Special Reports and ReviewsPathology of mouse models of intestinal cancer: Consensus report and recommendations☆,☆☆
Section snippets
Mouse pathology nomenclature
The committee came to a consensus on recommended nomenclature for intestinal neoplasia in mouse models (Table 1).Hyperplasia Gross thickening of the mucosa; some growths may be pedunculated; mitosis are always located in the lower two thirds of the mucosa; nuclei lack significant atypia, are basally located, ovoid to round, usually uniformly dark, with occasional visible nucleoli; crypts take on a star-shaped appearance in
Morphology of intestinal neoplasia in GEM and comparison with human lesions
Mouse models of intestinal neoplasia may be broadly divided into 5 groups: Apc and related models with mutations in Wnt signaling, MMR GEM, GEM with alterations in transforming growth factor (TGF) β signaling, immune-deficient mice with colitis, and carcinogen-treated mice. The following descriptions are a compilation of meeting findings as well as published reports on murine models of intestinal cancer. Original terminology from the published reports has not been changed to reflect the
Modifiers of cancer phenotypes
It became clear during the review of specimens during the meeting that strain, nutrition, and bacterial status, as in other disease processes in mice, were of critical importance in modifying neoplastic development and progression. For example, the incidence of neoplasia in the ApcMin/+ mouse is well known to be strain dependent.7, 78, 79, 80 A major modifier locus, known as Modifier-of-Min (Mom1), contributes 50% of the phenotypic variance between C57BL/6J and AKR/J mice. Genetic mapping78 and
Summary
The marked diversity in the phenotype of intestinal neoplasia in murine models offers opportunities to model many characteristics of human CRC, including tumor progression, metastasis, gross morphology, and histology. However, the lack of a consistent model of metastasis is of particular concern in developing mouse models of human CRC. AOM-treated mice consistently develop metastasis, but the absence of control by known genetic mutations under carcinogen treatment makes this model system less
References (92)
Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings
Cancer Lett
(1987)- et al.
Mutation in the mismatch repair gene Msh6 causes cancer susceptibility
Cell
(1997) - et al.
MADR2 maps to 18q21 and encodes a TGFβ-regulated MAD-related protein that is functionally mutated in colorectal carcinoma
Cell
(1996) - et al.
Somatic alterations of the DPC4 gene in human colorectal cancers in vivo
Gastroenterology
(1996) - et al.
Smad3 mutant mice develop metastatic colorectal cancer
Cell
(1998) - et al.
Gastro-intestinal tumorigenesis in Smad4 mutant mice
Cytokine Growth Factor Rev
(2000) - et al.
Limited CD4 T-cell diversity associated with colitis in T-cell receptor mutant mice requires a T helper 2 environment
Gastroenterology
(2000) - et al.
Superinfection with Helicobacter hepaticus does not alter the natural course of colitis in IL10-deficient mice (abstr)
Gastroenterology
(1998) - et al.
Structure of the murine homeobox gene cdx-2. Expression in embryonic and adult intestinal epithelium
J Biol Chem
(1994) - et al.
Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse
Cell
(1993)
The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia
Cell
A novel methodological approach to study the level of specific protein and gene expression in aberrant crypt foci putative preneoplastic colonic lesions by Western blotting and RT-PCR
Cancer Lett
Azoxymethane-induced colon tumors and aberrant crypt foci in mice of different genetic susceptibility
Cancer Lett
The identification of monoclonality in human aberrant crypt foci
Cancer Res
Aberrant crypts: putative preneoplastic foci in human colonic mucosa
Cancer Res
A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse
Science
Homozygosity for the Min allele of Apc results in disruption of mouse development prior to gastrulation
Dev Dyn
The min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system
J Cell Biol
Tumorigenesis in the multiple intestinal neoplasia mouse: redundancy of negative regulators and specificity of modifiers
Proc Natl Acad Sci U S A
Mlh1 deficiency enhances several phenotypes of ApcMin/+ mice
Oncogene
Msh2 deficiency contributes to accelerated Apc-mediated intestinal tumorigenesis
Cancer Res
Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncation Apc gene
Proc Natl Acad Sci U S A
Morphological and molecular processes of polyp formation in ApcΔ716 knockout mice
Cancer Res
A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors
Proc Natl Acad Sci U S A
Aberrant crypt foci develop spontaneously in APC1638 heterozygous mice
Proc Am Assoc Cancer Res
Loss of Apc and the entire chromosome 18 but absence of mutations at the Ras and Tp53 genes in intestinal tumors from Apc1638N, a mouse model for Apc-driven carcinogenesis
Carcinogenesis
Intestinal adenomas can develop with a stable karyotype and stable microsatellites
Proc Natl Acad Sci U S A
Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development
Genes Dev
Piroxicam and acarbose as chemopreventive agents for spontaneous intestinal adenomas in Apc gene 1309 knockout mice
Jpn J Cancer Res
Nuclear translocation of β-catenin in hereditary and carcinogen-induced intestinal adenomas
Carcinogenesis
Intestinal dysplasia and adenoma in transgenic mice after overexpression of an activated β-catenin
Cancer Res
Effects of forced expression of an NH2-termal truncated β-catenin on mouse intestinal epithelial homeostasis
J Cell Biol
Intestinal polyposis in mice with a dominant stable mutation of the β-catenin gene
Eur Mol Biol Org J
A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer
Cancer Res
Morphology of sporadic colorectal cancer with DNA replication errors
Gut
Medullary-type poorly differentiated adenocarcinoma of the large bowel: a distinct clinicopathologic entity characterized by microsatellite instability and improved survival
J Clin Oncol
Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DNA mismatch repair
Nat Genet
Heterozygous DNA mismatch repair gene Pms2-knockout mice are susceptible to intestinal tumor induction with N-methyl-N-nitrosourea
Carcinogenesis
Spontaneous intestinal carcinomas and skin neoplasms in Msh2-deficient mice
Cancer Res
The DNA mismatch repair genes Msh3 and Msh6 cooperate in intestinal tumor suppression
Cancer Res
HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions
Nat Genet
TGF-β signaling in tumor suppression and cancer progression
Nat Genet
Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability
Science
Microsatellite instability and mutations of the transforming growth factor β II receptor gene in colorectal cancer
Cancer Res
Mutations of the transforming growth factor-β type II receptor gene are strongly related to sporadic proximal colon carcinomas with microsatellite instability
Cancer
Cited by (429)
CD44-targeted nanoparticles for co-delivery of docetaxel and an Akt inhibitor against colorectal cancer
2023, Biomaterials AdvancesAzithromycin induces read-through of the nonsense Apc allele and prevents intestinal tumorigenesis in C3B6F1 Apc<sup>Min/+</sup> mice
2023, Biomedicine and PharmacotherapyTumor models to assess immune response and tumor-microbiome interactions in colorectal cancer
2022, Pharmacology and TherapeuticsNovel formulation approaches for gastrointestinal targeting: characterization and animal model considerations
2022, Oral Delivery of Therapeutic Peptides and ProteinsMicro(nano)-plastics in the environment and risk of carcinogenesis: Insight into possible mechanisms
2021, Journal of Hazardous Materials
- ☆
Supported by the Mouse Models of Human Cancers Consortium sponsored by the National Cancer Institute.
- ☆☆
Address requests for reprints to: Gregory P. Boivin, D.V.M., M.S., Department of Pathology and Laboratory Medicine, University of Cincinnati and Cincinnati Veterans Affairs Medical Center, 231 Albert Sabin Way (ML 0529), Cincinnati, Ohio 45267-0529. e-mail: [email protected]; fax: (513) 558-2487.