Mouse model of colorectal and intestinal cancer
Mouse models of colorectal cancer and intestinal cancer are experimental systems in which mice are genetically manipulated, fed a modified diet, or challenged with chemicals to develop malignancies in the gastrointestinal tract. These models enable researchers to study the onset, progression of the disease, and understand in depth the molecular events that contribute to the development and spread of colorectal cancer. They also provide a valuable biological system, to simulate human physiological conditions, suitable for testing therapeutics.[1][2][3]
Colorectal and intestinal cancer
Familial Adenomatous Polyposis
Familial Adenomatous Polyposis (
APC mutant mice
The first mouse mutant in the Apc gene came from a colony of randomly mutagenized mice.[5] This mouse model is called Min (multiple intestinal neoplasia) mouse. It was found to carry a truncation mutation at codon 850 of the Apc gene. The Min mouse can develop up to 100 polyps in the small intestine in addition to colon tumors. Later, new knock-out mutants of the Apc gene were engineered. A truncating mutation at codon 716 (ApcΔ716) [6] results in a mouse that develops more than 300 polyps in the small intestine, while truncation at codon 1638 (Apc1638N) [7] results in the formation of about only 3 polyps in the same region of the gastrointestinal tract.[8] More recently a new mutant Apc mouse model was constructed in which multiple polyps form in the distal colon.[9] In this model mutation in the Cdx2 gene in the ApcΔ716 mouse model shifted the formation of the polyps from the intestine to the colon, resembling the human FAP. The Apc mutant mice are characterized by early lethality. There are genes modifying the cancer susceptibility of these mouse models. The most well-established is the modifier of Min locus (Mom1).[10] With combination of Min and Mom1 mutations the lifespan of FAP mouse models of colorectal cancer is increased.
APC was found to associate with catenins.
Hereditary nonpolyposis colorectal cancer
The most frequent mutations in Hereditary nonpolyposis colorectal cancer (HNPCC) are mutations in the MSH2 and MLH1 genes.[14] These genes play an important role in repairing incorrectly positioned nucleotides. Another gene involved in DNA mismatch repair is Msh6. Both the Msh6 [15] and Msh2 [16] mutant mice develop gastrointestinal cancer but the tumours differ in their microsatellite instability (MI) status. While MSH2 deficiency promotes MI-high tumours, MSH6 deficiency results in MI-low tumours. Another component of the DNA repair machinery in the cell is the protein MLH1. Ablation of MLH1 in mice causes development of gastrointestinal tumours in the small intestine [17] – adenomas and invasive carcinomas.[18] The combination of MLH1 deficiency with the Apc1638N [6] mutant mouse results in strong reduction of viability and increased tumour burden. The tumours were classified as adenomas, invasive adenocarcinomas and late stage carcinomas. Similarly, mice deficient for Msh2 combined with Apc Min demonstrate accelerated rate of tumorigenesis.[19] Another similar mouse model of HNPCC is the combination of PMS2 mutant mouse with the Min Apc allele resulting in increased number of tumours in the gastrointestinal tract compared to Min.[20] Yet these adenocarcinomas do not metastasize and their histopathology is similar to that of the right side colon cancer in human with frequent mutation of the type II receptor for TGF-β.
Mutations in other genes
Mice with mutations in
Human
Humans with high levels of the diet-related bile acid deoxycholate (DOC) in their colons are at a substantially increased risk of developing colon cancer (see Bile acids and colon cancer). A diet-related mouse model of colon cancer was devised.[28][29] In this model, wild type mice are fed a standard diet plus DOC to give a level of DOC in mouse colon comparable to that in the colons of humans on a high fat diet.[28] After 8–10 months, 45% to 56% of the mice developed colonic adenocarcinomas, and no mice had cancers of the small intestine.
On the basis of
Chemically-induced colorectal cancer
Azoxymethane (AOM) is a genotoxic colonic carcinogen and is routinely used to induce colon tumours in mice.[30] The AOM-induced tumours form in the last three centimeters of the distal colon but a p21 knock out mouse treated with AOM shows tumour distribution throughout the colon.[31] AOM-induced tumours are characterized with mutations in the Apc gene.[32]
A novel inflammation-related mouse model of colorectal carcinogenesis combines AOM and dextran sodium sulphate (DSS) to induce colon lesions, positive for beta-catenin, COX-2 and inducible nitric oxide synthase.[33]
See also
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