Transforming growth factor beta receptor type II inactivation promotes the establishment and progression of colon cancer.

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.

• Authors: Swati Biswas, Anna Chytil, Kay Washington, Judith Romero-Gallo, Agnieszka E Gorska, Pamela S Wirth, Shiva Gautam, Harold L Moses, William M Grady
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 14 Pg. 4687-92 (Jul 15 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15256431 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carcinogens
• Carrier Proteins
• Fatty Acid-Binding Proteins
• Isoenzymes
• Receptors, Transforming Growth Factor beta
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type II
• Azoxymethane

Topics

• Animals
• Apoptosis (genetics)
• Azoxymethane
• Carcinogens
• Carrier Proteins (genetics)
• Cell Differentiation (genetics)
• Cell Division (genetics)
• Cell Transformation, Neoplastic (chemically induced, genetics)
• Colon (cytology, drug effects, metabolism, physiology)
• Colonic Neoplasms (chemically induced, genetics, pathology)
• Cyclooxygenase 2
• Disease Models, Animal
• Disease Progression
• Fatty Acid-Binding Proteins
• Female
• Gene Silencing
• Genetic Predisposition to Disease
• Isoenzymes (biosynthesis)
• Male
• Mice
• Mutation
• Prostaglandin-Endoperoxide Synthases (biosynthesis)
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type II
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors, genetics)