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

Colorectal cancer is one of the most common fatal malignancies worldwide., with an incidence second only to lung cancer. However, the molecular pathogenesis of colorectal cancer is still poorly understood. Several lines of evidence suggest an important role of TGF-beta signaling in cancer development, although the molecular and immunological mechanisms are largely unknown. We have analyzed the role of TGF-beta signaling in a murine model of colon carcinoma. In the present manuscript we provide evidence that TGF-beta signaling in infiltrating CD4+ T cells is important to control the growth of dysplastic epithelial cells. Mice overexpressing a dominant negative TGF-betaRII developed more and larger tumors than wildtype control animals. Screening of the cytokine expression pattern in these animals revealed an overexpression of IL–6 in transgenic mice as compared to controls. We then found that colitis dependant IL–6 induction coincided with the first appearance of rapidly growing dysplastic lesions around day 20 of the experiments. Immunohistochemical staining of tumors demonstrated a strong down regulation of the IL–6 receptor alpha chain on dysplastic epithelial cells. However, dysplastic epithelial cells maintained strong nuclear staining for phospho-STAT–3, a target molecule of IL–6 signaling. We therefore tested whether IL–6 transsignaling could induce proliferation of dysplastic epithelial cells. Accordingly the injection of hyper-IL–6 resulted in a stronger proliferation of dysplastic epithelial cells as measured by immunohistochemistry for the proliferation marker KI–67. Taken together our data show for the first time that colon tumor genesis is promoted by IL–6 transsignaling and that TGF-beta signaling in T cells interferes with this.

Key words

IL-6 - TGF-beta - colon cancer - trans-signalling