Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis.
The transforming growth factor beta (TGF-beta) pathway is known to play an important role in both human and urine colon cancer. However, the staging, ligand specificity, and mechanism underlying the tumor suppressive activity of this pathway are unknown. We developed a mouse model for colon cancer that identifies an early role for TGF-beta1 in tumor suppression and implicates TGF-beta2 or TGF-beta3 in the prevention of metastasis. Analysis of the development of colon cancer in TGF-beta1 knockout mice pinpoints the defect to the hyperplasty/adenoma transition and reveals that the mechanism involves an inability to maintain epithelial tissue organization and not a loss of growth control, increased inflammatory activity, or increased genetic instability. These mice provide a unique opportunity to investigate the specific role of TGF-beta1 at this critical transition in the development of colon cancer.
Engle
S J
SJ
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Ohio 45267, USA.
Hoying
J B
JB
Boivin
G P
GP
Ormsby
I
I
Gartside
P S
PS
Doetschman
T
T
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000236:Adenoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers; D002432:Cecum / Q000201:enzymology / Q000473:pathology; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D003106:Colon / Q000201:enzymology / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003433:Crosses, Genetic; D003598:Cytoskeletal Proteins / Q000032:analysis; D004247:DNA / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins; D018450:Disease Progression; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D006801:Humans; D006965:Hyperplasia; D007249:Inflammation / Q000201:enzymology; D007413:Intestinal Mucosa / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018895:Microsatellite Repeats; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins; D013047:Specific Pathogen-Free Organisms; D015534:Trans-Activators; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology / Q000627:therapeutic use*; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; D015415:Biomarkers; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C064655:V(D)J recombination activating protein 2; D051176:beta Catenin; D004247:DNA