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. 2004 Oct;21(4):491-501.
doi: 10.1016/j.immuni.2004.07.020.

TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling

Christoph Becker  1 , Massimo C Fantini, Christoph Schramm, Hans A Lehr, Stefan Wirtz, Alexei Nikolaev, Jürgen Burg, Susanne Strand, Ralf Kiesslich, Samuel Huber, Hiroaki Ito, Norihiro Nishimoto, Kazuyuki Yoshizaki, Tadamitsu Kishimoto, Peter R Galle, Manfred Blessing, Stefan Rose-John, Markus F Neurath
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Free article

TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling

Christoph Becker et al. Immunity. 2004 Oct.
Free article

Abstract

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.

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