGF-b (24). Therefore, we decided to analyze whether NKG2DL expression is also modulated during EMT driven by TGF-b in HaCaT immortalized keratinocytes, which are responsive to this cytokine.…”
Section: Expression Of Nkg2dls Is Induced Upon Tgf-b-driven Emtmentioning
confidence: 99%
“…CAFs have been identified as potent stimulators of cancer metastasis (102,103). They contribute to remodeling of the tumor microenvironment and promote its stiffness mediating a mesenchymal phenotype in epithelial cells by loosing their cell-cell junctions and polarity (104,105).…”
Section: Exosome Mediated Interplay Between Tumor Cells With Fibroblamentioning
confidence: 99%