OBJECTIVE: Expression of the Wnt target gene ASCL2 is elevated in 78% of intestinal neoplasia datasets (Oncomine), suggesting a role for deregulated ASCL2 in the aetiology of intestinal tumourigenesis. Furthermore, ectopic expression of Ascl2 has previously been shown to lead to hyperplasia in the mouse. However, elevated levels of ASCL2 does not have an impact on the overall survival or recurrence-free survival rates in colorectal cancer patients. Here the authors use a novel mouse model to analyse the role of Ascl2 in intestinal tumourigenesis and address the controversy surrounding the relevance of this gene to the aetiology of colorectal cancer. DESIGN: The authors have generated a mouse possessing a transgene carrying the Ascl2 gene together with its endogenous promoter and regulatory regions, thereby elevating Ascl2 expression in an authentic manner. The authors have further intercrossed these Ascl2 overexpressers to the classic Apc(Min) model, to study the consequence of elevated Ascl2 expression in intestinal tumourigenesis. RESULTS: Here the authors genetically demonstrate that elevated expression of Ascl2 in a Wnt signalling dependent manner specifically in the stem cell compartment of the intestine neither increases tumour formation nor diminishes survival in a well established intestinal tumour model, the Apc(min) mouse. CONCLUSION: The authors conclude that ectopic expression of Ascl2 is more important in the aetiology of neoplasia than overexpression of Ascl2.
OBJECTIVE: Expression of the Wnt target gene ASCL2 is elevated in 78% of intestinal neoplasia datasets (Oncomine), suggesting a role for deregulated ASCL2 in the aetiology of intestinal tumourigenesis. Furthermore, ectopic expression of Ascl2 has previously been shown to lead to hyperplasia in the mouse. However, elevated levels of ASCL2 does not have an impact on the overall survival or recurrence-free survival rates in colorectal cancerpatients. Here the authors use a novel mouse model to analyse the role of Ascl2 in intestinal tumourigenesis and address the controversy surrounding the relevance of this gene to the aetiology of colorectal cancer. DESIGN: The authors have generated a mouse possessing a transgene carrying the Ascl2 gene together with its endogenous promoter and regulatory regions, thereby elevating Ascl2 expression in an authentic manner. The authors have further intercrossed these Ascl2 overexpressers to the classic Apc(Min) model, to study the consequence of elevated Ascl2 expression in intestinal tumourigenesis. RESULTS: Here the authors genetically demonstrate that elevated expression of Ascl2 in a Wnt signalling dependent manner specifically in the stem cell compartment of the intestine neither increases tumour formation nor diminishes survival in a well established intestinal tumour model, the Apc(min) mouse. CONCLUSION: The authors conclude that ectopic expression of Ascl2 is more important in the aetiology of neoplasia than overexpression of Ascl2.
Authors: Simon J Tunster; Mathew Van de Pette; Hugo D J Creeth; Louis Lefebvre; Rosalind M John Journal: Dis Model Mech Date: 2018-11-16 Impact factor: 5.758