Apc mice: Models, modifiers and mutants

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Abstract

The mouse provides an excellent in vivo system with which to model human diseases and to test therapies. Mutations in the Adenomatous polyposis coli (APC) gene are required to initiate familial adenomatous polyposis (FAP) and are also important in sporadic colorectal cancer tumorigenesis. The (multiple intestinal neoplasia Min) mouse contains a point mutation in the Apc gene, develops numerous adenomas and was the first model used to study the involvement of the Apc gene in intestinal tumorigenesis. The model has provided examples of modifying loci (called Modifiers of Min: Mom) in mice, demonstrating the principle of genetic modulation of disease severity. A spectrum of Apc mutant mice has since been developed, each with defining characteristics, some more able to accurately model human polyposis and colon cancer. We will focus our review on Apc mutant mouse models, the advent of models with concurrent or compound mutations and the importance of genetic background when modeling polyposis and cancer. Brief consideration will be given to the use of these models in drug testing.

Section snippets

Colorectal cancer and APC

Colorectal cancer (CRC) is the second leading cause of cancer-related death in the Western world and is currently the third most common form of cancer. Mutations in the Adenomatous polyposis coli (APC) gene are responsible for the familial adenomatous polyposis (FAP) syndrome, and are an early causative event in sporadic cancer development [45]. APC is a large multidomain protein (2843 amino acids) that functions to down-regulate the Wnt signalling pathway by binding to and promoting the

The Min mouse

The multiple intestinal neoplasia (Min) mouse was identified following random mutagenesis with ethylnitrosourea [42]. It was subsequently established that a truncating mutation at codon 850 of Apc was responsible for the phenotype, which resembles that of human FAP [74]. Mice carrying a heterozygous mutation, ApcMin/+, develop approximately 30 small intestinal polyps (both pedunculated polyps and flat adenomas) when on the C57BL/6 background; polyps only occasionally progress to invasive

Modifiers of the Min phenotype

Distinct human kindreds with identical mutant APC alleles display diverse phenotypes, including colonic polyp burden. Such diversity is often thought to be due to environment, particularly diet, or genetic modifiers: genes that alter disease severity by interacting, directly or indirectly, with the primary genetic mutation causing the disease. Interestingly, this scenario is repeated in the ApcMin/+ mouse, which under normal laboratory conditions is considered to be genetically and

Apc mutations and the mouse

Many genetically engineered mouse (GEM) strains have been generated in an attempt to more accurately model the mutations common in FAP kindreds and sporadic CRCs. These models, as for the Min model, require loss of the wild-type Apc allele in order for tumorigenesis to take place. While onset, severity and location of tumors is Apc mutation-dependent, the tumor histology of the various Apc mutant mice is similar [9]. Pertinent examples of such GEM are outlined in Table 2 and a schematic

Apc compound mutants

Despite the wealth of information that mouse models of Apc deficiency have provided about the in vivo biology of this protein, there are several critical drawbacks in relating these models to human intestinal neoplasia. For example, in Apc mouse models, polyp formation is favored in the small intestine, in contrast to human disease, which occurs predominantly in the colon. There is still no adequate explanation for this. Crucially, there is little or no invasion of tumors arising in Apc mouse

Apc mouse models provide insight into the role of Wnt pathway components in CRC

The pathological changes associated with Apc deficiency include increases in crypt size, cell proliferation and apoptosis. In addition, the cells in Apc-deficient crypts show reduced crypt to villus migration and differentiation [2]. There is considerable interest in understanding the molecular pathways associated with these phenotypes, and several investigations have been aimed at elucidating the additional genes involved. In contrast to what has been previously thought, studies using an

Genomic in stability

There are two types of genomic instability known to play a role in human tumorigenesis: chromosomal instability resulting in losses and/or gains of chromosomal regions and microsatellite instability, characteristic of mismatch repair (MMR) deficiency. Both types of instability have been shown to enhance intestinal neoplasia in Apc mouse models.

LOH of the wild-type Apc allele is one of the initiating events of tumor formation in Apc mouse models of intestinal neoplasia, and mitotic recombination

Epigenetic modifiers

Aberrant epigenetic state is a hallmark of cancer, due to dual roles in genome stability and gene expression. Human cancers are known to be associated with both hypo- and hyper-methylation of genomic DNA [83]. Deficiency of DNA methyltransferases and methyl-binding proteins suppress intestinal polyp formation in ApcMin/+ mice while promoting tumorigenesis in other tissues [38], [59], [84]. Notably, while loss of the maintenance DNA methyltransferase, Dnmt1, was implicated in promoting colonic

Prostaglandin biosynthesis

Prostaglandins are thought to contribute to tumorigenesis through their role in cell proliferation, apoptosis, differentiation and angiogenesis. Apc mouse models have provided considerable insight into the importance of these metabolites in vivo, revealing that many of the genes involved in their production have dramatic effects on tumor multiplicity and size. Disruption of the genes encoding Cox-1 and Cox-2 (Ptgs1 and Ptgs2), led to an approximately 80% reduction of polyp numbers and decrease

Compound mice giving rise to adenocarcinoma

Due to the general lack of invasive tumors in Apc mouse models, studies have focused particular attention on the influence of genes known to be important in the adenoma–carcinoma transition in efforts to recapitulate invasive disease in the mouse. The signal transducer Kras is found mutated in 40–50% of all human CRCs [61], but not in polyps from Apc mouse models [47], [70]. Apc-deficient mice (Apc580D) carrying an oncogenic Kras allele showed that 17% of tumors developed into aggressive

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    These authors contributed equally.

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