Article: article from journal or magazin.
IL-6 signaling promotes tumor growth in colorectal cancer
PT - Journal Article
Recent investigations support an important role for TGF-beta in the development of colorectal cancer. However, the molecular consequences of TGF-beta signaling in the colon remains incompletely understood. In a recent study in Immunity, we analyzed the role of TGF-beta in a murine model of colon cancer. Using transgenic mice overexpressing TGF-beta or a dominant negative TGF-beta receptor II under control of the CD2 minigene, we show that TGF-beta signaling in tumor infiltrating T lymphocytes regulates the growth of dysplastic colon epithelial cells, as determined by histology and a novel system for high resolution chromoendoscopy in vivo. 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. Similar to these observations in mice, here we show that human colon cancer tissue expressed only low amounts of membrane bound IL-6R. In contrast, expression and activity of the matrix metalloproteinase TACE were increased. In summary, our data provide novel insights into the role of TGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on an inhibition of TGF-beta-dependent IL-6 trans-signaling
ADAM Proteins/genetics/metabolism/Animals/Antigens,CD2/physiology/Antineoplastic Agents/pharmacology/therapeutic use/Cell Proliferation/Colorectal Neoplasms/drug therapy/Pathology/physiopathology/Gene Expression Regulation/Gene Expression Regulation,Neoplastic/Interleukin-6/antagonists & inhibitors/Mice/Mice,Transgenic/Receptors,Interleukin-6/Receptors,Transforming Growth Factor beta/STAT3 Transcription Factor/Signal Transduction/drug effects/T-Lymphocytes/Transforming Growth Factor beta
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