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Transforming Growth Factor ß Receptor Type II Inactivation Promotes the Establishment and Progression of Colon Cancer

Departments of ¹ Medicine, ² Cancer Biology, and ³ Pathology, Vanderbilt University Medical School, Nashville, Tennessee; ⁴ Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee; and ⁵ Department of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts

Deregulation of members of the transforming growth factor (TGF)-ß signaling pathway occurs often in colon cancers and is believed to affect the formation of primary colon cancer. Mutational inactivation of TGFBR2 is the most common genetic event affecting the TGF-ß signaling pathway and occurs in 20–30% of all colon cancers. By mating Fabpl^4xat-132 Cre mice with Tgfbr2^flx/flx mice, we have generated a mouse model that is null for Tgfbr2 in the colonic epithelium, and in this model system, we have assessed the effect of loss of TGF-ß signaling in vivo on colon cancer formation induced by azoxymethane (AOM). We have observed a significant increase in the number of AOM-induced adenomas and adenocarcinomas in the Fabpl^4xat-132 Cre Tgfbr2^flx/flx mice compared with Tgfbr2^flx/flx mice, which have intact TGF-ß receptor type II (TGFBR2) in the colon epithelium, and we have found increased proliferation in the neoplasms occurring in the Fabpl^4xat-132 Cre Tgfbr2^flx/flx mice. These results implicate the loss of TGF-ß-mediated growth inhibition as one of the in vivo mechanisms through which TGFBR2 inactivation contributes to colon cancer formation. Thus, we have demonstrated that loss of TGFBR2 in colon epithelial cells promotes the establishment and progression of AOM-induced colon neoplasms, providing evidence from an in vivo model system that TGFBR2 is a tumor suppressor gene in the colon.

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