Table 3.
Mouse allele | Rationale | Strategy | Advantages | Disadvantages |
---|---|---|---|---|
ApcMin/+ 47, 48 | • N/A | • Germline truncating mutation (N terminus) | • Model of human familial adenomatous polyposis (FAP) syndrome and >80% of sporadic CRCs contain mutations 2, 4 | • Developed hundreds of low‐grade adenomas |
• Ethylnitrosurea (ENU) mutagenesis screen | • Loss of heterozygosity occurs at wildtype allele in tumours | • Short‐lived for rapid studies | • Short‐lived as tumour burden causes obstruction, prolapse and bleeding | |
• Tumour multiplicity easily quantifiable | • Short life‐span means that adenomas do not acquire sufficient mutations to progress to adenocarcinoma and metastasise 56, 57 | |||
• Tumours predominantly located in small rather than large intestine | ||||
Msh2−/− 54 | • Msh2 mutations common in CRC | • Germline knock‐out | • Model of Hereditary non‐polyposis CRC (HNPCC) or Lynch Syndrome (3% of all CRCs) | • Msh2 mutation in all cells of body and mice are predisposed to lymphomas |
Villin‐Cre/Msh2LoxP 55 | • To restrict malignancy to intestine to prevent lymphoma | • Conditional | • Developed intestinal adenomas and adenocarcinomas | • Do not develop metastases |
• Cre recombinase a expressed from promoter of intestinal specific gene (Villin) | • No deaths from lymphoma | |||
Apc580S/580S 64 | • To model advanced CRC by restricting tumours to colon and reducing tumour burden | • Conditional Adenoviral Cre recombinase a is administered through the anus to inactivate Apc | • Live >1 year. | • Do not develop metastases |
• Developed two or three intestinal adenomas | • Conditional allele (unactivated) reduces Apc expression in all cells, similar to Apcfl/fl 10, which results in development of life‐limiting hepatocellular carcinomas by 14 months (REM unpublished observations of Apc580S/580S) | |||
• Some mice developed adenocarcinomas | ||||
Apclox15/+; Fabpl‐Cre 109 | • To model advanced CRC by restricting tumours to the colon and reducing tumour burden | • Conditional | • Live >1 year. | • Do not develop metastases |
• Cre‐recombinase a is expressed in the distal small intestinal and colonic epithelia to inactivate Apc | • Developed two or three intestinal adenomas | |||
• Some mice developed adenocarcinomas | ||||
ApcMin/+Trp53−/− 110 | • To model advanced CRC through addition of cooperating gene mutations | • Germline mutations in Apc and Trp53 | • Do not develop metastases | |
Apc2lox14/+ KrasLSL‐G12D and Fabpl‐Cre 111 | • To model advanced CRC through addition of cooperating gene mutations | • Conditional | • Developed more adenocarcinomas than single mutant (Apc or Kras alone) control mice | • Do not develop metastases |
• Cre‐recombinase a is expressed in the distal small intestine/colonic epithelia and results in constitutive activation of K‐Ras and inactivation of Apc | ||||
Apc mutant with disruption of Tgfbr2, Smad2 or Smad4. 112, 113, 114 | • To model advanced CRC through addition of cooperating gene mutations | • Developed more adenocarcinomas than single mutant control mice. | • Do not develop metastases | |
ApcMin/+ Villin Cre Fbxw7(ΔG) 115 | • To model advanced CRC through addition of cooperating gene mutations | • Germline mutation of Apc | • Decreased lifespan | • Do not develop adenocarcinomas or metastases |
• Conditional mutation of Fbxw7 | • Increased tumour burden | |||
• Cre recombinase a expressed from promoter of intestinal specific gene (Villin) | • Fbxw7 null control mice developed adenomas by 9‐10 months of age | |||
ApcCKO/CKO‐LSL‐G12D; Krastm4tyj/+ 62 | • To model advanced CRC through addition of cooperating mutations. To restrict tumours to the colon and reduce tumour burden | • Adenoviral Cre solution administered via the anus to simultaneously disrupt Apc and activate K‐ras | • Developed adenocarcinomas after five months | • Labour intensive mouse surgery required to clamp a section of colon to deliver Adenoviral Cre solution to the colon via the anus |
• Developed metastases to distant organs after six months e.g. liver | ||||
• In vivo monitoring via colonoscopy |
CRC, Colorectal carcinoma.
Cre recombinases catalyse recombination between two loxP sites that are situated in the introns surrounding a critical exon(s) and result in excision of the DNA between the sites.