6533b82cfe1ef96bd128f5df

RESEARCH PRODUCT

TGF-β Suppresses Tumor Progression in Colon Cancer by Inhibition of IL-6 trans-Signaling

Hans A. LehrMassimo FantiniNorihiro NishimotoTadamitsu KishimotoKazuyuki YoshizakiRalf KiesslichManfred BlessingJürgen BurgChristoph SchrammStefan Rose JohnChristoph BeckerHiroaki ItoSusanne StrandStefan WirtzSamuel HuberPeter R. GalleMarkus F. NeurathAlexei Nikolaev

subject

Genetically modified mouseSTAT3 Transcription FactorColorectal cancerRecombinant Fusion ProteinsT-LymphocytesImmunologyBlotting WesternEnzyme-Linked Immunosorbent AssayMice TransgenicProtein Serine-Threonine KinasesMiceIn vivoTransforming Growth Factor betamedicineImmunology and AllergyAnimalsHumansEndoscopy Digestive SystemIntestinal MucosaInterleukin 6Autocrine signallingMice KnockoutbiologyInterleukin-6Reverse Transcriptase Polymerase Chain ReactionReceptor Transforming Growth Factor-beta Type IIHistologymedicine.diseaseImmunohistochemistryReceptors Interleukin-6DNA-Binding ProteinsDisease Models AnimalInfectious DiseasesTumor progressionImmunologyColonic NeoplasmsCancer researchbiology.proteinDisease ProgressionTrans-ActivatorsReceptors Transforming Growth Factor betaTransforming growth factorSignal Transduction

description

Alterations of TGF-beta signaling have been described in colorectal cancer, although the molecular consequences are largely unknown. By using transgenic mice overexpressing TGF-beta or a dominant-negative TGF-betaRII, we demonstrate that TGF-beta signaling in tumor infiltrating T lymphocytes controls the growth of dysplastic epithelial cells in experimental colorectal cancer, as determined by histology and a novel system for high-resolution chromoendoscopy. At the molecular level, TGF-beta signaling in T cells regulated STAT-3 activation in tumor cells via IL-6. IL-6 signaling required tumor cell-derived soluble IL-6R rather than membrane bound IL-6R and suppression of such TGF-beta-dependent IL-6 trans-signaling prevented tumor progression in vivo. Taken together, our data provide novel insights into TGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on inhibition of TGF-beta-dependent IL-6 trans-signaling.

yearjournalcountryeditionlanguage
2004-10-01Immunity
10.1016/j.immuni.2004.07.020http://dx.doi.org/10.1016/j.immuni.2004.07.020