IngentaConnect Conditional loss of TGF- signalling leads to increased susceptibi...

Authors: Hahm, K-B.¹; Lee, K. M.¹; Kim, Y. B.¹; Hong, W. S.²; Lee, W. H.¹; Han, S. U.¹; Kim, M. W.¹; Ahn, B. O.³; Oh, T. Y.³; Lee, M. H.¹; Green, J.⁴; Kim, S. J.⁴

Source: Alimentary Pharmacology & Therapeutics, Volume 16, Supplement 2, April 2002 , pp. 115-127(13)

Publisher: Blackwell Publishing

Abstract:

Background:

Downregulation of TGF-β receptors is implicated in colon cancer development. Inactivation of either of the two transmembrane serine/threonine kinases, TGF-β1 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-β 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-β 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-β 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-β signalling in the gastrointestinal tract seems to be important either for preventing abnormal mucosal proliferation, or for suppressing or retarding carcinogenesis.

Document Type: Research article

DOI: 10.1046/j.1365-2036.16.s2.3.x

Affiliations: 1: Ajou Helicobacter Research Group, Ajou University School of Medicine, Suwon, Korea, 2: Asan Medical Center, Ulsan University School of Medicine, Seoul, Korea, 3: Dong-A Pharmaceutical Research Institute, Yongin, Korea, 4: Laboratory of Cell Regulation and Carcinogenesis, NCI, Bethesda, MD, USA

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