Conditional loss of TGF-beta signalling leads to increased susceptibility to gastrointestinal carcinogenesis in mice.
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.
Hahm
K-B
KB
Ajou Helicobacter Research Group, Ajou University School of Medicine, Wonchon-dong, Padal-ku, Suwon, Korea. hahmkb@hotmail.com
Lee
K M
KM
Kim
Y B
YB
Hong
W S
WS
Lee
W H
WH
Han
S U
SU
Kim
M W
MW
Ahn
B O
BO
Oh
T Y
TY
Lee
M H
MH
Green
J
J
Kim
S J
SJ
D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002277:Carcinoma / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004198:Disease Susceptibility; D005756:Gastritis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016481:Helicobacter Infections / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016480:Helicobacter pylori; D051379:Mice; D008822:Mice, Transgenic; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D002273:Carcinogens; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D001397:Azoxymethane