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Transforming Growth Factor ß Receptor Type II Inactivation Induces the Malignant Transformation of Intestinal Neoplasms Initiated by Apc Mutation

Departments of ¹ Cancer Biology, ² Pathology, and ³ Medicine, Vanderbilt University Medical School, Nashville, Tennessee; ⁴ Clinical Research and ⁵ Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center; Departments of ⁶ Pathology and ⁷ Medicine, University of Washington Medical School; ⁸ Howard Hughes Medical Institute; ⁹ Department of Veterans Affairs R&D Service, Puget Sound Healthcare System, Seattle, Washington; and ¹⁰ Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan

Requests for reprints: William M. Grady, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D4-100, Seattle, WA 98109. Phone: 206-667-1107; Fax: 206-667-2917; E-mail: wgrady{at}fhcrc.org.

The transforming growth factor-ß (TGF-ß) signaling pathway is a tumor-suppressor pathway that is commonly inactivated in colon cancer. TGF-ß 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-ß1 secretion in the conditioned medium. Similarly, primary tumor tissues from the Apc^1638N/wt;Tgfbr2^IEKO mice also showed elevated amounts of TGF-ß1 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 Apc mutation, providing evidence that Wnt signaling deregulation and TGF-ß signaling inactivation cooperate to drive the initiation and progression, respectively, of intestinal cancers in vivo. (Cancer Res 2006; 66(20): 9837-44)

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