Conditional loss of TGF-beta signalling leads to increased susceptibility to gastrointestinal carcinogenesis in mice.
2002
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.
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