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

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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2004-07, Vol.64 (14), p.4687-4692
Main Authors: BISWAS, Swati, CHYTIL, Anna, WASHINGTON, Kay, ROMERO-GALLO, Judith, GORSKA, Agnieszka E, WIRTH, Pamela S, GAUTAM, Shiva, MOSES, Harold L, GRADY, William M
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Apoptosis - genetics
Azoxymethane
Biological and medical sciences
Carcinogens
Carrier Proteins - genetics
Cell Differentiation - genetics
Cell Division - genetics
Cell Transformation, Neoplastic - chemically induced
Cell Transformation, Neoplastic - genetics
Colon - cytology
Colon - drug effects
Colon - metabolism
Colon - physiology
Colonic Neoplasms - chemically induced
Colonic Neoplasms - genetics
Colonic Neoplasms - pathology
Cyclooxygenase 2
Disease Models, Animal
Disease Progression
Fatty Acid-Binding Proteins
Female
Gene Silencing
Genetic Predisposition to Disease
Isoenzymes - biosynthesis
Male
Medical sciences
Mice
Mutation
Pharmacology. Drug treatments
Prostaglandin-Endoperoxide Synthases - biosynthesis
Protein-Serine-Threonine Kinases
Receptors, Transforming Growth Factor beta - antagonists & inhibitors
Receptors, Transforming Growth Factor beta - genetics
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-03-3255