A hypermorphic epithelial beta-catenin mutation facilitates intestinal tumorigenesis in mice in response to compounding WNT-pathway mutations.
Fiche publication
Date publication
août 2015
Auteurs
Membres identifiés du Cancéropôle Est :
Dr OREND Gertraud
Tous les auteurs :
Buchert M, Rohde F, Eissmann M, Tebbutt N, Williams B, Tan CW, Owen A, Hirokawa Y, Gnann A, Orend G, Orner G, Dashwood RH, Heath JK, Ernst M, Janssen KP
Lien Pubmed
Résumé
Activation of the Wnt/beta-catenin pathway occurs in a vast majority of colorectal cancers. However, the outcome of the disease strongly varies from patient to patient, even within the same tumor stage. This heterogeneity is governed in large parts by the genetic makeup of individual tumors and the combination of oncogenic mutations.To express throughout the intestinal epithelium a degradation resistant beta-catenin (Ctnnb1) which lacks the first 131 amino acids, we inserted an epitope-tagged DeltaN(1-131)-beta-catenin encoding cDNA as a knockin transgene into the endogenous gpA33 gene locus in mice. The resulting gpA33DeltaN-Bcat mice show increased constitutive Wnt/beta-catenin pathway activation that shifts the cell fate towards the Paneth cell lineage in pre-malignant intestinal epithelium. Furthermore, 19% of all heterozygous and 37% of all homozygous gpA33DeltaN-Bcat mice spontaneously develop aberrant crypt foci and adenomatous polyps, at frequencies and latencies akin to that observed in sporadic colon cancer in humans. Consistent with this, the Wnt target genes, MMP7 and Tenascin-C, which are expressed highest in benign human adenomas and early tumor stages, were up-regulated in pre-malignant tissue of gpA33DeltaN-Bcat mice, but not those Wnt target genes associated with excessive proliferation (i.e Cdnn1, c-myc). We also detected diminished expression of membrane-associated alpha-catenin and increased intestinal permeability in gpA33DeltaN-Bcat mice under challenged conditions, providing a potential explanation for the observed mild chronic intestinal inflammation and increased susceptibility to azoxymethane and mutant Apc-dependent tumorigenesis. Collectively, our data indicate that epithelial expression of DeltaN(1-131)-beta-catenin in the intestine creates an inflammatory microenvironment and cooperates with other mutations in the Wnt/beta-catenin pathway to facilitate and promote tumorigenesis.
Référence
Dis Model Mech. 2015 Aug 6. pii: dmm.019844.