The transforming growth factor-B (TGF-B) signaling pathway is a tumor-suppressor pathway that is commonly inactivated in colon cancer. TGF-B is a secreted ligand that mediates its effects through a transmembrane heteromeric receptor complex, which consists of type I (TGFBR1) and type II subunits (TGFBR2). Approximately 30% of colon cancers carry TGFBR2 mutations, demonstrating that it is a common target for mutational inactivation in this cancer. To assess the functional role of TGFBR2 inactivation in the multistep progression sequence of colon cancer, we generated a mouse model that recapitulates two common genetic events observed in human colon cancer by mating Apc 1638N/wt mice with mice that are null for Tgfbr2 in the intestinal epithelium, VillinCre;Tgfbr2E2flx/E2flx mice. mice showed enhanced expression and activity of matrix metalloproteinase MMP-2 and MMP-9, as well as increased TGF-B1 secretion in the conditioned medium. Similarly, primary tumor tissues from the Apc 1638N/wt ;Tgfbr2 IEKO mice also showed elevated amounts of TGF-B1 as well as higher MMP-2 activity in comparison with Apc 1638N/wt ;Tgfbr2E2fl x/E2fl x -derived tumors. Thus, loss of TGFBR2 in intestinal epithelial cells promotes the invasion and malignant transformation of tumors initiated by Apc mutation, providing evidence that Wnt signaling deregulation and TGF-B signaling inactivation cooperate to drive the initiation and progression, respectively, of intestinal cancers in vivo.

As an established mediator of inflammation, IL-6 is implicated to facilitate prostate cancer progression to androgen independence through transactivation of the androgen receptor. However, whether IL-6 plays a causative role in de novo prostate tumorigenesis was never investigated. We now provide the first evidence that IL-6 can induce tumorigenic conversion and further progression to an invasive phenotype of non-tumorigenic benign prostate epithelial cells. Moreover, we find that paracrine IL-6 stimulates autocrine IL-6 loop and autocrine activation of IGF-IR to confer the tumorigenic property and that activation of STAT3 is critical in these processes. Inhibition of STAT3 activation or IGF-IR signaling suppresses IL-6-mediated malignant conversion and the associated invasive phenotype. Inhibition of STAT3 activation suppresses IL-6-induced upregulation of IGF-IR and its ligands IGF-I and IGF-II. These findings indicate IL-6 signaling cooperates with IGF-IR signaling in the prostate microenvironment to promote prostate tumorigenesis and progression to aggressiveness. Our findings suggest that STAT3 and IGF-IR may represent potential effective targets for prevention or treatment of prostate cancer.