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Transforming Growth Factor β Receptor Type II Inactivation Induces the Malignant Transformation of Intestinal Neoplasms Initiated by Apc Mutation
- Source :
- Cancer Research. 66:9837-9844
- Publication Year :
- 2006
- Publisher :
- American Association for Cancer Research (AACR), 2006.
-
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 Apc1638N/wt mice with mice that are null for Tgfbr2 in the intestinal epithelium, Villin-Cre;Tgfbr2E2flx/E2flx mice. In this model, we observed a dramatic increase in the number of intestinal adenocarcinomas in the Apc1638N/wt;Villin-Cre;Tgfbr2E2flx/E2flx mice (called Apc1638N/wt;Tgfbr2IEKO) compared with those mice with intact Tgfbr2 (Apc1638N/wt;Tgfbr2E2flx/E2flx). Additionally, in vitro analyses of epithelial tumor cells derived from the Apc1638N/wt;Tgfbr2IEKO 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 Apc1638N/wt;Tgfbr2IEKO mice also showed elevated amounts of TGF-β1 as well as higher MMP-2 activity in comparison with Apc1638N/wt;Tgfbr2E2flx/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-β signaling inactivation cooperate to drive the initiation and progression, respectively, of intestinal cancers in vivo. (Cancer Res 2006; 66(20): 9837-44)
- Subjects :
- Male
Cancer Research
Receptor complex
medicine.medical_specialty
Genes, APC
Tumor suppressor gene
Colorectal cancer
Mice, Transgenic
Cell Growth Processes
Protein Serine-Threonine Kinases
Biology
medicine.disease_cause
Malignant transformation
Mice
Internal medicine
medicine
Animals
Neoplasm Invasiveness
Gene Silencing
Intestinal Mucosa
Receptor, Transforming Growth Factor-beta Type II
Wnt signaling pathway
medicine.disease
Intestinal epithelium
Gene Expression Regulation, Neoplastic
Cell Transformation, Neoplastic
Endocrinology
Oncology
Colonic Neoplasms
Mutation
Disease Progression
Cancer research
Female
Carcinogenesis
Receptors, Transforming Growth Factor beta
Transforming growth factor
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 66
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....e6fcd628340d8223d93ff3de7f19d9ae