A key regulatory role of TGFβ in Ulcerative Colitis associated Colon Cancer development

Colon cancer is a well known complication of ulcerative colitis, a clinical condition where colon mucosa is involved by inflammatory flares alternated to periods of remission. The role played by this inflammatory process in determining the events at the basis of colon cancer initiation and progression in Ulcerative Colitis has not been yet clearly determinated. To shed light on this field we have focused our attention on TGF-beta, a key molecule involved in the modulation of the inflammatory responses. For this purpose we have developed an inflammation associated colon cancer model in the FVB mouse strain based on a pre-treatment with azoxymethane (AOM), a mutagenous agent and repeated seven days cycles of Dextran Sulfate (DSS) alternated to DSS-free periods to induce a relapsing colitis for a period of 80 days. This cancer model has been applied to FVB wild type mice and to FVB transgenic mice carrying a transgene for TGF-beta under the control of the CD2 promoter/enhancer as well as transgenic mice with a dominant negative type II TGF-beta receptor (dnTGFBetaRII) in T cells. Cancer development was tightly monitored in the colon by high resolution endoscopy and chromoendoscopy with bioptic sampling of the suspected early lesions by mean of a newly developed miniendoscope (Coloview system). Wild type mice have developed Aberrant Crypt Foci (ACFs) and DALM-like lesions (Dysplasia Associated Lesion or Mass) as early as 40 days mainly localized in the terminal part of the colon. At the same date of the treatment protocol dnTGF-BetaRII transgenic mice showed a massive involvement of the distal colon with more ACFs and DALMs as compared to the wild type mice, while TGF-Beta transgenic mice showed the presence of few polypoid lesions only in a minority of cases.

On the basis of these results TGF-Beta seems to be of fundamental relevance in controlling the initiation and progression steps in this Ulcerative Colitis associated Colon Cancer model acting, at least in part, on the immune system cells through the modulation of the inflammatory process localized in the colon mucosa.