Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation.
A role for WNT signalling in gastric carcinogenesis has been suggested due to two major observations. First, patients with germline mutations in adenomatous polyposis coli (APC) are susceptible to stomach polyps and second, in gastric cancer, WNT activation confers a poor prognosis. However, the functional significance of deregulated WNT signalling in gastric homoeostasis and cancer is still unclear. In this study we have addressed this by investigating the immediate effects of WNT signalling activation within the stomach epithelium. We have specifically activated the WNT signalling pathway within the mouse adult gastric epithelium via deletion of either glycogen synthase kinase 3 (GSK3) or APC or via expression of a constitutively active β-catenin protein. WNT pathway deregulation dramatically affects stomach homoeostasis at very short latencies. In the corpus, there is rapid loss of parietal cells with fundic gland polyp (FGP) formation and adenomatous change, which are similar to those observed in familial adenomatous polyposis. In the antrum, adenomas occur from 4 days post-WNT activation. Taken together, these data show a pivotal role for WNT signalling in gastric homoeostasis, FGP formation and adenomagenesis. Loss of the parietal cell population and corresponding FGP formation, an early event in gastric carcinogenesis, as well as antral adenoma formation are immediate effects of nuclear β-catenin translocation and WNT target gene expression. Furthermore, our inducible murine model will permit a better understanding of the molecular changes required to drive tumourigenesis in the stomach.
CR-UK Beatson Institute of Cancer Research, Glasgow, UK.
S
S
Radulescu
R A
RA
Ridgway
J
J
Cordero
D
D
Athineos
P
P
Salgueiro
R
R
Poulsom
J
J
Neumann
A
A
Jung
S
S
Patel
J
J
Woodgett
N
N
Barker
D M
DM
Pritchard
K
K
Oien
O J
OJ
Sansom
D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019076:Transgenes; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D051153:Wnt Proteins; D051176:beta Catenin