Transforming growth factor β receptor type II inactivation induces the malignant transformation of intestinal neoplasms initiated by Apc mutation

Nina M. Muñoz, Melissa Upton, Andres Rojas, M. Kay Washington, Li Lin, Anna Chytil, Elif G. Sozmen, Blair B. Madison, Ambra Pozzi, Randall T. Moon, Harold L. Moses, William M. Grady

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124 Scopus citations

Abstract

The transforming growth factor-β (TGF-β) signaling pathway is a tumor-suppressor pathway that is commonly inactivated in colon cancer. TGF-β 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, Villin-Cre;Tgfbr2 E2flx/E2flx mice. In this model, we observed a dramatic increase in the number of intestinal adenocarcinomas in the Apc 1638N/wt;Villin-Cre;Tgfbr2 E2flx/E2flx mice (called Apc 1638N/wt; Tgfbr2 IEKO) compared with those mice with intact Tgfbr2 (Apc 1638N/wt;Tgfbr2 E2flx/E2flx). Additionally, in vitro analyses of epithelial tumor cells derived from the Apc 1638N/wt;Tgfbr2 IEKO mice showed enhanced expression and activity of matrix metalloproteinase MMP-2 and MMP-9, as well as increased TGF-β1 secretion in the conditioned medium. Similarly, primary tumor tissues from the Apc 1638N/wt;Tgfbr2 IEKO mice also showed elevated amounts of TGF-β1 as well as higher MMP-2 activity in comparison with Apc 1638N/wt;Tgfbr2 E2flx/E2flx-derived tumors. Thus, loss of TGFBR2 in intestinal epithelial cells promotes the invasion and malignant transformation of tumors initiated by Ape mutation, providing evidence that Wnt signaling deregulation and TGF-β signaling inactivation cooperate to drive the initiation and progression, respectively, of intestinal cancers in vivo.

Original languageEnglish
Pages (from-to)9837-9844
Number of pages8
JournalCancer research
Volume66
Issue number20
DOIs
StatePublished - Oct 15 2006

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    Muñoz, N. M., Upton, M., Rojas, A., Washington, M. K., Lin, L., Chytil, A., Sozmen, E. G., Madison, B. B., Pozzi, A., Moon, R. T., Moses, H. L., & Grady, W. M. (2006). Transforming growth factor β receptor type II inactivation induces the malignant transformation of intestinal neoplasms initiated by Apc mutation. Cancer research, 66(20), 9837-9844. https://doi.org/10.1158/0008-5472.CAN-06-0890