Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers.
Murine models of familial adenomatous polyposis harbor a germinal heterozygous mutation on Apc tumor suppressor gene. They are valuable tools for studying intestinal carcinogenesis, as most human sporadic cancers contain inactivating mutations of APC. However, Apc(+/-) mice, such as the well-characterized Apc(Min/+) model, develop cancers principally in the small intestine, while humans develop mainly colorectal cancers. We used a Cre-loxP strategy to achieve a new model of germline Apc invalidation in which exon 14 is deleted. We compared the phenotype of these Apc(Delta14/+) mice to that of the classical Apc(Min/+). The main phenotypic difference is the shift of the tumors in the distal colon and rectum, often associated with a rectal prolapse. Thus, the severity of the colorectal phenotype is partly due to the particular mutation Delta14, but also to environmental parameters, as mice raised in conventional conditions developed more colon cancers than those raised in pathogen-free conditions. All lesions, including early lesions, revealed Apc LOH and loss of Apc gene expression. They accumulated beta-catenin, overexpressed the beta-catenin target genes cyclin D1 and c-Myc, and the distribution pattern of glutamine synthetase, a beta-catenin target gene recently identified in the liver, was mosaic in intestinal adenomas. The Apc(Delta14/+) model is thus a useful new tool for studies on the molecular mechanisms of colorectal tumorigenesis.
Colnot
Sabine
S
Departement Genetique, Developpement et Pathologie Moleculaire, Institut Cochin--INSERM, CNRS UMR 8104, Universite Paris V, Paris, France.
Niwa-Kawakita
Michiko
M
Hamard
Ghislaine
G
Godard
Cécile
C
Le Plenier
Servane
S
Houbron
Christophe
C
Romagnolo
Béatrice
B
Berrebi
Dominique
D
Giovannini
Marco
M
Perret
Christine
C
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002999:Clone Cells; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D004273:DNA, Neoplasm / Q000235:genetics; D004195:Disease Models, Animal; D004777:Environment; D005091:Exons; D017353:Gene Deletion; D015723:Gene Library; D017491:Genes, APC / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D012334:RNA, Neoplasm / Q000235:genetics; D012004:Rectal Neoplasms / Q000235:genetics / Q000473:pathology; D017384:Sequence Deletion
D004273:DNA, Neoplasm; D012334:RNA, Neoplasm