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 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.[1][2] These observations gave rationale to treat human patients suffering from the familial form of the disease FAP with selective COX-2 inhibitors.

Colorectal and intestinal cancer

Familial Adenomatous Polyposis

Familial Adenomatous Polyposis (FAP) 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.[3]

APC mutant mice

The first mouse mutant in the Apc gene came from a colony of randomly mutagenized mice.[4] 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) [5] results in a mouse that develops more than 300 polyps in the small intestine, while truncation at codon 1638 (Apc1638N) [6] results in the formation of about only 3 polyps in the same region of the gastrointestinal tract.[7] More recently a new mutant Apc mouse model was constructed in which multiple polyps form in the distal colon.[8] 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).[9] 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.[10] 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.[11] 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.[12]

Hereditary nonpolyposis colorectal cancer

The most frequent mutations in Hereditary nonpolyposis colorectal cancer (HNPCC) are mutations in the MSH2 and MLH1 genes.[13] These genes play an important role in repairing incorrectly positioned nucleotides. Another gene involved in DNA mismatch repair is Msh6. Both the Msh6 [14] and Msh2 [15] 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 [16] – adenomas and invasive carcinomas.[17] The combination of MLH1 deficiency with the Apc1638N [5] 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.[18] 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.[19] 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 transforming growth factor-β1 gene introduced into 129/Sv Rag2 mutant mouse [20] accelerates adenocarcinomas with strong local invasion suggesting a role for genetic background in tumor development. Colon-specific expression of activated mutant of K-ras (protein) (K-rasG12D) results in development of single or multiple lesions.[21] 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.[22] 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.[23]

Inflammation related colon cancer

In human Inflammatory Bowel Disease 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.[24] Mutant mice for interleukin 2 and beta microglobulin genes also produce ulcerative colitis- like phenotype and develop adenocarcinomas in the colon.[25] A mouse mutant for N-cadherin suffers inflammatory bowel disease conditions and adenomas but does not develop carcinomas.[26]

Diet-related model

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.[27][28] 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.[27] 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 histopathology and by expression of specific markers, the colonic tumors in the mice were virtually identical to those in humans.[28] In humans, characteristic aberrant changes in molecular markers are detected both in field defects surrounding cancers (from which the cancers arise) and within cancers. In the colonic tissues of mice fed diet plus DOC similar changes in biomarkers occurred. Thus, 8-OH-dG was increased, DNA repair protein ERCC1 was decreased, autophagy protein beclin-1 was increased and, in the stem cell region at the base of crypts, there was substantial nuclear localization of beta-catenin as well as increased cytoplasmic beta-catenin. However, in mice fed diet plus DOC plus the antioxidant chlorogenic acid, the frequency of colon cancer was reduced.[27] Furthermore, when evaluated for ERCC1, beclin-1, and beta-catenin in the stem cell region of crypts, the colonic tissues of chlorogenic acid-fed mice showed amelioration of the molecular aberrancies,[28] suggesting that chlorogenic acid is protective at the molecular level against colon cancer. This is the first diet-related model of colon cancer that closely parallels human progression to colon cancer, both at the histopathology level as well as in its molecular profile.

Chemically-induced colorectal cancer

Azoxymethane (AOM) is a genotoxic colonic carcinogen and is routinely used to induce colon tumours in mice.[29] 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.[30] AOM-induced tumours are characterized with mutations in the Apc gene.[31]

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.[32]

See also

External links

References

  1. ↑ Oshima M, Dinchuk JE, Kargman SL, et al. (1996). "Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2)". Cell 87 (5): 803–9. doi:10.1016/S0092-8674(00)81988-1. PMID 8945508.
  2. ↑ Chulada PC, Thompson MB, Mahler JF, et al. (2000). "Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice". Cancer Res. 60 (17): 4705–8. PMID 10987272.
  3. ↑ Groden J, Thliveris A, Samowitz W, et al. (1991). "Identification and characterization of the familial adenomatous polyposis coli gene". Cell 66 (3): 589–600. doi:10.1016/0092-8674(81)90021-0. PMID 1651174.
  4. ↑ Moser AR, Pitot HC, Dove WF (1990). "A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse". Science 247 (4940): 322–4. doi:10.1126/science.2296722. PMID 2296722.
  5. 1 2 Fodde R, Edelmann W, Yang K, et al. (1994). "A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors". Proc. Natl. Acad. Sci. U.S.A. 91 (19): 8969–73. doi:10.1073/pnas.91.19.8969. PMC 44728. PMID 8090754.
  6. ↑ Oshima M, Oshima H, Kitagawa K, Kobayashi M, Itakura C, Taketo M (1995). "Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene". Proc. Natl. Acad. Sci. U.S.A. 92 (10): 4482–6. doi:10.1073/pnas.92.10.4482. PMC 41968. PMID 7753829.
  7. ↑ Taketo MM (2006). "Mouse models of gastrointestinal tumors". Cancer Sci. 97 (5): 355–61. doi:10.1111/j.1349-7006.2006.00190.x. PMID 16630131.
  8. ↑ Aoki K, Tamai Y, Horiike S, Oshima M, Taketo MM (2003). "Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/- compound mutant mice". Nat. Genet. 35 (4): 323–30. doi:10.1038/ng1265. PMID 14625550.
  9. ↑ Dietrich WF, Lander ES, Smith JS, et al. (1993). "Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse". Cell 75 (4): 631–9. doi:10.1016/0092-8674(93)90484-8. PMID 8242739.
  10. ↑ Su LK, Vogelstein B, Kinzler KW (1993). "Association of the APC tumor suppressor protein with catenins". Science 262 (5140): 1734–7. doi:10.1126/science.8259519. PMID 8259519.
  11. ↑ Harada N, Tamai Y, Ishikawa T, et al. (1999). "Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene". EMBO J. 18 (21): 5931–42. doi:10.1093/emboj/18.21.5931. PMC 1171659. PMID 10545105.
  12. ↑ Takaku K, Oshima M, Miyoshi H, Matsui M, Seldin MF, Taketo MM (1998). "Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes". Cell 92 (5): 645–56. doi:10.1016/S0092-8674(00)81132-0. PMID 9506519.
  13. ↑ Kolodner R (1996). "Biochemistry and genetics of eukaryotic mismatch repair". Genes Dev. 10 (12): 1433–42. doi:10.1101/gad.10.12.1433. PMID 8666228.
  14. ↑ Edelmann W, Yang K, Umar A, et al. (1997). "Mutation in the mismatch repair gene Msh6 causes cancer susceptibility". Cell 91 (4): 467–77. doi:10.1016/S0092-8674(00)80433-X. PMID 9390556.
  15. ↑ Reitmair AH, Redston M, Cai JC, et al. (1996). "Spontaneous intestinal carcinomas and skin neoplasms in Msh2-deficient mice". Cancer Res. 56 (16): 3842–9. PMID 8706033.
  16. ↑ Baker SM, Plug AW, Prolla TA, et al. (1996). "Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over". Nat. Genet. 13 (3): 336–42. doi:10.1038/ng0796-336. PMID 8673133.
  17. ↑ Edelmann W, Yang K, Kuraguchi M, et al. (1999). "Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice". Cancer Res. 59 (6): 1301–7. PMID 10096563.
  18. ↑ Reitmair AH, Cai JC, Bjerknes M, et al. (1996). "MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis". Cancer Res. 56 (13): 2922–6. PMID 8674041.
  19. ↑ Baker SM, Harris AC, Tsao JL, et al. (1998). "Enhanced intestinal adenomatous polyp formation in Pms2-/-;Min mice". Cancer Res. 58 (6): 1087–9. PMID 9515784.
  20. ↑ Engle SJ, Hoying JB, Boivin GP, Ormsby I, Gartside PS, Doetschman T (1999). "Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis". Cancer Res. 59 (14): 3379–86. PMID 10416598.
  21. ↑ Janssen KP, el-Marjou F, Pinto D, et al. (2002). "Targeted expression of oncogenic K- ras in intestinal epithelium causes spontaneous tumorigenesis in mice". Gastroenterology 123 (2): 492–504. doi:10.1053/gast.2002.34786. PMID 12145803.
  22. ↑ Calcagno SR, Li S, Colon M, et al. (2008). "Oncogenic K-ras promotes early carcinogenesis in the mouse proximal colon". Int. J. Cancer 122 (11): 2462–70. doi:10.1002/ijc.23383. PMID 18271008.
  23. ↑ Velcich A, Yang W, Heyer J, et al. (2002). "Colorectal cancer in mice genetically deficient in the mucin Muc2". Science 295 (5560): 1726–9. doi:10.1126/science.1069094. PMID 11872843.
  24. ↑ Berg DJ, Davidson N, Kühn R, et al. (1996). "Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses". J. Clin. Invest. 98 (4): 1010–20. doi:10.1172/JCI118861. PMC 507517. PMID 8770874.
  25. ↑ Shah SA, Simpson SJ, Brown LF, et al. (1998). "Development of colonic adenocarcinomas in a mouse model of ulcerative colitis". Inflamm. Bowel Dis. 4 (3): 196–202. doi:10.1002/ibd.3780040305. PMID 9741021.
  26. ↑ Hermiston ML, Gordon JI (1995). "Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin". Science 270 (5239): 1203–7. doi:10.1126/science.270.5239.1203. PMID 7502046.
  27. 1 2 3 Bernstein C, Holubec H, Bhattacharyya AK, Nguyen H, Payne CM, Zaitlin B, Bernstein H (2011). "Carcinogenicity of deoxycholate, a secondary bile acid". Arch. Toxicol. 85 (8): 863–71. doi:10.1007/s00204-011-0648-7. PMC 3149672. PMID 21267546.
  28. 1 2 3 Prasad AR, Prasad S, Nguyen H, Facista A, Lewis C, Zaitlin B, Bernstein H, Bernstein C (2014). "Novel diet-related mouse model of colon cancer parallels human colon cancer". World J Gastrointest Oncol 6 (7): 225–43. doi:10.4251/wjgo.v6.i7.225. PMC 4092339. PMID 25024814.
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  30. ↑ Poole AJ, Heap D, Carroll RE, Tyner AL (2004). "Tumor suppressor functions for the Cdk inhibitor p21 in the mouse colon". Oncogene 23 (49): 8128–34. doi:10.1038/sj.onc.1207994. PMID 15377995.
  31. ↑ Maltzman T, Whittington J, Driggers L, Stephens J, Ahnen D (1997). "AOM-induced mouse colon tumors do not express full-length APC protein". Carcinogenesis 18 (12): 2435–9. doi:10.1093/carcin/18.12.2435. PMID 9450492.
  32. ↑ Tanaka T, Kohno H, Suzuki R, Yamada Y, Sugie S, Mori H (2003). "A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate". Cancer Sci. 94 (11): 965–73. doi:10.1111/j.1349-7006.2003.tb01386.x. PMID 14611673.
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