Recent investigations support an important role for TGF-? in the development of colorectal cancer. However, the molecular consequences ofTGF-? signaling in the colon remains incompletely understood. In a recent study in Immunity, we analyzed the role of TGF-? in a murine model of colon cancer. Using transgenic mice overexpressing TGF-? or a dominant negative TGF-? receptor II under control of the CD2 minigene, we show that TGF-? 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-? 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-?-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-? signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on an inhibition of TGF-?-dependent IL-6 trans-signaling.