Abstract
Deregulation of members of the transforming growth factor (TGF)-beta 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-beta signaling pathway and occurs in approximately 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-beta 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-beta 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-beta-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.
Highlights
Members of the transforming growth factor (TGF)- signaling pathway are common targets for mutation in colon cancers
The intact Tgfbr2flx allele was detected in colon epithelium of the Tgfbr2flx/flx mice
Our results demonstrate that Fabpl4xat-132 Cre Tgfbr2flx/flx mice do not express TGFBR2 in the majority of the colonic epithelium and that this Tgfbr2-null colon epithelium is highly susceptible to devel
Summary
Members of the transforming growth factor (TGF)- signaling pathway are common targets for mutation in colon cancers. Deregulation of this pathway appears to play an important role in colon carcinogenesis by affecting TGF--mediated growth inhibition, apoptosis, and differentiation as well as other TGF--regulated processes [1, 2]. We observed an increase in the number and pathological stage of colon neoplasms in the Fabpl4xat-132 Cre Tgfbr2flx/flx mice compared with the Tgfbr2flx/flx mice. These findings are consistent with TGFBR2 functioning as a tumor suppressor gene that has its predominant effect on impeding the progression of colon neoplasms toward malignancy
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