Colorectal cancer (CRC) is a heterogeneous disease that includes both hereditary and sporadic types of tumors. Tumor initiation and growth is driven by mutational or epigenetic changes that alter the function or expression of multiple genes. The genes predominantly encode components of various intracellular signaling cascades. In this review, we present mouse intestinal cancer models that include alterations in the Wnt, Hippo, p53, epidermal growth factor (EGF), and transforming growth factor β (TGFβ) pathways; models of impaired DNA mismatch repair and chemically induced tumorigenesis are included. Based on their molecular biology characteristics and mutational and epigenetic status, human colorectal carcinomas were divided into four so-called consensus molecular subtype (CMS) groups. It was shown subsequently that the CMS classification system could be applied to various cell lines derived from intestinal tumors and tumor-derived organoids. Although the CMS system facilitates characterization of human CRC, individual mouse models were not assigned to some of the CMS groups. Thus, we also indicate the possible assignment of described animal models to the CMS group. This might be helpful for selection of a suitable mouse strain to study a particular type of CRC.

Institute of Molecular Genetics of the Czech Academy of Sciences Videnska 1083 142 20 Prague Czech Republic

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Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2019. CA Cancer J. Clin. 2019;69:7–34. doi: 10.3322/caac.21551. PubMed DOI

Kinzler K.W., Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87:159–170. doi: 10.1016/S0092-8674(00)81333-1. PubMed DOI

Jen J., Powell S.M., Papadopoulos N., Smith K.J., Hamilton S.R., Vogelstein B., Kinzler K.W. Molecular determinants of dysplasia in colorectal lesions. Cancer Res. 1994;54:5523–5526. PubMed

Janssen K.P., Alberici P., Fsihi H., Gaspar C., Breukel C., Franken P., Rosty C., Abal M., El Marjou F., Smits R., et al. APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology. 2006;131:1096–1109. doi: 10.1053/j.gastro.2006.08.011. PubMed DOI

Smith A.J., Stern H.S., Penner M., Hay K., Mitri A., Bapat B.V., Gallinger S. Somatic APC and K-ras codon 12 mutations in aberrant crypt foci from human colons. Cancer Res. 1994;54:5527–5530. PubMed

Rodrigues N.R., Rowan A., Smith M.E., Kerr I.B., Bodmer W.F., Gannon J.V., Lane D.P. p53 mutations in colorectal cancer. Proc. Natl. Acad. Sci. USA. 1990;87:7555–7559. doi: 10.1073/pnas.87.19.7555. PubMed DOI PMC

Vogelstein B., Fearon E.R., Hamilton S.R., Kern S.E., Preisinger A.C., Leppert M., Nakamura Y., White R., Smits A.M., Bos J.L. Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 1988;319:525–532. doi: 10.1056/NEJM198809013190901. PubMed DOI

Weinberg R.A. Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res. 1989;49:3713–3721. PubMed

Mattar M.C., Lough D., Pishvaian M.J., Charabaty A. Current management of inflammatory bowel disease and colorectal cancer. Gastrointest. Cancer Res. 2011;4:53–61. PubMed PMC

Van Der Kraak L., Gros P., Beauchemin N. Colitis-associated colon cancer: Is it in your genes? World J. Gastroenterol. 2015;21:11688–11699. doi: 10.3748/wjg.v21.i41.11688. PubMed DOI PMC

Brentnall T.A., Crispin D.A., Rabinovitch P.S., Haggitt R.C., Rubin C.E., Stevens A.C., Burmer G.C. Mutations in the p53 gene: An early marker of neoplastic progression in ulcerative colitis. Gastroenterology. 1994;107:369–378. doi: 10.1016/0016-5085(94)90161-9. PubMed DOI

Shenoy A.K., Fisher R.C., Butterworth E.A., Pi L., Chang L.J., Appelman H.D., Chang M., Scott E.W., Huang E.H. Transition from colitis to cancer: High Wnt activity sustains the tumor-initiating potential of colon cancer stem cell precursors. Cancer Res. 2012;72:5091–5100. doi: 10.1158/0008-5472.CAN-12-1806. PubMed DOI PMC

Yaeger R., Shah M.A., Miller V.A., Kelsen J.R., Wang K., Heins Z.J., Ross J.S., He Y., Sanford E., Yantiss R.K., et al. Genomic Alterations Observed in Colitis-Associated Cancers Are Distinct From Those Found in Sporadic Colorectal Cancers and Vary by Type of Inflammatory Bowel Disease. Gastroenterology. 2016;151:278–287. doi: 10.1053/j.gastro.2016.04.001. PubMed DOI PMC

Ullman T.A., Itzkowitz S.H. Intestinal inflammation and cancer. Gastroenterology. 2011;140:1807–1816. doi: 10.1053/j.gastro.2011.01.057. PubMed DOI

Andreyev H.J., Norman A.R., Cunningham D., Oates J.R., Clarke P.A. Kirsten ras mutations in patients with colorectal cancer: The multicenter “RASCAL” study. J. Natl. Cancer Inst. 1998;90:675–684. doi: 10.1093/jnci/90.9.675. PubMed DOI

Smith G., Carey F.A., Beattie J., Wilkie M.J., Lightfoot T.J., Coxhead J., Garner R.C., Steele R.J., Wolf C.R. Mutations in APC, Kirsten-ras, and p53—Alternative genetic pathways to colorectal cancer. Proc. Natl. Acad. Sci. USA. 2002;99:9433–9438. doi: 10.1073/pnas.122612899. PubMed DOI PMC

Robles A.I., Traverso G., Zhang M., Roberts N.J., Khan M.A., Joseph C., Lauwers G.Y., Selaru F.M., Popoli M., Pittman M.E., et al. Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers. Gastroenterology. 2016;150:931–943. doi: 10.1053/j.gastro.2015.12.036. PubMed DOI PMC

Budinska E., Popovici V., Tejpar S., D’Ario G., Lapique N., Sikora K.O., Di Narzo A.F., Yan P., Hodgson J.G., Weinrich S., et al. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J. Pathol. 2013;231:63–76. doi: 10.1002/path.4212. PubMed DOI PMC

Marisa L., de Reynies A., Duval A., Selves J., Gaub M.P., Vescovo L., Etienne-Grimaldi M.C., Schiappa R., Guenot D., Ayadi M., et al. Gene expression classification of colon cancer into molecular subtypes: Characterization, validation, and prognostic value. PLoS Med. 2013;10:e1001453. doi: 10.1371/journal.pmed.1001453. PubMed DOI PMC

Roepman P., Schlicker A., Tabernero J., Majewski I., Tian S., Moreno V., Snel M.H., Chresta C.M., Rosenberg R., Nitsche U., et al. Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition. Int. J. Cancer. 2014;134:552–562. doi: 10.1002/ijc.28387. PubMed DOI PMC

De Sousa E.M.F., Wang X., Jansen M., Fessler E., Trinh A., de Rooij L.P., de Jong J.H., de Boer O.J., van Leersum R., Bijlsma M.F., et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat. Med. 2013;19:614–618. doi: 10.1038/nm.3174. PubMed DOI

Sadanandam A., Lyssiotis C.A., Homicsko K., Collisson E.A., Gibb W.J., Wullschleger S., Ostos L.C., Lannon W.A., Grotzinger C., Del Rio M., et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat. Med. 2013;19:619–625. doi: 10.1038/nm.3175. PubMed DOI PMC

Schlicker A., Beran G., Chresta C.M., McWalter G., Pritchard A., Weston S., Runswick S., Davenport S., Heathcote K., Castro D.A., et al. Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines. BMC Med. Genom. 2012;5:66. doi: 10.1186/1755-8794-5-66. PubMed DOI PMC

Guinney J., Dienstmann R., Wang X., de Reynies A., Schlicker A., Soneson C., Marisa L., Roepman P., Nyamundanda G., Angelino P., et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 2015;21:1350–1356. doi: 10.1038/nm.3967. PubMed DOI PMC

Ning C., Li Y.Y., Wang Y., Han G.C., Wang R.X., Xiao H., Li X.Y., Hou C.M., Ma Y.F., Sheng D.S., et al. Complement activation promotes colitis-associated carcinogenesis through activating intestinal IL-1β/IL-17A axis. Mucosal Immunol. 2015;8:1275–1284. doi: 10.1038/mi.2015.18. PubMed DOI

Linnekamp J.F., Hooff S.R.V., Prasetyanti P.R., Kandimalla R., Buikhuisen J.Y., Fessler E., Ramesh P., Lee K., Bochove G.G.W., de Jong J.H., et al. Consensus molecular subtypes of colorectal cancer are recapitulated in in vitro and in vivo models. Cell Death Differ. 2018;25:616–633. doi: 10.1038/s41418-017-0011-5. PubMed DOI PMC

Phesse T.J., Durban V.M., Sansom O.J. Defining key concepts of intestinal and epithelial cancer biology through the use of mouse models. Carcinogenesis. 2017;38:953–965. doi: 10.1093/carcin/bgx080. PubMed DOI PMC

Taketo M.M., Edelmann W. Mouse models of colon cancer. Gastroenterology. 2009;136:780–798. doi: 10.1053/j.gastro.2008.12.049. PubMed DOI

Park S.Y., Lee H.S., Choe G., Chung J.H., Kim W.H. Clinicopathological characteristics, microsatellite instability, and expression of mucin core proteins and p53 in colorectal mucinous adenocarcinomas in relation to location. Virchows Arch. 2006;449:40–47. doi: 10.1007/s00428-006-0212-7. PubMed DOI

Oshima H., Nakayama M., Han T.S., Naoi K., Ju X., Maeda Y., Robine S., Tsuchiya K., Sato T., Sato H., et al. Suppressing TGFβ signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer. Cancer Res. 2015;75:766–776. doi: 10.1158/0008-5472.CAN-14-2036. PubMed DOI

Reitmair A.H., Redston M., Cai J.C., Chuang T.C., Bjerknes M., Cheng H., Hay K., Gallinger S., Bapat B., Mak T.W. Spontaneous intestinal carcinomas and skin neoplasms in Msh2-deficient mice. Cancer Res. 1996;56:3842–3849. PubMed

Su L.K., Kinzler K.W., Vogelstein B., Preisinger A.C., Moser A.R., Luongo C., Gould K.A., Dove W.F. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science. 1992;256:668–670. doi: 10.1126/science.1350108. PubMed DOI

Sasai H., Masaki M., Wakitani K. Suppression of polypogenesis in a new mouse strain with a truncated Apc∆474 by a novel COX-2 inhibitor, JTE-522. Carcinogenesis. 2000;21:953–958. doi: 10.1093/carcin/21.5.953. PubMed DOI

Colnot S., Niwa-Kawakita M., Hamard G., Godard C., Le Plenier S., Houbron C., Romagnolo B., Berrebi D., Giovannini M., Perret C. Colorectal cancers in a new mouse model of familial adenomatous polyposis: Influence of genetic and environmental modifiers. Lab. Investig. J. Tech. Methods Pathol. 2004;84:1619–1630. doi: 10.1038/labinvest.3700180. PubMed DOI

Russo A., Bazan V., Iacopetta B., Kerr D., Soussi T., Gebbia N. The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: Influence of tumor site, type of mutation, and adjuvant treatment. J. Clin. Oncol. 2005;23:7518–7528. doi: 10.1200/JCO.2005.00.471. PubMed DOI

Mercer K., Giblett S., Green S., Lloyd D., DaRocha Dias S., Plumb M., Marais R., Pritchard C. Expression of endogenous oncogenic V600EB-raf induces proliferation and developmental defects in mice and transformation of primary fibroblasts. Cancer Res. 2005;65:11493–11500. doi: 10.1158/0008-5472.CAN-05-2211. PubMed DOI PMC

Samowitz W.S., Sweeney C., Herrick J., Albertsen H., Levin T.R., Murtaugh M.A., Wolff R.K., Slattery M.L. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 2005;65:6063–6069. doi: 10.1158/0008-5472.CAN-05-0404. PubMed DOI

Ito N., Hasegawa R., Sano M., Tamano S., Esumi H., Takayama S., Sugimura T. A new colon and mammary carcinogen in cooked food, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) Carcinogenesis. 1991;12:1503–1506. doi: 10.1093/carcin/12.8.1503. PubMed DOI

Ochiai M., Imai H., Sugimura T., Nagao M., Nakagama H. Induction of intestinal tumors and lymphomas in C57BL/6N mice by a food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Jpn. J. Cancer Res. 2002;93:478–483. doi: 10.1111/j.1349-7006.2002.tb01281.x. PubMed DOI PMC

Nakagama H., Nakanishi M., Ochiai M. Modeling human colon cancer in rodents using a food-borne carcinogen, PhIP. Cancer Sci. 2005;96:627–636. doi: 10.1111/j.1349-7006.2005.00107.x. PubMed DOI PMC

Yang J., Shikata N., Mizuoka H., Tsubura A. Colon carcinogenesis in shrews by intrarectal infusion of N-methyl-N-nitrosourea. Cancer Lett. 1996;110:105–112. doi: 10.1016/S0304-3835(96)04468-0. PubMed DOI

Rosenberg D.W., Giardina C., Tanaka T. Mouse models for the study of colon carcinogenesis. Carcinogenesis. 2009;30:183–196. doi: 10.1093/carcin/bgn267. PubMed DOI PMC

Deschner E.E., Long F.C. Colonic neoplasms in mice produced with six injections of 1,2-dimethylhydrazine. Oncology. 1977;34:255–257. doi: 10.1159/000225236. PubMed DOI

Maltzman T., Whittington J., Driggers L., Stephens J., Ahnen D. AOM-induced mouse colon tumors do not express full-length APC protein. Carcinogenesis. 1997;18:2435–2439. doi: 10.1093/carcin/18.12.2435. PubMed DOI

Takahashi M., Nakatsugi S., Sugimura T., Wakabayashi K. Frequent mutations of the β-catenin gene in mouse colon tumors induced by azoxymethane. Carcinogenesis. 2000;21:1117–1120. PubMed

Vivona A.A., Shpitz B., Medline A., Bruce W.R., Hay K., Ward M.A., Stern H.S., Gallinger S. K-ras mutations in aberrant crypt foci, adenomas and adenocarcinomas during azoxymethane-induced colon carcinogenesis. Carcinogenesis. 1993;14:1777–1781. doi: 10.1093/carcin/14.9.1777. PubMed DOI

Wang Q.S., Papanikolaou A., Sabourin C.L., Rosenberg D.W. Altered expression of cyclin D1 and cyclin-dependent kinase 4 in azoxymethane-induced mouse colon tumorigenesis. Carcinogenesis. 1998;19:2001–2006. doi: 10.1093/carcin/19.11.2001. PubMed DOI

Chen J., Huang X.F. The signal pathways in azoxymethane-induced colon cancer and preventive implications. Cancer Biol. Ther. 2009;8:1313–1317. doi: 10.4161/cbt.8.14.8983. PubMed DOI

Waaler J., Machon O., Tumova L., Dinh H., Korinek V., Wilson S.R., Paulsen J.E., Pedersen N.M., Eide T.J., Machonova O., et al. A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. Cancer Res. 2012;72:2822–2832. doi: 10.1158/0008-5472.CAN-11-3336. PubMed DOI

Bissahoyo A., Pearsall R.S., Hanlon K., Amann V., Hicks D., Godfrey V.L., Threadgill D.W. Azoxymethane is a genetic background-dependent colorectal tumor initiator and promoter in mice: Effects of dose, route, and diet. Toxicol. Sci. 2005;88:340–345. doi: 10.1093/toxsci/kfi313. PubMed DOI

Greten F.R., Eckmann L., Greten T.F., Park J.M., Li Z.W., Egan L.J., Kagnoff M.F., Karin M. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004;118:285–296. doi: 10.1016/j.cell.2004.07.013. PubMed DOI

Neufert C., Becker C., Neurath M.F. An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression. Nat. Protoc. 2007;2:1998–2004. doi: 10.1038/nprot.2007.279. PubMed DOI

Tanaka T., Kohno H., Suzuki R., Yamada Y., Sugie S., Mori H. A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci. 2003;94:965–973. doi: 10.1111/j.1349-7006.2003.tb01386.x. PubMed DOI PMC

De Robertis M., Massi E., Poeta M.L., Carotti S., Morini S., Cecchetelli L., Signori E., Fazio V.M. The AOM/DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies. J. Carcinog. 2011;10:9. doi: 10.4103/1477-3163.78279. PubMed DOI PMC

Aoki K., Taketo M.M. Adenomatous polyposis coli (APC): A multi-functional tumor suppressor gene. J. Cell Sci. 2007;120:3327–3335. doi: 10.1242/jcs.03485. PubMed DOI

Valenta T., Hausmann G., Basler K. The many faces and functions of β-catenin. EMBO J. 2012;31:2714–2736. doi: 10.1038/emboj.2012.150. PubMed DOI PMC

Kimelman D., Xu W. β-catenin destruction complex: Insights and questions from a structural perspective. Oncogene. 2006;25:7482–7491. doi: 10.1038/sj.onc.1210055. PubMed DOI

Stamos J.L., Weis W.I. The β-catenin destruction complex. Cold Spring Harb. Perspect. Biol. 2013;5:a007898. doi: 10.1101/cshperspect.a007898. PubMed DOI PMC

Saito-Diaz K., Chen T.W., Wang X., Thorne C.A., Wallace H.A., Page-McCaw A., Lee E. The way Wnt works: Components and mechanism. Growth Factors. 2013;31:1–31. doi: 10.3109/08977194.2012.752737. PubMed DOI PMC

He T.C., Sparks A.B., Rago C., Hermeking H., Zawel L., da Costa L.T., Morin P.J., Vogelstein B., Kinzler K.W. Identification of c-MYC as a target of the APC pathway. Science. 1998;281:1509–1512. doi: 10.1126/science.281.5382.1509. PubMed DOI

Shtutman M., Zhurinsky J., Simcha I., Albanese C., D’Amico M., Pestell R., Ben-Ze’ev A. The cyclin D1 gene is a target of the β-catenin/LEF-1 pathway. Proc. Natl. Acad. Sci. USA. 1999;96:5522–5527. doi: 10.1073/pnas.96.10.5522. PubMed DOI PMC

Wielenga V.J., Smits R., Korinek V., Smit L., Kielman M., Fodde R., Clevers H., Pals S.T. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am. J. Pathol. 1999;154:515–523. doi: 10.1016/S0002-9440(10)65297-2. PubMed DOI PMC

Coppede F., Lopomo A., Spisni R., Migliore L. Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer. World J. Gastroenterol. 2014;20:943–956. doi: 10.3748/wjg.v20.i4.943. PubMed DOI PMC

Segditsas S., Tomlinson I. Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene. 2006;25:7531–7537. doi: 10.1038/sj.onc.1210059. PubMed DOI

Shimizu Y., Ikeda S., Fujimori M., Kodama S., Nakahara M., Okajima M., Asahara T. Frequent alterations in the Wnt signaling pathway in colorectal cancer with microsatellite instability. Genes Chromosomes Cancer. 2002;33:73–81. doi: 10.1002/gcc.1226. PubMed DOI

Mazzoni S.M., Fearon E.R. AXIN1 and AXIN2 variants in gastrointestinal cancers. Cancer Lett. 2014;355:1–8. doi: 10.1016/j.canlet.2014.09.018. PubMed DOI PMC

Nishisho I., Nakamura Y., Miyoshi Y., Miki Y., Ando H., Horii A., Koyama K., Utsunomiya J., Baba S., Hedge P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. 1991;253:665–669. doi: 10.1126/science.1651563. PubMed DOI

Groden J., Thliveris A., Samowitz W., Carlson M., Gelbert L., Albertsen H., Joslyn G., Stevens J., Spirio L., Robertson M., et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell. 1991;66:589–600. doi: 10.1016/0092-8674(81)90021-0. PubMed DOI

Galiatsatos P., Foulkes W.D. Familial adenomatous polyposis. Am. J. Gastroenterol. 2006;101:385–398. doi: 10.1111/j.1572-0241.2006.00375.x. PubMed DOI

Rubinfeld B., Albert I., Porfiri E., Fiol C., Munemitsu S., Polakis P. Binding of GSK3β to the APC-β-catenin complex and regulation of complex assembly. Science. 1996;272:1023–1026. doi: 10.1126/science.272.5264.1023. PubMed DOI

Behrens J., Jerchow B.A., Wurtele M., Grimm J., Asbrand C., Wirtz R., Kuhl M., Wedlich D., Birchmeier W. Functional interaction of an axin homolog, conductin, with β-catenin, APC, and GSK3β. Science. 1998;280:596–599. doi: 10.1126/science.280.5363.596. PubMed DOI

Miyoshi Y., Nagase H., Ando H., Horii A., Ichii S., Nakatsuru S., Aoki T., Miki Y., Mori T., Nakamura Y. Somatic mutations of the APC gene in colorectal tumors: Mutation cluster region in the APC gene. Hum. Mol. Genet. 1992;1:229–233. PubMed

Miyaki M., Konishi M., Kikuchi-Yanoshita R., Enomoto M., Igari T., Tanaka K., Muraoka M., Takahashi H., Amada Y., Fukayama M., et al. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res. 1994;54:3011–3020. PubMed

Hayashi S., Rubinfeld B., Souza B., Polakis P., Wieschaus E., Levine A.J. A Drosophila homolog of the tumor suppressor gene adenomatous polyposis coli down-regulates β-catenin but its zygotic expression is not essential for the regulation of Armadillo. Proc. Natl. Acad. Sci. USA. 1997;94:242–247. doi: 10.1073/pnas.94.1.242. PubMed DOI PMC

Moser A.R., Pitot H.C., Dove W.F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science. 1990;247:322–324. doi: 10.1126/science.2296722. PubMed DOI

Moser A.R., Mattes E.M., Dove W.F., Lindstrom M.J., Haag J.D., Gould M.N. ApcMin, a mutation in the murine Apc gene, predisposes to mammary carcinomas and focal alveolar hyperplasias. Proc. Natl. Acad. Sci. USA. 1993;90:8977–8981. doi: 10.1073/pnas.90.19.8977. PubMed DOI PMC

Tomita H., Yamada Y., Oyama T., Hata K., Hirose Y., Hara A., Kunisada T., Sugiyama Y., Adachi Y., Linhart H., et al. Development of gastric tumors in ApcMin/+ mice by the activation of the β-catenin/Tcf signaling pathway. Cancer Res. 2007;67:4079–4087. doi: 10.1158/0008-5472.CAN-06-4025. PubMed DOI

Svendsen C., Alexander J., Knutsen H.K., Husoy T. The min mouse on FVB background: Susceptibility to spontaneous and carcinogen-induced intestinal tumourigenesis. Anticancer Res. 2011;31:785–788. PubMed

Sodring M., Gunnes G., Paulsen J.E. Spontaneous initiation, promotion and progression of colorectal cancer in the novel A/J Min/+ mouse. Int. J. Cancer. 2016;138:1936–1946. doi: 10.1002/ijc.29928. PubMed DOI

Cooper H.S., Chang W.C., Coudry R., Gary M.A., Everley L., Spittle C.S., Wang H., Litwin S., Clapper M.L. Generation of a unique strain of multiple intestinal neoplasia (Apc+/Min-FCCC) mice with significantly increased numbers of colorectal adenomas. Mol. Carcinog. 2005;44:31–41. doi: 10.1002/mc.20114. PubMed DOI

Bashir O., FitzGerald A.J., Goodlad R.A. Both suboptimal and elevated vitamin intake increase intestinal neoplasia and alter crypt fission in the ApcMin/+ mouse. Carcinogenesis. 2004;25:1507–1515. doi: 10.1093/carcin/bgh137. PubMed DOI

Lawrance A.K., Deng L., Brody L.C., Finnell R.H., Shane B., Rozen R. Genetic and nutritional deficiencies in folate metabolism influence tumorigenicity in Apcmin/+ mice. J. Nutr. Biochem. 2007;18:305–312. doi: 10.1016/j.jnutbio.2006.06.001. PubMed DOI

Mutanen M., Pajari A.M., Oikarinen S.I. Beef induces and rye bran prevents the formation of intestinal polyps in ApcMin mice: Relation to β-catenin and PKC isozymes. Carcinogenesis. 2000;21:1167–1173. doi: 10.1093/carcin/21.6.1167. PubMed DOI

Yang K., Lamprecht S.A., Shinozaki H., Fan K., Yang W., Newmark H.L., Kopelovich L., Edelmann W., Jin B., Gravaghi C., et al. Dietary calcium and cholecalciferol modulate cyclin D1 expression, apoptosis, and tumorigenesis in intestine of adenomatous polyposis coli1638N/+ mice. J. Nutr. 2008;138:1658–1663. doi: 10.1093/jn/138.9.1658. PubMed DOI

Kwong L.N., Dove W.F. APC and its modifiers in colon cancer. Adv. Exp. Med. Biol. 2009;656:85–106. PubMed PMC

Lamlum H., Ilyas M., Rowan A., Clark S., Johnson V., Bell J., Frayling I., Efstathiou J., Pack K., Payne S., et al. The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: A new facet to Knudson’s ‘two-hit’ hypothesis. Nat. Med. 1999;5:1071–1075. doi: 10.1038/12511. PubMed DOI

Sieber O.M., Heinimann K., Gorman P., Lamlum H., Crabtree M., Simpson C.A., Davies D., Neale K., Hodgson S.V., Roylance R.R., et al. Analysis of chromosomal instability in human colorectal adenomas with two mutational hits at APC. Proc. Natl. Acad. Sci. USA. 2002;99:16910–16915. doi: 10.1073/pnas.012679099. PubMed DOI PMC

Lewis A., Segditsas S., Deheragoda M., Pollard P., Jeffery R., Nye E., Lockstone H., Davis H., Clark S., Stamp G., et al. Severe polyposis in Apc1322T mice is associated with submaximal Wnt signalling and increased expression of the stem cell marker Lgr5. Gut. 2010;59:1680–1686. doi: 10.1136/gut.2009.193680. PubMed DOI PMC

Pollard P., Deheragoda M., Segditsas S., Lewis A., Rowan A., Howarth K., Willis L., Nye E., McCart A., Mandir N., et al. The Apc1322T mouse develops severe polyposis associated with submaximal nuclear β-catenin expression. Gastroenterology. 2009;136:2204–2213. doi: 10.1053/j.gastro.2009.02.058. PubMed DOI

Bakker E.R., Hoekstra E., Franken P.F., Helvensteijn W., van Deurzen C.H., van Veelen W., Kuipers E.J., Smits R. β-Catenin signaling dosage dictates tissue-specific tumor predisposition in Apc-driven cancer. Oncogene. 2013;32:4579–4585. doi: 10.1038/onc.2012.449. PubMed DOI

Quesada C.F., Kimata H., Mori M., Nishimura M., Tsuneyoshi T., Baba S. Piroxicam and acarbose as chemopreventive agents for spontaneous intestinal adenomas in APC gene 1309 knockout mice. Jpn. J. Cancer Res. 1998;89:392–396. doi: 10.1111/j.1349-7006.1998.tb00576.x. PubMed DOI PMC

Niho N., Takahashi M., Kitamura T., Shoji Y., Itoh M., Noda T., Sugimura T., Wakabayashi K. Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands. Cancer Res. 2003;63:6090–6095. PubMed

Deka J., Kuhlmann J., Muller O. A domain within the tumor suppressor protein APC shows very similar biochemical properties as the microtubule-associated protein tau. Eur. J. Biochem. 1998;253:591–597. doi: 10.1046/j.1432-1327.1998.2530591.x. PubMed DOI

Lewis A., Davis H., Deheragoda M., Pollard P., Nye E., Jeffery R., Segditsas S., East P., Poulsom R., Stamp G., et al. The C-terminus of Apc does not influence intestinal adenoma development or progression. J. Pathol. 2012;226:73–83. doi: 10.1002/path.2972. PubMed DOI PMC

Fodde R., Edelmann W., Yang K., van Leeuwen C., Carlson C., Renault B., Breukel C., Alt E., Lipkin M., Khan P.M., et al. A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc. Natl. Acad. Sci. USA. 1994;91:8969–8973. doi: 10.1073/pnas.91.19.8969. PubMed DOI PMC

Smits R., van der Houven van Oordt W., Luz A., Zurcher C., Jagmohan-Changur S., Breukel C., Khan P.M., Fodde R. Apc1638N: A mouse model for familial adenomatous polyposis-associated desmoid tumors and cutaneous cysts. Gastroenterology. 1998;114:275–283. doi: 10.1016/S0016-5085(98)70478-0. PubMed DOI

Caspari R., Olschwang S., Friedl W., Mandl M., Boisson C., Boker T., Augustin A., Kadmon M., Moslein G., Thomas G., et al. Familial adenomatous polyposis: Desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444. Hum. Mol. Genet. 1995;4:337–340. doi: 10.1093/hmg/4.3.337. PubMed DOI

Davies D.R., Armstrong J.G., Thakker N., Horner K., Guy S.P., Clancy T., Sloan P., Blair V., Dodd C., Warnes T.W., et al. Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. Am. J. Hum. Genet. 1995;57:1151–1158. PubMed PMC

Ikenoue T., Yamaguchi K., Komura M., Imoto S., Yamaguchi R., Shimizu E., Kasuya S., Shibuya T., Hatakeyama S., Miyano S., et al. Attenuated familial adenomatous polyposis with desmoids caused by an APC mutation. Hum. Genome Var. 2015;2:15011. doi: 10.1038/hgv.2015.11. PubMed DOI PMC

Wang T., Onouchi T., Yamada N.O., Matsuda S., Senda T. A disturbance of intestinal epithelial cell population and kinetics in APC1638T mice. Med. Mol. Morphol. 2017;50:94–102. doi: 10.1007/s00795-016-0152-5. PubMed DOI

Smits R., Kielman M.F., Breukel C., Zurcher C., Neufeld K., Jagmohan-Changur S., Hofland N., van Dijk J., White R., Edelmann W., et al. Apc1638T: A mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. Genes Dev. 1999;13:1309–1321. doi: 10.1101/gad.13.10.1309. PubMed DOI PMC

Xu Q., Wang Y.S., Dabdoub A., Smallwood P.M., Williams J., Woods C., Kelley M.W., Jiang L., Tasman W., Zhang K., et al. Vascular development in the retina and inner ear: Control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell. 2004;116:883–895. doi: 10.1016/S0092-8674(04)00216-8. PubMed DOI

Gaspar C., Franken P., Molenaar L., Breukel C., van der Valk M., Smits R., Fodde R. A targeted constitutive mutation in the APC tumor suppressor gene underlies mammary but not intestinal tumorigenesis. PLoS Genet. 2009;5:e1000547. doi: 10.1371/journal.pgen.1000547. PubMed DOI PMC

Crist R.C., Roth J.J., Baran A.A., McEntee B.J., Siracusa L.D., Buchberg A.M. The armadillo repeat domain of Apc suppresses intestinal tumorigenesis. Mamm. Genome Off. J. Int. Mamm. Genome Soc. 2010;21:450–457. doi: 10.1007/s00335-010-9288-0. PubMed DOI PMC

Oshima M., Oshima H., Kitagawa K., Kobayashi M., Itakura C., Taketo M. Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. Proc. Natl. Acad. Sci. USA. 1995;92:4482–4486. doi: 10.1073/pnas.92.10.4482. PubMed DOI PMC

Shibata H., Toyama K., Shioya H., Ito M., Hirota M., Hasegawa S., Matsumoto H., Takano H., Akiyama T., Toyoshima K., et al. Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. Science. 1997;278:120–123. doi: 10.1126/science.278.5335.120. PubMed DOI

Kuraguchi M., Wang X.P., Bronson R.T., Rothenberg R., Ohene-Baah N.Y., Lund J.J., Kucherlapati M., Maas R.L., Kucherlapati R. Adenomatous polyposis coli (APC) is required for normal development of skin and thymus. PLoS Genet. 2006;2:e146. doi: 10.1371/journal.pgen.0020146. PubMed DOI PMC

Colnot S., Decaens T., Niwa-Kawakita M., Godard C., Hamard G., Kahn A., Giovannini M., Perret C. Liver-targeted disruption of Apc in mice activates β-catenin signaling and leads to hepatocellular carcinomas. Proc. Natl. Acad. Sci. USA. 2004;101:17216–17221. doi: 10.1073/pnas.0404761101. PubMed DOI PMC

El Marjou F., Janssen K.P., Chang B.H., Li M., Hindie V., Chan L., Louvard D., Chambon P., Metzger D., Robine S. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis. 2004;39:186–193. doi: 10.1002/gene.20042. PubMed DOI

Barker N., van Es J.H., Kuipers J., Kujala P., van den Born M., Cozijnsen M., Haegebarth A., Korving J., Begthel H., Peters P.J., et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449:1003–1007. doi: 10.1038/nature06196. PubMed DOI

Horazna M., Janeckova L., Svec J., Babosova O., Hrckulak D., Vojtechova M., Galuskova K., Sloncova E., Kolar M., Strnad H., et al. Msx1 loss suppresses formation of the ectopic crypts developed in the Apc-deficient small intestinal epithelium. Sci. Rep. 2019;9:1629. doi: 10.1038/s41598-018-38310-y. PubMed DOI PMC

Robanus-Maandag E.C., Koelink P.J., Breukel C., Salvatori D.C., Jagmohan-Changur S.C., Bosch C.A., Verspaget H.W., Devilee P., Fodde R., Smits R. A new conditional Apc-mutant mouse model for colorectal cancer. Carcinogenesis. 2010;31:946–952. doi: 10.1093/carcin/bgq046. PubMed DOI

Cheung A.F., Carter A.M., Kostova K.K., Woodruff J.F., Crowley D., Bronson R.T., Haigis K.M., Jacks T. Complete deletion of Apc results in severe polyposis in mice. Oncogene. 2010;29:1857–1864. doi: 10.1038/onc.2009.457. PubMed DOI PMC

Gao C., Wang Y.M., Broaddus R., Sun L.H., Xue F.X., Zhang W. Exon 3 mutations of CTNNB1 drive tumorigenesis: A review. Oncotarget. 2018;9:5492–5508. doi: 10.18632/oncotarget.23695. PubMed DOI PMC

Kim S., Jeong S. Mutation Hotspots in the β-Catenin Gene: Lessons from the Human Cancer Genome Databases. Mol. Cells. 2019;42:8–16. doi: 10.14348/molcells.2018.0436. PubMed DOI PMC

Harada N., Tamai Y., Ishikawa T., Sauer B., Takaku K., Oshima M., Taketo M.M. Intestinal polyposis in mice with a dominant stable mutation of the β-catenin gene. EMBO J. 1999;18:5931–5942. doi: 10.1093/emboj/18.21.5931. PubMed DOI PMC

Kriz V., Korinek V. Wnt, RSPO and Hippo Signalling in the Intestine and Intestinal Stem Cells. Genes. 2018;9:20. doi: 10.3390/genes9010020. PubMed DOI PMC

Seshagiri S., Stawiski E.W., Durinck S., Modrusan Z., Storm E.E., Conboy C.B., Chaudhuri S., Guan Y., Janakiraman V., Jaiswal B.S., et al. Recurrent R-spondin fusions in colon cancer. Nature. 2012;488:660–664. doi: 10.1038/nature11282. PubMed DOI PMC

Hashimoto T., Ogawa R., Yoshida H., Taniguchi H., Kojima M., Saito Y., Sekine S. EIF3E-RSPO2 and PIEZO1-RSPO2 fusions in colorectal traditional serrated adenoma. Histopathology. 2019 doi: 10.1111/his.13867. PubMed DOI

Hilkens J., Timmer N.C., Boer M., Ikink G.J., Schewe M., Sacchetti A., Koppens M.A.J., Song J.Y., Bakker E.R.M. RSPO3 expands intestinal stem cell and niche compartments and drives tumorigenesis. Gut. 2017;66:1095–1105. doi: 10.1136/gutjnl-2016-311606. PubMed DOI PMC

Han T., Schatoff E.M., Murphy C., Zafra M.P., Wilkinson J.E., Elemento O., Dow L.E. R-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine. Nat. Commun. 2017;8:15945. doi: 10.1038/ncomms15945. PubMed DOI PMC

Zhao B., Tumaneng K., Guan K.L. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat. Cell Boil. 2011;13:877–883. doi: 10.1038/ncb2303. PubMed DOI PMC

Yu F.X., Meng Z., Plouffe S.W., Guan K.L. Hippo pathway regulation of gastrointestinal tissues. Annu. Rev. Physiol. 2015;77:201–227. doi: 10.1146/annurev-physiol-021014-071733. PubMed DOI

Wang L., Shi S., Guo Z., Zhang X., Han S., Yang A., Wen W., Zhu Q. Overexpression of YAP and TAZ is an independent predictor of prognosis in colorectal cancer and related to the proliferation and metastasis of colon cancer cells. PLoS ONE. 2013;8:e65539. doi: 10.1371/journal.pone.0065539. PubMed DOI PMC

Yuen H.F., McCrudden C.M., Huang Y.H., Tham J.M., Zhang X., Zeng Q., Zhang S.D., Hong W. TAZ expression as a prognostic indicator in colorectal cancer. PLoS ONE. 2013;8:e54211. doi: 10.1371/journal.pone.0054211. PubMed DOI PMC

Avruch J., Zhou D., Bardeesy N. YAP oncogene overexpression supercharges colon cancer proliferation. Cell Cycle. 2012;11:1090–1096. doi: 10.4161/cc.11.6.19453. PubMed DOI PMC

Cho S.Y., Gwak J.W., Shin Y.C., Moon D., Ahn J., Sol H.W., Kim S., Kim G., Shin H.M., Lee K.H., et al. Expression of Hippo pathway genes and their clinical significance in colon adenocarcinoma. Oncol. Lett. 2018;15:4926–4936. doi: 10.3892/ol.2018.7911. PubMed DOI PMC

Wang Q., Gao X., Yu T., Yuan L., Dai J., Wang W., Chen G., Jiao C., Zhou W., Huang Q., et al. REGγ Controls Hippo Signaling and Reciprocal NF-κB-YAP Regulation to Promote Colon Cancer. Clin. Cancer Res. 2018;24:2015–2025. doi: 10.1158/1078-0432.CCR-17-2986. PubMed DOI

Camargo F.D., Gokhale S., Johnnidis J.B., Fu D., Bell G.W., Jaenisch R., Brummelkamp T.R. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr. Boil. CB. 2007;17:2054–2060. doi: 10.1016/j.cub.2007.10.039. PubMed DOI

Barry E.R., Morikawa T., Butler B.L., Shrestha K., de la Rosa R., Yan K.S., Fuchs C.S., Magness S.T., Smits R., Ogino S., et al. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature. 2013;493:106–110. doi: 10.1038/nature11693. PubMed DOI PMC

Zhou D., Zhang Y., Wu H., Barry E., Yin Y., Lawrence E., Dawson D., Willis J.E., Markowitz S.D., Camargo F.D., et al. Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance. Proc. Natl. Acad. Sci. USA. 2011;108:E1312–E1320. doi: 10.1073/pnas.1110428108. PubMed DOI PMC

Cai J., Zhang N., Zheng Y., de Wilde R.F., Maitra A., Pan D. The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev. 2010;24:2383–2388. doi: 10.1101/gad.1978810. PubMed DOI PMC

Muller P.A., Vousden K.H. Mutant p53 in cancer: New functions and therapeutic opportunities. Cancer Cell. 2014;25:304–317. doi: 10.1016/j.ccr.2014.01.021. PubMed DOI PMC

Oliner J.D., Pietenpol J.A., Thiagalingam S., Gyuris J., Kinzler K.W., Vogelstein B. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature. 1993;362:857–860. doi: 10.1038/362857a0. PubMed DOI

Amaral J.D., Xavier J.M., Steer C.J., Rodrigues C.M. The role of p53 in apoptosis. Discov. Med. 2010;9:145–152. PubMed

Abukhdeir A.M., Park B.H. P21 and p27: Roles in carcinogenesis and drug resistance. Expert Rev. Mol. Med. 2008;10:e19. doi: 10.1017/S1462399408000744. PubMed DOI PMC

Baker S.J., Preisinger A.C., Jessup J.M., Paraskeva C., Markowitz S., Willson J.K., Hamilton S., Vogelstein B. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res. 1990;50:7717–7722. PubMed

Hainaut P., Hollstein M. p53 and human cancer: The first ten thousand mutations. Adv. Cancer Res. 2000;77:81–137. PubMed

Lopez I., Oliveira L.P., Tucci P., Alvarez-Valin F., Coudry R.A., Marin M. Different mutation profiles associated to P53 accumulation in colorectal cancer. Gene. 2012;499:81–87. doi: 10.1016/j.gene.2012.02.011. PubMed DOI

Li X.L., Zhou J., Chen Z.R., Chng W.J. P53 mutations in colorectal cancer—Molecular pathogenesis and pharmacological reactivation. World J. Gastroenterol. 2015;21:84–93. doi: 10.3748/wjg.v21.i1.84. PubMed DOI PMC

Ogino S., Nosho K., Shima K., Baba Y., Irahara N., Kirkner G.J., Hazra A., De Vivo I., Giovannucci E.L., Meyerhardt J.A., et al. p21 expression in colon cancer and modifying effects of patient age and body mass index on prognosis. Cancer Epidemiol. Biomark. Prev. 2009;18:2513–2521. doi: 10.1158/1055-9965.EPI-09-0451. PubMed DOI PMC

Ogino S., Kawasaki T., Kirkner G.J., Ogawa A., Dorfman I., Loda M., Fuchs C.S. Down-regulation of p21 (CDKN1A/CIP1) is inversely associated with microsatellite instability and CpG island methylator phenotype (CIMP) in colorectal cancer. J. Pathol. 2006;210:147–154. doi: 10.1002/path.2030. PubMed DOI

Jacks T., Remington L., Williams B.O., Schmitt E.M., Halachmi S., Bronson R.T., Weinberg R.A. Tumor spectrum analysis in p53-mutant mice. Curr. Boil. CB. 1994;4:1–7. doi: 10.1016/S0960-9822(00)00002-6. PubMed DOI

Lang G.A., Iwakuma T., Suh Y.A., Liu G., Rao V.A., Parant J.M., Valentin-Vega Y.A., Terzian T., Caldwell L.C., Strong L.C., et al. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell. 2004;119:861–872. doi: 10.1016/j.cell.2004.11.006. PubMed DOI

Halberg R.B., Katzung D.S., Hoff P.D., Moser A.R., Cole C.E., Lubet R.A., Donehower L.A., Jacoby R.F., Dove W.F. Tumorigenesis in the multiple intestinal neoplasia mouse: Redundancy of negative regulators and specificity of modifiers. Proc. Natl. Acad. Sci. USA. 2000;97:3461–3466. doi: 10.1073/pnas.97.7.3461. PubMed DOI PMC

Funabashi H., Uchida K., Kado S., Matsuoka Y., Ohwaki M. Establishment of a Tcrb and Trp53 genes deficient mouse strain as an animal model for spontaneous colorectal cancer. Exp. Anim. 2001;50:41–47. doi: 10.1538/expanim.50.41. PubMed DOI

Cooks T., Pateras I.S., Tarcic O., Solomon H., Schetter A.J., Wilder S., Lozano G., Pikarsky E., Forshew T., Rosenfeld N., et al. Mutant p53 prolongs NF-κB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell. 2013;23:634–646. doi: 10.1016/j.ccr.2013.03.022. PubMed DOI PMC

Chang W.C., Coudry R.A., Clapper M.L., Zhang X., Williams K.L., Spittle C.S., Li T., Cooper H.S. Loss of p53 enhances the induction of colitis-associated neoplasia by dextran sulfate sodium. Carcinogenesis. 2007;28:2375–2381. doi: 10.1093/carcin/bgm134. PubMed DOI

Vyas M., Yang X., Zhang X. Gastric Hamartomatous Polyps-Review and Update. Clin. Med. Insights Gastroenterol. 2016;9:3–10. doi: 10.4137/CGast.S38452. PubMed DOI PMC

Karuman P., Gozani O., Odze R.D., Zhou X.C., Zhu H., Shaw R., Brien T.P., Bozzuto C.D., Ooi D., Cantley L.C., et al. The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death. Mol. Cell. 2001;7:1307–1319. doi: 10.1016/S1097-2765(01)00258-1. PubMed DOI

Tiainen M., Vaahtomeri K., Ylikorkala A., Makela T.P. Growth arrest by the LKB1 tumor suppressor: Induction of p21(WAF1/CIP1) Hum. Mol. Genet. 2002;11:1497–1504. doi: 10.1093/hmg/11.13.1497. PubMed DOI

Tiainen M., Ylikorkala A., Makela T.P. Growth suppression by Lkb1 is mediated by a G1 cell cycle arrest. Proc. Natl. Acad. Sci. USA. 1999;96:9248–9251. doi: 10.1073/pnas.96.16.9248. PubMed DOI PMC

Miyoshi H., Nakau M., Ishikawa T.O., Seldin M.F., Oshima M., Taketo M.M. Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res. 2002;62:2261–2266. PubMed

Wei C.J., Amos C.I., Stephens L.C., Campos I., Deng J.M., Behringer R.R., Rashid A., Frazier M.L. Mutation of Lkb1 and p53 genes exert a cooperative effect on tumorigenesis. Cancer Res. 2005;65:11297–11303. doi: 10.1158/0008-5472.CAN-05-0716. PubMed DOI

Deng C., Zhang P., Harper J.W., Elledge S.J., Leder P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell. 1995;82:675–684. doi: 10.1016/0092-8674(95)90039-X. PubMed DOI

Brugarolas J., Chandrasekaran C., Gordon J.I., Beach D., Jacks T., Hannon G.J. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature. 1995;377:552–557. doi: 10.1038/377552a0. PubMed DOI

Martin-Caballero J., Flores J.M., Garcia-Palencia P., Serrano M. Tumor susceptibility of p21Waf1/Cip1-deficient mice. Cancer Res. 2001;61:6234–6238. PubMed

Poole A.J., Heap D., Carroll R.E., Tyner A.L. Tumor suppressor functions for the Cdk inhibitor p21 in the mouse colon. Oncogene. 2004;23:8128–8134. doi: 10.1038/sj.onc.1207994. PubMed DOI

Jackson R.J., Engelman R.W., Coppola D., Cantor A.B., Wharton W., Pledger W.J. p21Cip1 nullizygosity increases tumor metastasis in irradiated mice. Cancer Res. 2003;63:3021–3025. PubMed

Yang W.C., Mathew J., Velcich A., Edelmann W., Kucherlapati R., Lipkin M., Yang K., Augenlicht L.H. Targeted inactivation of the p21WAF1/cip1 gene enhances Apc-initiated tumor formation and the tumor-promoting activity of a Western-style high-risk diet by altering cell maturation in the intestinal mucosal. Cancer Res. 2001;61:565–569. PubMed

Zirbes T.K., Baldus S.E., Moenig S.P., Nolden S., Kunze D., Shafizadeh S.T., Schneider P.M., Thiele J., Hoelscher A.H., Dienes H.P. Prognostic impact of p21/waf1/cip1 in colorectal cancer. Int. J. Cancer. 2000;89:14–18. doi: 10.1002/(SICI)1097-0215(20000120)89:1<14::AID-IJC3>3.0.CO;2-L. PubMed DOI

Wee P., Wang Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers. 2017;9:52. doi: 10.3390/cancers9050052. PubMed DOI PMC

Tuveson D.A., Shaw A.T., Willis N.A., Silver D.P., Jackson E.L., Chang S., Mercer K.L., Grochow R., Hock H., Crowley D., et al. Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell. 2004;5:375–387. doi: 10.1016/S1535-6108(04)00085-6. PubMed DOI

Johnson L., Mercer K., Greenbaum D., Bronson R.T., Crowley D., Tuveson D.A., Jacks T. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature. 2001;410:1111–1116. doi: 10.1038/35074129. PubMed DOI

Yamashita N., Minamoto T., Ochiai A., Onda M., Esumi H. Frequent and characteristic K-ras activation and absence of p53 protein accumulation in aberrant crypt foci of the colon. Gastroenterology. 1995;108:434–440. doi: 10.1016/0016-5085(95)90071-3. PubMed DOI

Roerink S.F., Sasaki N., Lee-Six H., Young M.D., Alexandrov L.B., Behjati S., Mitchell T.J., Grossmann S., Lightfoot H., Egan D.A., et al. Intra-tumour diversification in colorectal cancer at the single-cell level. Nature. 2018;556:457–462. doi: 10.1038/s41586-018-0024-3. PubMed DOI

Kavuri S.M., Jain N., Galimi F., Cottino F., Leto S.M., Migliardi G., Searleman A.C., Shen W., Monsey J., Trusolino L., et al. HER2 activating mutations are targets for colorectal cancer treatment. Cancer Discov. 2015;5:832–841. doi: 10.1158/2159-8290.CD-14-1211. PubMed DOI PMC

Dougherty U., Cerasi D., Taylor I., Kocherginsky M., Tekin U., Badal S., Aluri L., Sehdev A., Cerda S., Mustafi R., et al. Epidermal growth factor receptor is required for colonic tumor promotion by dietary fat in the azoxymethane/dextran sulfate sodium model: Roles of transforming growth factor-α and PTGS2. Clin. Cancer Res. 2009;15:6780–6789. doi: 10.1158/1078-0432.CCR-09-1678. PubMed DOI PMC

Dube P.E., Yan F., Punit S., Girish N., McElroy S.J., Washington M.K., Polk D.B. Epidermal growth factor receptor inhibits colitis-associated cancer in mice. J. Clin. Investig. 2012;122:2780–2792. doi: 10.1172/JCI62888. PubMed DOI PMC

Roberts R.B., Min L., Washington M.K., Olsen S.J., Settle S.H., Coffey R.J., Threadgill D.W. Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis. Proc. Natl. Acad. Sci. USA. 2002;99:1521–1526. doi: 10.1073/pnas.032678499. PubMed DOI PMC

Nagahara H., Mimori K., Ohta M., Utsunomiya T., Inoue H., Barnard G.F., Ohira M., Hirakawa K., Mori M. Somatic mutations of epidermal growth factor receptor in colorectal carcinoma. Clin. Cancer Res. 2005;11:1368–1371. doi: 10.1158/1078-0432.CCR-04-1894. PubMed DOI

Moroni M., Veronese S., Benvenuti S., Marrapese G., Sartore-Bianchi A., Di Nicolantonio F., Gambacorta M., Siena S., Bardelli A. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: A cohort study. Lancet Oncol. 2005;6:279–286. doi: 10.1016/S1470-2045(05)70102-9. PubMed DOI

Brink M., de Goeij A.F., Weijenberg M.P., Roemen G.M., Lentjes M.H., Pachen M.M., Smits K.M., de Bruine A.P., Goldbohm R.A., van den Brandt P.A. K-ras oncogene mutations in sporadic colorectal cancer in The Netherlands Cohort Study. Carcinogenesis. 2003;24:703–710. doi: 10.1093/carcin/bgg009. PubMed DOI

Haigis K.M., Kendall K.R., Wang Y., Cheung A., Haigis M.C., Glickman J.N., Niwa-Kawakita M., Sweet-Cordero A., Sebolt-Leopold J., Shannon K.M., et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat. Genet. 2008;40:600–608. doi: 10.1038/ng.115. PubMed DOI PMC

Guerra C., Mijimolle N., Dhawahir A., Dubus P., Barradas M., Serrano M., Campuzano V., Barbacid M. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell. 2003;4:111–120. doi: 10.1016/S1535-6108(03)00191-0. PubMed DOI

Ireland H., Kemp R., Houghton C., Howard L., Clarke A.R., Sansom O.J., Winton D.J. Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: Effect of loss of β-catenin. Gastroenterology. 2004;126:1236–1246. doi: 10.1053/j.gastro.2004.03.020. PubMed DOI

Luo F., Brooks D.G., Ye H., Hamoudi R., Poulogiannis G., Patek C.E., Winton D.J., Arends M.J. Mutated K-rasAsp12 promotes tumourigenesis in ApcMin mice more in the large than the small intestines, with synergistic effects between K-ras and Wnt pathways. Int. J. Exp. Pathol. 2009;90:558–574. doi: 10.1111/j.1365-2613.2009.00667.x. PubMed DOI PMC

Hung K.E., Maricevich M.A., Richard L.G., Chen W.Y., Richardson M.P., Kunin A., Bronson R.T., Mahmood U., Kucherlapati R. Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment. Proc. Natl. Acad. Sci. USA. 2010;107:1565–1570. doi: 10.1073/pnas.0908682107. PubMed DOI PMC

Poulin E.J., Bera A.K., Lu J., Lin Y.J., Strasser S.D., Paulo J.A., Huang T.Q., Morales C., Yan W., Cook J., et al. Tissue-Specific Oncogenic Activity of KRASA146T. Cancer Discov. 2019 doi: 10.1158/2159-8290.CD-18-1220. PubMed DOI PMC

Davies H., Bignell G.R., Cox C., Stephens P., Edkins S., Clegg S., Teague J., Woffendin H., Garnett M.J., Bottomley W., et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954. doi: 10.1038/nature00766. PubMed DOI

Rajagopalan H., Bardelli A., Lengauer C., Kinzler K.W., Vogelstein B., Velculescu V.E. Tumorigenesis—RAF/RAS oncogenes and mismatch-repair status. Nature. 2002;418:934. doi: 10.1038/418934a. PubMed DOI

Dankort D., Filenova E., Collado M., Serrano M., Jones K., McMahon M. A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev. 2007;21:379–384. doi: 10.1101/gad.1516407. PubMed DOI PMC

Rad R., Cadinanos J., Rad L., Varela I., Strong A., Kriegl L., Constantino-Casas F., Eser S., Hieber M., Seidler B., et al. A Genetic Progression Model of BrafV600E-Induced Intestinal Tumorigenesis Reveals Targets for Therapeutic Intervention. Cancer Cell. 2013;24:15–29. doi: 10.1016/j.ccr.2013.05.014. PubMed DOI PMC

Tao Y., Kang B., Petkovich D.A., Bhandari Y.R., In J., Stein-O’Brien G., Kong X., Xie W., Zachos N., Maegawa S., et al. Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and BrafV600)-Induced Tumorigenesis. Cancer Cell. 2019;35:315–328.e6. doi: 10.1016/j.ccell.2019.01.005. PubMed DOI PMC

Biemer-Huttmann A.E., Walsh M.D., McGuckin M.A., Simms L.A., Young J., Leggett B.A., Jass J.R. Mucin core protein expression in colorectal cancers with high levels of microsatellite instability indicates a novel pathway of morphogenesis. Clin. Cancer Res. 2000;6:1909–1916. PubMed

Walsh M.D., Clendenning M., Williamson E., Pearson S.A., Walters R.J., Nagler B., Packenas D., Win A.K., Hopper J.L., Jenkins M.A., et al. Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype. Mod. Pathol. 2013;26:1642–1656. doi: 10.1038/modpathol.2013.101. PubMed DOI

Winterford C.M., Walsh M.D., Leggett B.A., Jass J.R. Ultrastructural localization of epithelial mucin core proteins in colorectal tissues. J. Histochem. Cytochem. 1999;47:1063–1074. doi: 10.1177/002215549904700811. PubMed DOI

Velcich A., Yang W., Heyer J., Fragale A., Nicholas C., Viani S., Kucherlapati R., Lipkin M., Yang K., Augenlicht L. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science. 2002;295:1726–1729. doi: 10.1126/science.1069094. PubMed DOI

Stambolic V., Suzuki A., de la Pompa J.L., Brothers G.M., Mirtsos C., Sasaki T., Ruland J., Penninger J.M., Siderovski D.P., Mak T.W. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998;95:29–39. doi: 10.1016/S0092-8674(00)81780-8. PubMed DOI

Velho S., Oliveira C., Ferreira A., Ferreira A.C., Suriano G., Schwartz S., Jr., Duval A., Carneiro F., Machado J.C., Hamelin R., et al. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur. J. Cancer. 2005;41:1649–1654. doi: 10.1016/j.ejca.2005.04.022. PubMed DOI

Samuels Y., Waldman T. Oncogenic mutations of PIK3CA in human cancers. Curr. Top. Microbiol. Immunol. 2010;347:21–41. doi: 10.1007/82_2010_68. PubMed DOI PMC

Mitchell C.B., Phillips W.A. Mouse Models for Exploring the Biological Consequences and Clinical Significance of PIK3CA Mutations. Biomolecules. 2019;9:158. doi: 10.3390/biom9040158. PubMed DOI PMC

Goel A., Arnold C.N., Niedzwiecki D., Carethers J.M., Dowell J.M., Wasserman L., Compton C., Mayer R.J., Bertagnolli M.M., Boland C.R. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res. 2004;64:3014–3021. doi: 10.1158/0008-5472.CAN-2401-2. PubMed DOI

Berg M., Danielsen S.A., Ahlquist T., Merok M.A., Agesen T.H., Vatn M.H., Mala T., Sjo O.H., Bakka A., Moberg I., et al. DNA sequence profiles of the colorectal cancer critical gene set KRAS-BRAF-PIK3CA-PTEN-TP53 related to age at disease onset. PLoS ONE. 2010;5:e13978. doi: 10.1371/journal.pone.0013978. PubMed DOI PMC

Carpten J.D., Faber A.L., Horn C., Donoho G.P., Briggs S.L., Robbins C.M., Hostetter G., Boguslawski S., Moses T.Y., Savage S., et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature. 2007;448:439–444. doi: 10.1038/nature05933. PubMed DOI

Bleeker F.E., Felicioni L., Buttitta F., Lamba S., Cardone L., Rodolfo M., Scarpa A., Leenstra S., Frattini M., Barbareschi M., et al. AKT1E17K in human solid tumours. Oncogene. 2008;27:5648–5650. doi: 10.1038/onc.2008.170. PubMed DOI

Xu Y., Pasche B. TGF-β signaling alterations and susceptibility to colorectal cancer. Hum. Mol. Genet. 2007;16:R14–R20. doi: 10.1093/hmg/ddl486. PubMed DOI PMC

Meulmeester E., Ten Dijke P. The dynamic roles of TGF-β in cancer. J. Pathol. 2011;223:205–218. doi: 10.1002/path.2785. PubMed DOI

Lampropoulos P., Zizi-Sermpetzoglou A., Rizos S., Kostakis A., Nikiteas N., Papavassiliou A.G. TGF-β signalling in colon carcinogenesis. Cancer Lett. 2012;314:1–7. doi: 10.1016/j.canlet.2011.09.041. PubMed DOI

Xie W., Rimm D.L., Lin Y., Shih W.J., Reiss M. Loss of Smad signaling in human colorectal cancer is associated with advanced disease and poor prognosis. Cancer J. 2003;9:302–312. doi: 10.1097/00130404-200307000-00013. PubMed DOI

Fleming N.I., Jorissen R.N., Mouradov D., Christie M., Sakthianandeswaren A., Palmieri M., Day F., Li S., Tsui C., Lipton L., et al. SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. Cancer Res. 2013;73:725–735. doi: 10.1158/0008-5472.CAN-12-2706. PubMed DOI

Miyaki M., Iijima T., Konishi M., Sakai K., Ishii A., Yasuno M., Hishima T., Koike M., Shitara N., Iwama T., et al. Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene. 1999;18:3098–3103. doi: 10.1038/sj.onc.1202642. PubMed DOI

Takagi Y., Kohmura H., Futamura M., Kida H., Tanemura H., Shimokawa K., Saji S. Somatic alterations of the DPC4 gene in human colorectal cancers in vivo. Gastroenterology. 1996;111:1369–1372. doi: 10.1053/gast.1996.v111.pm8898652. PubMed DOI

Howe J.R., Roth S., Ringold J.C., Summers R.W., Jarvinen H.J., Sistonen P., Tomlinson I.P., Houlston R.S., Bevan S., Mitros F.A., et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science. 1998;280:1086–1088. doi: 10.1126/science.280.5366.1086. PubMed DOI

Calon A., Lonardo E., Berenguer-Llergo A., Espinet E., Hernando-Momblona X., Iglesias M., Sevillano M., Palomo-Ponce S., Tauriello D.V., Byrom D., et al. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat. Genet. 2015;47:320–329. doi: 10.1038/ng.3225. PubMed DOI

Nakagawa H., Liyanarachchi S., Davuluri R.V., Auer H., Martin E.W., Jr., de la Chapelle A., Frankel W.L. Role of cancer-associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles. Oncogene. 2004;23:7366–7377. doi: 10.1038/sj.onc.1208013. PubMed DOI

Calon A., Espinet E., Palomo-Ponce S., Tauriello D.V., Iglesias M., Cespedes M.V., Sevillano M., Nadal C., Jung P., Zhang X.H., et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012;22:571–584. doi: 10.1016/j.ccr.2012.08.013. PubMed DOI PMC

Kulkarni A.B., Huh C.G., Becker D., Geiser A., Lyght M., Flanders K.C., Roberts A.B., Sporn M.B., Ward J.M., Karlsson S. Transforming Growth Factor-β-1 Null Mutation in Mice Causes Excessive Inflammatory Response and Early Death. Proc. Natl. Acad. Sci. USA. 1993;90:770–774. doi: 10.1073/pnas.90.2.770. PubMed DOI PMC

Shull M.M., Ormsby I., Kier A.B., Pawlowski S., Diebold R.J., Yin M.Y., Allen R., Sidman C., Proetzel G., Calvin D., et al. Targeted Disruption of the Mouse Transforming Growth Factor-β-1 Gene Results in Multifocal Inflammatory Disease. Nature. 1992;359:693–699. doi: 10.1038/359693a0. PubMed DOI PMC

Engle S.J., Hoying J.B., Boivin G.P., Ormsby I., Gartside P.S., Doetschman T. Transforming growth factor β1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis. Cancer Res. 1999;59:3379–3386. PubMed

Takaku K., Miyoshi H., Matsunaga A., Oshima M., Sasaki N., Taketo M.M. Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. Cancer Res. 1999;59:6113–6117. PubMed

Zhu Y., Richardson J.A., Parada L.F., Graff J.M. Smad3 mutant mice develop metastatic colorectal cancer. Cell. 1998;94:703–714. doi: 10.1016/S0092-8674(00)81730-4. PubMed DOI

Kaiser S., Park Y.K., Franklin J.L., Halberg R.B., Yu M., Jessen W.J., Freudenberg J., Chen X., Haigis K., Jegga A.G., et al. Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer. Genome Biol. 2007;8:R131. doi: 10.1186/gb-2007-8-7-r131. PubMed DOI PMC

Zeng Q., Phukan S., Xu Y., Sadim M., Rosman D.S., Pennison M., Liao J., Yang G.Y., Huang C.C., Valle L., et al. Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development. Cancer Res. 2009;69:678–686. doi: 10.1158/0008-5472.CAN-08-3980. PubMed DOI PMC

Alberici P., Jagmohan-Changur S., De Pater E., Van Der Valk M., Smits R., Hohenstein P., Fodde R. Smad4 haploinsufficiency in mouse models for intestinal cancer. Oncogene. 2006;25:1841–1851. doi: 10.1038/sj.onc.1209226. PubMed DOI

Sodir N.M., Chen X., Park R., Nickel A.E., Conti P.S., Moats R., Bading J.R., Shibata D., Laird P.W. Smad3 deficiency promotes tumorigenesis in the distal colon of ApcMin/+ mice. Cancer Res. 2006;66:8430–8438. doi: 10.1158/0008-5472.CAN-06-1437. PubMed DOI

Aguilera O., Fraga M.F., Ballestar E., Paz M.F., Herranz M., Espada J., Garcia J.M., Munoz A., Esteller M., Gonzalez-Sancho J.M. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene. 2006;25:4116–4121. doi: 10.1038/sj.onc.1209439. PubMed DOI

Takaku K., Oshima M., Miyoshi H., Matsui M., Seldin M.F., Taketo M.M. Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell. 1998;92:645–656. doi: 10.1016/S0092-8674(00)81132-0. PubMed DOI

Hamamoto T., Beppu H., Okada H., Kawabata M., Kitamura T., Miyazono K., Kato M. Compound disruption of Smad2 accelerates malignant progression of intestinal tumors in Apc knockout mice. Cancer Res. 2002;62:5955–5961. PubMed

Kunkel T.A. Evolving views of DNA replication (in)fidelity. Cold Spring Harb. Symp. Quant. Biol. 2009;74:91–101. doi: 10.1101/sqb.2009.74.027. PubMed DOI PMC

O’Sullivan J.N., Bronner M.P., Brentnall T.A., Finley J.C., Shen W.T., Emerson S., Emond M.J., Gollahon K.A., Moskovitz A.H., Crispin D.A., et al. Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat. Genet. 2002;32:280–284. doi: 10.1038/ng989. PubMed DOI

Poulogiannis G., Frayling I.M., Arends M.J. DNA mismatch repair deficiency in sporadic colorectal cancer and Lynch syndrome. Histopathology. 2010;56:167–179. doi: 10.1111/j.1365-2559.2009.03392.x. PubMed DOI

Boland C.R., Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138:2073–2087. doi: 10.1053/j.gastro.2009.12.064. PubMed DOI PMC

Edelmann W., Yang K., Kuraguchi M., Heyer J., Lia M., Kneitz B., Fan K., Brown A.M., Lipkin M., Kucherlapati R. Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice. Cancer Res. 1999;59:1301–1307. PubMed

de Wind N., Dekker M., Claij N., Jansen L., van Klink Y., Radman M., Riggins G., van der Valk M., van’t Wout K., te Riele H. HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions. Nat. Genet. 1999;23:359–362. doi: 10.1038/15544. PubMed DOI

Prolla T.A., Baker S.M., Harris A.C., Tsao J.L., Yao X., Bronner C.E., Zheng B., Gordon M., Reneker J., Arnheim N., et al. Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DNA mismatch repair. Nat. Genet. 1998;18:276–279. doi: 10.1038/ng0398-276. PubMed DOI

Chen P.C., Dudley S., Hagen W., Dizon D., Paxton L., Reichow D., Yoon S.R., Yang K., Arnheim N., Liskay R.M., et al. Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse. Cancer Res. 2005;65:8662–8670. doi: 10.1158/0008-5472.CAN-05-0742. PubMed DOI

Lakso M., Pichel J.G., Gorman J.R., Sauer B., Okamoto Y., Lee E., Alt F.W., Westphal H. Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc. Natl. Acad. Sci. USA. 1996;93:5860–5865. doi: 10.1073/pnas.93.12.5860. PubMed DOI PMC

Kucherlapati M.H., Lee K., Nguyen A.A., Clark A.B., Hou H., Jr., Rosulek A., Li H., Yang K., Fan K., Lipkin M., et al. An Msh2 conditional knockout mouse for studying intestinal cancer and testing anticancer agents. Gastroenterology. 2010;138:993–1002. doi: 10.1053/j.gastro.2009.11.009. PubMed DOI PMC

Reitmair A.H., Cai J.C., Bjerknes M., Redston M., Cheng H., Pind M.T., Hay K., Mitri A., Bapat B.V., Mak T.W., et al. MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis. Cancer Res. 1996;56:2922–2926. PubMed

Luo F., Brooks D.G., Ye H., Hamoudi R., Poulogiannis G., Patek C.E., Winton D.J., Arends M.J. Conditional expression of mutated K-ras accelerates intestinal tumorigenesis in Msh2-deficient mice. Oncogene. 2007;26:4415–4427. doi: 10.1038/sj.onc.1210231. PubMed DOI

Kuraguchi M., Edelmann W., Yang K., Lipkin M., Kucherlapati R., Brown A.M. Tumor-associated Apc mutations in Mlh1−/−Apc1638N mice reveal a mutational signature of Mlh1 deficiency. Oncogene. 2000;19:5755–5763. doi: 10.1038/sj.onc.1203962. PubMed DOI

Kuraguchi M., Yang K., Wong E., Avdievich E., Fan K., Kolodner R.D., Lipkin M., Brown A.M., Kucherlapati R., Edelmann W. The distinct spectra of tumor-associated Apc mutations in mismatch repair-deficient Apc1638N mice define the roles of MSH3 and MSH6 in DNA repair and intestinal tumorigenesis. Cancer Res. 2001;61:7934–7942. PubMed

Takeda H., Rust A.G., Ward J.M., Yew C.C., Jenkins N.A., Copeland N.G. Sleeping Beauty transposon mutagenesis identifies genes that cooperate with mutant Smad4 in gastric cancer development. Proc. Natl. Acad. Sci. USA. 2016;113:E2057–E2065. doi: 10.1073/pnas.1603223113. PubMed DOI PMC

Starr T.K., Allaei R., Silverstein K.A., Staggs R.A., Sarver A.L., Bergemann T.L., Gupta M., O’Sullivan M.G., Matise I., Dupuy A.J., et al. A transposon-based genetic screen in mice identifies genes altered in colorectal cancer. Science. 2009;323:1747–1750. doi: 10.1126/science.1163040. PubMed DOI PMC

Drost J., van Jaarsveld R.H., Ponsioen B., Zimberlin C., van Boxtel R., Buijs A., Sachs N., Overmeer R.M., Offerhaus G.J., Begthel H., et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature. 2015;521:43–47. doi: 10.1038/nature14415. PubMed DOI

Matano M., Date S., Shimokawa M., Takano A., Fujii M., Ohta Y., Watanabe T., Kanai T., Sato T. Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat. Med. 2015;21:256–262. doi: 10.1038/nm.3802. PubMed DOI

TROP2 Represents a Negative Prognostic Factor in Colorectal Adenocarcinoma and Its Expression Is Associated with Features of Epithelial-Mesenchymal Transition and Invasiveness

Special Issue: Animal Modeling in Cancer