Journal
CANCER CELL
Volume 15, Issue 2, Pages 91-102Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2009.01.002
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Funding
- Wilhelm Sander-Stiftung [2005.146.1]
- Deutsche Krebshilfe [107977, 106772]
- National Health and Medical Research Council of Australia (NHMRC)
- Deutsche Forschungsgemeinschaft [Gr1916/2-2, SFB 456]
- Fritz Thyssen Stiftung [10.05.2.168]
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Although gastrointestinal cancers are frequently associated with chronic inflammation, the underlying molecular links have not been comprehensively deciphered. Using loss- and gain-of-function mice in a colitis-associated cancer model, we establish here a link comprising the gp130/Stat3 transcription factor signaling axis. Mutagen-induced tumor growth and multiplicity are reduced following intestinal epithelial cell (IEC)-specific Stat3 ablation, while its hyperactivation promotes tumor incidence and growth. Conversely, IEC-specific Stat3 deficiency enhances susceptibility to chemically induced epithelial damage and subsequent mucosal inflammation, while excessive Stat3 activation confers resistance to colitis. Stat3 has the capacity to mediate IL-6- and IL-11-dependent IEC survival and to promote proliferation through G1 and G2/M cell-cycle progression as the common tumor cell-autonomous mechanism that bridges chronic inflammation to tumor promotion.
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