Mouse models of colorectal and intestinal cancer
Encyclopedia
Mouse models
of colorectal cancer
and intestinal cancer are experimental systems in which mice are genetically manipulated 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 that can potentially benefit patients. An important example is the development of the APC mutant mouse model of colorectal cancer and the subsequent observation that cyclooxygenase
expression is an early event in colorectal carcinogenesis. Genetic disruption of the cyclooxygenase-2 (COX-2) gene or inhibition of the activity of COX-2 with chemical inhibitors reduced the polyp burden in mice. These observations gave rationale to treat human patients suffering from the familial form of the disease FAP
with specific COX-2 inhibitors.
is a hereditary disease that is characterized with development of numerous colon polyps. A genetic analysis of some FAP kindreds revealed that a common feature of the disease is a deletion of the APC gene. Further analysis of the APC gene revealed the existence of various mutations in cancer sufferers that also play a role in the onset of the sporadic form of colorectal cancer.
APC was found to associate with catenins. Today we know that the beta-catenin
protein (part of the Wnt signaling pathway
) is implicated in colorectal carcinogenesis and its stability in the cell is regulated by APC. A mouse model with deregulation of beta-catenin levels was created. The conditional stabilizing mutation in the beta-catenin gene caused formation of up to 3000 polyps in the small intestine of this mouse model.
A mouse model carrying mutations in ApcΔ716 and Smad4 (mothers against decapentaplegic homolog 4
) is characterized with development of invasive adencarcinomas.
and MLH1
genes. These genes play an important role in repairing incorrectly positioned nucleotides. Another gene involved in DNA mismatch repair
is Msh6. Both the Msh6 and Msh2 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 – adenomas and invasive carcinomas. The combination of MLH1 deficiency with the Apc1638N 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. 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. 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.
-β1 gene introduced into Rag2 mutant mouse promotes adenocarcinomas with strong local invasion. Colon-specific expression of activated mutant of K-ras (protein)
(K-rasG12D) results in development of single or multiple lesions. Oncogenic K-rasG12D allele activated in colon epithelium induces expression of procarcinogenic protein kinase C
-βII (PKCβII) and increases cell proliferation of epithelial cells, while in the distal colon the mutant form of K-ras has the opposite effects on PKCβII expression and cell proliferation. Treatment of this mouse model with the procarcinogen azoxymethane
(AOM) leads to formation of dysplastic microadenomas in the proximal but not in the distal colon. Thus the K-rasG12D mutant is a valuable mouse model of proximal colon carcinogenesis.
Mutation in the Muc2 gene causes adenomas and adenocarcinomas in the intestine of mice.
is a group of inflammatory conditions in the large and small intestine. It is well known that chronic inflammation in the colon can cause cancer. There are genetic mouse models for inflammatory bowel disease associated colon cancer. Interleukin 10
knock out mice develop invasive adenocarcinoma in the colon. Mutant mice for interleukin 2
and beta microglobulin genes also produce ulcerative colitis- like phenotype and develop adenocarcinomas in the colon. A mouse mutant for N-cadherin
suffers inflammatory bowel disease conditions and adenomas but does not develop carcinomas.
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.
Model organism
A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. Model organisms are in vivo models and are widely used to...
of colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
and intestinal cancer are experimental systems in which mice are genetically manipulated 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 that can potentially benefit patients. An important example is the development of the APC mutant mouse model of colorectal cancer and the subsequent observation that cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
expression is an early event in colorectal carcinogenesis. Genetic disruption of the cyclooxygenase-2 (COX-2) gene or inhibition of the activity of COX-2 with chemical inhibitors reduced the polyp burden in mice. These observations gave rationale to treat human patients suffering from the familial form of the disease FAP
FAP
FAP may refer to:Technology and industry* FORTRAN Assembly Program, the macro assembler for some IBM mainframe computers* Fair Access Policy, a term for a bandwidth cap, limiting Internet usage...
with specific COX-2 inhibitors.
Mouse Models for Familial Adenomatous Polyposis (FAP)
FAPFAP
FAP may refer to:Technology and industry* FORTRAN Assembly Program, the macro assembler for some IBM mainframe computers* Fair Access Policy, a term for a bandwidth cap, limiting Internet usage...
is a hereditary disease that is characterized with development of numerous colon polyps. A genetic analysis of some FAP kindreds revealed that a common feature of the disease is a deletion of the APC gene. Further analysis of the APC gene revealed the existence of various mutations in cancer sufferers that also play a role in the onset of the sporadic form of colorectal cancer.
APC mutant mice
The first mouse mutant in the Apc gene came from a colony of randomly mutagenized mice. 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) results in a mouse that develops more than 300 polyps in the small intestine, while truncation at codon 1638 (Apc1638N) results in the formation of about only 3 polyps in the same region of the gastrointestinal tract. More recently a new mutant Apc mouse model was constructed in which multiple polyps form in the distal colon. 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). 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. Today we know that the beta-catenin
Beta-catenin
Beta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
protein (part of the Wnt signaling pathway
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
) is implicated in colorectal carcinogenesis and its stability in the cell is regulated by APC. A mouse model with deregulation of beta-catenin levels was created. The conditional stabilizing mutation in the beta-catenin gene caused formation of up to 3000 polyps in the small intestine of this mouse model.
A mouse model carrying mutations in ApcΔ716 and Smad4 (mothers against decapentaplegic homolog 4
Mothers against decapentaplegic homolog 4
SMAD family member 4, also known as SMAD4, is a protein that in humans is encoded by the SMAD4 gene.SMAD4 is a 552-amino acid protein involved in cell signaling. It belongs to the Darfwin family of proteins that modulate members of the TGFβ protein superfamily...
) is characterized with development of invasive adencarcinomas.
Mouse Models for Hereditary nonpolyposis colorectal cancer (HNPCC)
The most frequent mutations in HNPCC are mutations in the MSH2MSH2
MSH2 is a gene commonly associated with Hereditary nonpolyposis colorectal cancer.-Interactions:MSH2 has been shown to interact with Exonuclease 1, MSH3, MSH6, CHEK2, MAX, Ataxia telangiectasia and Rad3 related and BRCA1.-Further reading:...
and MLH1
MLH1
MutL homolog 1, colon cancer, nonpolyposis type 2 , also known as MLH1, is a human gene located on Chromosome 3. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer.It can also be associated with Turcot syndrome....
genes. These genes play an important role in repairing incorrectly positioned nucleotides. Another gene involved in DNA mismatch repair
DNA mismatch repair
DNA mismatch repair is a system for recognizing and repairing erroneous insertion, deletion and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage....
is Msh6. Both the Msh6 and Msh2 mutant mice develop gastrointestinal cancer but the tumours differ in their microsatellite instability
Microsatellite instability
Microsatellites are repeated sequences of DNA. Although the length of these microsatellites is highly variable from person to person, each individual has microsatellites of a set length. These repeated sequences are common, and normal...
(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 – adenomas and invasive carcinomas. The combination of MLH1 deficiency with the Apc1638N 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. Another similar mouse model of HNPCC is the combination of PMS2
PMS2
Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the PMS2 gene.-Further reading:-External links:* from the National Institute of Health*...
mutant mouse with the Min Apc allele resulting in increased number of tumours in the gastrointestinal tract compared to Min. 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.
Colon Cancer Models with mutations in other genes
Mice with mutations in transforming growth factorTransforming growth factor
Transforming growth factor is used to describe two classes of polypeptide growth factors, TGFα and TGFβ....
-β1 gene introduced into Rag2 mutant mouse promotes adenocarcinomas with strong local invasion. Colon-specific expression of activated mutant of K-ras (protein)
(K-rasG12D) results in development of single or multiple lesions. Oncogenic K-rasG12D allele activated in colon epithelium induces expression of procarcinogenic protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
-βII (PKCβII) and increases cell proliferation of epithelial cells, while in the distal colon the mutant form of K-ras has the opposite effects on PKCβII expression and cell proliferation. Treatment of this mouse model with the procarcinogen azoxymethane
Azoxymethane
Azoxymethane is a carcinogenic and neurotoxic chemical compound used in biological research. It is the oxide of azomethane. It is particularly effective in inducing colon carcinomas....
(AOM) leads to formation of dysplastic microadenomas in the proximal but not in the distal colon. Thus the K-rasG12D mutant is a valuable mouse model of proximal colon carcinogenesis.
Mutation in the Muc2 gene causes adenomas and adenocarcinomas in the intestine of mice.
Mouse models for inflammation related colon cancer
In human Inflammatory Bowel DiseaseInflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...
is a group of inflammatory conditions in the large and small intestine. It is well known that chronic inflammation in the colon can cause cancer. There are genetic mouse models for inflammatory bowel disease associated colon cancer. Interleukin 10
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
knock out mice develop invasive adenocarcinoma in the colon. Mutant mice for interleukin 2
Interleukin 2
Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...
and beta microglobulin genes also produce ulcerative colitis- like phenotype and develop adenocarcinomas in the colon. A mouse mutant for N-cadherin
Cadherin
Cadherins are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, ensuring that cells within tissues are bound together. They are dependent on calcium ions to function, hence their name.The cadherin superfamily includes cadherins, protocadherins, desmogleins, and...
suffers inflammatory bowel disease conditions and adenomas but does not develop carcinomas.
Mouse models of chemically induced colorectal cancer
Azoxymethane (AOM) is a genotoxic colonic carcinogen and is routinely used to induce colon tumours in mice. 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. AOM-induced tumours are characterized with mutations in the Apc gene.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.