Conditional loss of TGF-beta signalling leads to increased susceptibility to gastrointestinal carcinogenesis in mice.

Abstract

BACKGROUND:

Downregulation of TGF-beta receptors is implicated in colon cancer development. Inactivation of either of the two transmembrane serine/threonine kinases, TGF-beta1 types I/II receptors, is now implicated in carcinogenesis, especially gastrointestinal carcinogenesis.

METHODS:

We generated transgenic mice, called pS2-dnRII or ITF-dnRII, of which the dominant negative mutant of the TGF-beta type II receptor was expressed under the control of tissue-specific promoters, the pS2 promoter for stomach and ITF for intestine. They were either infected with H.pylori (ATCC 43504 strain, CagA+ and VacA+) or administered with azoxymethane to determine the significance of loss of TGF-beta signalling in gastrointestinal carcinogenesis.

RESULTS:

Gastric adenocarcinoma developed in pS2-dnRII mice, whereas only chronic active gastritis was noted in wild-type littermates after 36 weeks of H.pylori infection. Mice lacking in TGF-beta signalling specifically in the stomach showed a significantly higher proliferation cell nuclear antigen-labelling index when infected with H.pylori than wild-type littermates (P < 0.01). Development of colonic aberrant crypt foci was provoked in mice by intraperitoneal injections of azoxymethane, and ITF-dnRII mice showed significantly higher incidences of ACF and colon cancers than wild-type littermates.

CONCLUSIONS:

Maintaining normal TGF-beta signalling in the gastrointestinal tract seems to be important either for preventing abnormal mucosal proliferation, or for suppressing or retarding carcinogenesis.

• Authors: K-B Hahm, K M Lee, Y B Kim, W S Hong, W H Lee, S U Han, M W Kim, B O Ahn, T Y Oh, M H Lee, J Green, S J Kim
• Journal: Alimentary pharmacology & therapeutics (Aliment Pharmacol Ther) Vol. 16 Suppl 2 Pg. 115-27 (Apr 2002) ISSN: 0269-2813 [Print] England
• PMID: 11966532 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens
• Receptors, Transforming Growth Factor beta
• Transforming Growth Factor beta
• Azoxymethane

Topics

• Animals
• Azoxymethane (toxicity)
• Carcinogens (toxicity)
• Carcinoma (etiology, genetics, metabolism, pathology)
• Colonic Neoplasms (genetics, metabolism, pathology)
• Disease Susceptibility
• Gastritis (etiology, genetics, metabolism, pathology)
• Helicobacter Infections (complications, genetics, metabolism, pathology)
• Helicobacter pylori
• Mice
• Mice, Transgenic
• Receptors, Transforming Growth Factor beta (genetics, metabolism)
• Signal Transduction
• Stomach Neoplasms (etiology, genetics, metabolism, pathology)
• Transforming Growth Factor beta (genetics, metabolism)