Progress in the Application of Animal Disease Models in the Medical Research on Colorectal Cancer

doi:10.12300/j.issn.1674-5817.2023.076

Abstract

Abstract:

Colorectal cancer (CRC) is the third most common malignant tumor in the world. The latest statistics show that CRC accounts for 10% of all cancer cases worldwide and is the second leading cause of cancer deaths. CRC is a highly heterogeneous disease, the development of which is driven by functional abnormalities or epigenetic changes caused by multiple gene expression mutations, and there are different pathways that lead to tumor formation. Complex factors such as genetics, environment, ethics, and individual differences of patients themselves limit the study of CRC in humans, so the disease animal models have become an indispensable tool for the study of CRC, and play an important role in prevention, treatment, preclinical research and basic research. There are various types of CRC animal models, of which mouse models are the most widely used. According to different model establishing methods, the models are divided into spontaneous, chemically induced, transplanted tumor and genetic-engineering mouse models. Different models have different characteristics and application prospects. In this study, we focus on these mouse models of CRC in detail, and introduce the latest research progress of CRC models in rats, experimental pigs and zebrafish, to provide reference for the selection and application of animal models of CRC.

Key words: Colorectal cancer, Animal model, Transplanted tumor model, Chemical induced model, Genetic-engineering model

CLC Number:

R-332

Yanjuan CHEN, Ruling SHEN. Progress in the Application of Animal Disease Models in the Medical Research on Colorectal Cancer[J]. Laboratory Animal and Comparative Medicine, 2023, 43(5): 512-523.

Figures/Tables 2

References 81

1	张正杰, 程云章, 黄陈. 影像组学在结直肠癌诊疗中的应用及研究进展[J]. 生物医学工程研究, 2023, 42(1):96-99. DOI: 10.19529/j.cnki.1672-6278.2023.01.14 .
	ZHANG Z J, CHENG Y Z, HUANG C. Application and research progress of radiomics in the diagnosis and treatment of colorectal cancer[J]. J Biomed Eng Res, 2023, 42(1):96-99. DOI: 10.19529/j.cnki.1672-6278.2023.01.14 .
2	SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA A Cancer J Clin, 2021, 71(3):209-249. DOI: 10.3322/caac.21660 .
3	XIA C F, DONG X S, LI H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants[J]. Chin Med J (Engl), 2022, 135(5):584-590. DOI: 10.1097/CM9.0000000000002108 .
4	WEITZ J, KOCH M, DEBUS J, et al. Colorectal cancer[J]. Lancet, 2005, 365(9454):153-165. DOI: 10.1016/s0140-6736(05)17706-x .
5	GAO X H, LI J, LIU L J, et al. Trends, clinicopathological features, surgical treatment patterns and prognoses of early-onset versus late-onset colorectal cancer: a retrospective cohort study on 34067 patients managed from 2000 to 2021 in a Chinese tertiary center[J]. Int J Surg, 2022, 104:106780. DOI: 10.1016/j.ijsu.2022.106780 .
6	SARAIVA M R, ROSA I, CLARO I. Early-onset colorectal cancer: a review of current knowledge[J]. World J Gastroenterol, 2023, 29(8):1289-1303. DOI: 10.3748/wjg.v29.i8.1289 .
7	BÜRTIN F, MULLINS C S, LINNEBACHER M. Mouse models of colorectal cancer: past, present and future perspectives[J]. World J Gastroenterol, 2020, 26(13):1394-1426. DOI: 10.3748/wjg.v26.i13.1394 .
8	MOSER A R, PITOT H C, DOVE W F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse[J]. Science, 1990, 247(4940):322-324. DOI: 10.1126/science.2296722 .
9	STASTNA M, JANECKOVA L, HRCKULAK D, et al. Human colorectal cancer from the perspective of mouse models[J]. Genes, 2019, 10(10):788. DOI: 10.3390/genes10100788 .
10	COLUSSI D, BRANDI G, BAZZOLI F, et al. Molecular pathways involved in colorectal cancer: implications for disease behavior and prevention[J]. Int J Mol Sci, 2013, 14(8):16365-16385. DOI: 10.3390/ijms140816365 .
11	周雄, 胡明, 蒋栋铭, 等. 结直肠癌进展相关关键分子事件研究进展[J]. 肿瘤防治研究, 2023, 50(6): 609-615. DOI: 10.3971/j.issn.1000-8578.2023.22.1242 .
	ZHOU X, HU M, JIANG D M, et al. Research progress of key molecular events related to progression of colorectal cancer[J]. Cancer Res Prev Treat, 2023, 50(6): 609-615. DOI: 10.3971/j.issn.1000-8578.2023.22.1242 .
12	DEKKER E, TANIS P J, VLEUGELS J L A, et al. Colorectal cancer[J]. Lancet, 2019, 394(10207):1467-1480. DOI: 10.1016/S0140-6736(19)32319-0 .
13	CARBALLAL S, BALAGUER F, IJSPEERT J G. Serrated polyposis syndrome; epidemiology and management[J]. Best Pract Res Clin Gastroenterol, 2022, 58-59:101791. DOI: 10.1016/j.bpg.2022.101791 .
14	ZHOU Y J, LU X F, CHEN H M, et al. Single-cell transcriptomics reveals early molecular and immune alterations underlying the serrated neoplasia pathway toward colorectal cancer[J]. Cell Mol Gastroenterol Hepatol, 2023, 15(2):393-424. DOI: 10.1016/j.jcmgh.2022.10.001 .
15	CIARDIELLO F, CIARDIELLO D, MARTINI G, et al. Clinical management of metastatic colorectal cancer in the era of precision medicine[J]. CA A Cancer J Clin, 2022, 72(4):372-401. DOI: 10.3322/caac.21728 .
16	JOHNSON R L, FLEET J C. Animal models of colorectal cancer[J]. Cancer Metastasis Rev, 2013, 32(1):39-61. DOI: 10.1007/s10555-012-9404-6 .
17	ANISIMOV V N, ZABEZHINSKI M A, ROSSOLINI G, et al. Long-live euthymic BALB/c-nu mice. II: spontaneous tumors and other pathologies[J]. Mech Ageing Dev, 2001, 122(5):477-489. DOI: 10.1016/s0047-6374(01)00228-7 .
18	NEWMARK H L, YANG K, KURIHARA N, et al. Western-style diet-induced colonic tumors and their modulation by calcium and vitamin D in C57Bl/6 mice: a preclinical model for human sporadic colon cancer[J]. Carcinogenesis, 2009, 30(1):88-92. DOI: 10.1093/carcin/bgn229 .
19	YANG J, WEI H, ZHOU Y F, et al. High-fat diet promotes colorectal tumorigenesis through modulating gut microbiota and metabolites[J]. Gastroenterology, 2022, 162(1):135-149.e2. DOI: 10.1053/j.gastro.2021.08.041 .
20	SONG M Y, CHAN A T, SUN J. Influence of the gut microbiome, diet, and environment on risk of colorectal cancer[J]. Gastroenterology, 2020, 158(2):322-340. DOI: 10.1053/j.gastro.2019.06.048 .
21	DE ROBERTIS M, MASSI E, POETA M L, et al. The AOM/DSS murine model for the study of colon carcinogenesis: from pathways to diagnosis and therapy studies[J]. J Carcinog, 2011, 10:9. DOI: 10.4103/1477-3163.78279 .
22	SUGIMURA T. Nutrition and dietary carcinogens[J]. Carcinogenesis, 2000, 21(3):387-395. DOI: 10.1093/carcin/21.3.387 .
23	MCLELLAN E A, BIRD R P. Specificity study to evaluate induction of aberrant crypts in murine colons[J]. Cancer Res, 1988, 48(21):6183-6186.
24	EVANS J P, SUTTON P A, WINIARSKI B K, et al. From mice to men: Murine models of colorectal cancer for use in translational research[J]. Crit Rev Oncol, 2016, 98:94-105. DOI: 10.1016/j.critrevonc.2015.10.009 .
25	NARISAWA T, MAGADIA NE, WEISBURGER J H, et al. Promoting effect of bile acids on colon carcinogenesis after intrarectal instillation of N-methyl-N'-nitro-N-nitroso-guanidine in rats[J]. J Natl Cancer Inst, 1974, 53(4):1093-1097. DOI: 10.1093/jnci/53.4.1093 .
26	NEUFERT C, BECKER C, NEURATH M F. An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression[J]. Nat Protoc, 2007, 2(8):1998-2004. DOI: 10.1038/nprot.2007.279 .
27	SEDLAK J C, YILMAZ Ö H, ROPER J. Metabolism and colorectal cancer[J]. Annu Rev Pathol, 2023, 18:467-492. DOI: 10.1146/annurev-pathmechdis-031521-041113 .
28	FERNÁNDEZ-PONCE C, GERIBALDI-DOLDÁN N, SÁNCHEZ-GOMAR I, et al. The role of glycosyltransferases in colorectal cancer[J]. Int J Mol Sci, 2021, 22(11):5822. DOI: 10.3390/ijms 22115822 .
29	LIANG X, HU J N, HE J M. An optimized protocol of azoxymethane-dextran sodium sulfate induced colorectal tumor model in mice[J]. Chin Med Sci J, 2019, 34(4):281-288. DOI: 10.24920/003495 .
30	TANAKA T, KOHNO H, SUZUKI R, et al. A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate[J]. Cancer Sci, 2003, 94(11):965-973. DOI: 10.1111/j.1349-7006.2003.tb01386.x .
31	MODESTO R, ESTARREJA J, SILVA I, et al. Chemically induced colitis-associated cancer models in rodents for pharmacological modulation: A systematic review[J]. J Clin Med, 2022, 11(10):2739. DOI: 10.3390/jcm11102739 .
32	CORPET D E, PIERRE F. Point: From animal models to prevention of colon cancer. Systematic review of chemoprevention in Min mice and choice of the model system[J]. Cancer Epidemiol Biomarkers Prev, 2003, 12(5):391-400.
33	YANG Y S, LIU C Y, WEN D, et al. Recent advances in the development of transplanted colorectal cancer mouse models[J]. Transl Res, 2022, 249:128-143. DOI: 10.1016/j.trsl. 2022.07.003 .
34	LI C G, LAU H C H, ZHANG X, et al. Mouse models for application in colorectal cancer: understanding the pathogenesis and relevance to the human condition[J]. Biomedicines, 2022, 10(7):1710. DOI: 10.3390/biomedicines 10071710 .
35	RODRIGUEZ R, RITTER M A, FOWLER J F, et al. Kinetics of cell labeling and thymidine replacement after continuous infusion of halogenated pyrimidines in vivo [J]. Int J Radiat Oncol Biol Phys, 1994, 29(1):105-113. DOI: 10.1016/0360-3016(94)90232-1 .
36	BELLAMKONDA K, SATAPATHY S R, DOUGLAS D, et al. Montelukast, a CysLT1 receptor antagonist, reduces colon cancer stemness and tumor burden in a mouse xenograft model of human colon cancer[J]. Cancer Lett, 2018, 437:13-24. DOI: 10.1016/j.canlet.2018.08.019 .
37	BERNHARD O K, GREENING D W, BARNES T W, et al. Detection of cadherin-17 in human colon cancer LIM1215 cell secretome and tumour xenograft-derived interstitial fluid and plasma[J]. Biochim Biophys Acta, 2013, 1834(11):2372-2379. DOI: 10.1016/j.bbapap.2013.03.022 .
38	FLATMARK K, MAELANDSMO G M, MARTINSEN M, et al. Twelve colorectal cancer cell lines exhibit highly variable growth and metastatic capacities in an orthotopic model in nude mice[J]. Eur J Cancer, 2004, 40(10):1593-1598. DOI: 10.1016/j.ejca.2004.02.023 .
39	CÉSPEDES M V, ESPINA C, GARCÍA-CABEZAS M A, et al. Orthotopic microinjection of human colon cancer cells in nude mice induces tumor foci in all clinically relevant metastatic sites[J]. Am J Pathol, 2007, 170(3):1077-1085. DOI: 10.2353/ajpath.2007.060773 .
40	AHMED D, EIDE P W, EILERTSEN I A, et al. Epigenetic and genetic features of 24 colon cancer cell lines[J]. Oncogenesis, 2013, 2(9): e71. DOI: 10.1038/oncsis.2013.35 .
41	GAYET J, ZHOU X P, DUVAL A, et al. Extensive characterization of genetic alterations in a series of human colorectal cancer cell lines[J]. Oncogene, 2001, 20(36):5025-5032. DOI: 10.1038/sj.onc.1204611 .
42	KOUSTAS E, SARANTIS P, THEOHARIS S, et al. Autophagy-related proteins as a prognostic factor of patients with colorectal cancer[J]. Am J Clin Oncol, 2019, 42(10):767-776. DOI: 10.1097/coc.0000000000000592 .
43	KOUMAKI K, KONTOGIANNI G, KOSMIDOU V, et al. BRAF paradox breakers PLX8394, PLX7904 are more effective against BRAFV600Ε CRC cells compared with the BRAF inhibitor PLX4720 and shown by detailed pathway analysis[J]. Biochim Biophys Acta Mol Basis Dis, 2021, 1867(4):166061. DOI: 10.1016/j.bbadis.2020.166061 .
44	RIOS-DORIA J, STEVENS C, MADDAGE C, et al. Characterization of human cancer xenografts in humanized mice[J]. J Immunother Cancer, 2020, 8(1): e000416. DOI: 10.1136/jitc-2019-000416 .
45	CASTLE J C, LOEWER M, BOEGEL S, et al. Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma[J]. BMC Genomics, 2014, 15(1):190. DOI: 10.1186/1471-2164-15-190 .
46	RIVERA M, FICHTNER I, WULF-GOLDENBERG A, et al. Patient-derived xenograft (PDX) models of colorectal carcinoma (CRC) as a platform for chemosensitivity and biomarker analysis in personalized medicine[J]. Neoplasia, 2021, 23(1):21-35. DOI: 10.1016/j.neo.2020.11.005 .
47	ZHAO X F, JIANG Y H, LIU C L, et al. Organoid technology and clinical applications in digestive system cancer[J]. Engineering, 2022, 9:123-130. DOI: 10.1016/j.eng.2021.04.017 .
48	SATO T, VRIES R G, SNIPPERT H J, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche[J]. Nature, 2009, 459(7244):262-265. DOI: 10.1038/nature07935 .
49	SATO T, STANGE D E, FERRANTE M, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium[J]. Gastroenterology, 2011, 141(5):1762-1772. DOI: 10.1053/j.gastro. 2011.07.050 .
50	DROST J, VAN JAARSVELD R H, PONSIOEN B, et al. Sequential cancer mutations in cultured human intestinal stem cells[J]. Nature, 2015, 521(7550):43-47. DOI: 10.1038/nature14415 .
51	PAULI C, HOPKINS B D, PRANDI D, et al. Personalized in vitro and in vivo cancer models to guide precision medicine[J]. Cancer Discov, 2017, 7(5):462-477. DOI: 10.1158/2159-8290.CD-16-1154 .
52	PONSIOEN B, POST J B, BUISSANT DES AMORIE J R, et al. Quantifying single-cell ERK dynamics in colorectal cancer organoids reveals EGFR as an amplifier of oncogenic MAPK pathway signalling[J]. Nat Cell Biol, 2021, 23(4):377-390. DOI: 10.1038/s41556-021-00654-5 .
53	GOBERT A P, LATOUR Y L, ASIM M, et al. Protective role of spermidine in colitis and colon carcinogenesis[J]. Gastroenterology, 2022, 162(3):813-827.e8. DOI: 10.1053/j.gastro.2021.11.005 .
54	BAYDI Z, LIMAMI Y, KHALKI L, et al. An update of research animal models of inflammatory bowel disease[J]. Sci World J, 2021, 2021:7479540. DOI: 10.1155/2021/7479540 .
55	MIYOSHI Y, ANDO H, NAGASE H, et al. Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients[J]. Proc Natl Acad Sci USA, 1992, 89(10):4452-4456. DOI: 10.1073/pnas.89.10.4452 .
56	KUCHERLAPATI M H. Mouse models in colon cancer, inferences, and implications[J]. iScience, 2023, 26(6):106958. DOI: 10.1016/j.isci.2023.106958 .
57	MULLER P A J, CASWELL P T, DOYLE B, et al. Mutant p53 drives invasion by promoting integrin recycling[J]. Cell, 2009, 139(7):1327-1341. DOI: 10.1016/j.cell.2009.11.026 .
58	SANSOM O J, MENIEL V, WILKINS J A, et al. Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K-ras oncogene in vivo [J]. Proc Natl Acad Sci USA, 2006, 103(38):14122-14127. DOI: 10.1073/pnas.0604130103 .
59	ROMANO G, CHAGANI S, KWONG L N. The path to metastatic mouse models of colorectal cancer[J]. Oncogene, 2018, 37(19):2481-2489. DOI: 10.1038/s41388-018-0155-x .
60	HUNG K E, MARICEVICH M A, RICHARD L G, et al. Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment[J]. Proc Natl Acad Sci USA, 2010, 107(4):1565-1570. DOI: 10.1073/pnas. 0908682107 .
61	BOUTIN A T, LIAO W T, WANG M, et al. Oncogenic Kras drives invasion and maintains metastases in colorectal cancer[J]. Genes Dev, 2017, 31(4):370-382. DOI: 10.1101/gad.293449.116 .
62	RAD R, CADIÑANOS J, RAD L. A genetic progression model of BrafV600E-induced intestinal tumorigenesis reveals targets for therapeutic intervention[J]. Cancer Cell, 2013, 24(1):15-29. DOI: 10.1016/j.ccr.2013.05.014 .
63	TROBRIDGE P, KNOBLAUGH S, WASHINGTON M K, et al. TGF-beta receptor inactivation and mutant Kras induce intestinal neoplasms in mice via a beta-catenin-independent pathway[J]. Gastroenterology, 2009, 136(5):1680-1688.e7. DOI: 10.1053/j.gastro.2009.01.066 .
64	TONG Y G, YANG W C, KOEFFLER H P. Mouse models of colorectal cancer[J]. Chin J Cancer, 2011, 30(7):450-462. DOI: 10.5732/cjc.011.10041 .
65	VELCICH A, YANG W C, HEYER J, et al. Colorectal cancer in mice genetically deficient in the mucin Muc2[J]. Science, 2002, 295(5560):1726-1729. DOI: 10.1126/science.1069094 .
66	VAN DER KRAAK L, GROS P, BEAUCHEMIN N. Colitis-associated colon cancer: is it in your genes?[J]. World J Gastroenterol, 2015, 21(41):11688-11699. DOI: 10.3748/wjg.v21.i41.11688 .
67	BRISTOL I J, FARMER M A, CONG Y Z, et al. Heritable susceptibility for colitis in mice induced by IL-10 deficiency[J]. Inflamm Bowel Dis, 2000, 6(4):290-302. DOI: 10.1097/00054725-200011000-00006 .
68	TAKEDA H, WEI Z B, KOSO H, et al. Transposon mutagenesis identifies genes and evolutionary forces driving gastrointestinal tract tumor progression[J]. Nat Genet, 2015, 47(2):142-150. DOI: 10.1038/ng.3175 .
69	FEMIA A P, BECHERUCCI C, CRUCITTA S, et al. Apc-driven colon carcinogenesis in Pirc rat is strongly reduced by polyethylene glycol[J]. Int J Cancer, 2015, 137(9):2270-2273. DOI: 10.1002/ijc.29581 .
70	AMOS-LANDGRAF J M, KWONG L N, KENDZIORSKI C M, et al. A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer[J]. Proc Natl Acad Sci USA, 2007, 104(10):4036-4041. DOI: 10.1073/pnas. 0611690104 .
71	IRVING A A, YOSHIMI K, HART M L, et al. The utility of Apc-mutant rats in modeling human colon cancer[J]. Dis Model Mech, 2014, 7(11):1215-1225. DOI: 10.1242/dmm.016980 .
72	KALLA D, KIND A, SCHNIEKE A. Genetically engineered pigs to study cancer[J]. Int J Mol Sci, 2020, 21(2):488. DOI: 10.3390/ijms21020488 .
73	FLISIKOWSKA T, MERKL C, LANDMANN M, et al. A Porcine model of familial adenomatous polyposis[J]. Gastroenterology, 2012, 143(5):1173-1175.e7. DOI: 10.1053/j.gastro.2012.07.110 .
74	LI H H, CHENG W M, CHEN B W, et al. Efficient generation of P53 biallelic mutations in Diannan miniature pigs using RNA-guided base editing[J]. Life (Basel), 2021, 11(12):1417. DOI: 10.3390/life11121417 .
75	CALLESEN M M, ÁRNADÓTTIR S S, LYSKJÆR I, et al. A genetically inducible porcine model of intestinal cancer[J]. Mol Oncol, 2017, 11(11):1616-1629. DOI: 10.1002/1878-0261. 12136 .
76	TOBIA C, GARIANO G, DE SENA G, et al. Zebrafish embryo as a tool to study tumor/endothelial cell cross-talk[J]. Biochim Biophys Acta, 2013, 1832(9):1371-1377. DOI: 10.1016/j.bbadis. 2013.01.016 .
77	LOBERT V H, MOURADOV D, HEATH J K. Focusing the spotlight on the zebrafish intestine to illuminate mechanisms of colorectal cancer[J]. Adv Exp Med Biol, 2016, 916:411-437. DOI: 10.1007/978-3-319-30654-4_18 .
78	MARADONNA F, FONTANA C M, SELLA F, et al. A zebrafish HCT116 xenograft model to predict anandamide outcomes on colorectal cancer[J]. Cell Death Dis, 2022, 13(12):1069. DOI: 10.1038/s41419-022-05523-z .
79	HUEBNER K, ERLENBACH-WUENSCH K, PROCHAZKA J, et al. ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2[J]. Cell Mol Life Sci, 2022, 79(8):423. DOI: 10.1007/s00018-022-04445-5 .
80	JACKSTADT R, SANSOM O J. Mouse models of intestinal cancer[J]. J Pathol, 2016, 238(2):141-151. DOI: 10.1002/path. 4645 .
81	KAKIUCHI H, WATANABE M, USHIJIMA T, et al. Specific 5'-GGGA-3'-->5'-GGA-3' mutation of the Apc gene in rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine[J]. Proc Natl Acad Sci USA, 1995, 92(3):910-914. DOI: 10.1073/pnas.92.3.910 .

肿瘤细胞系名称 Tumor cell line names	来源 Source	MSI状态 MSI status	突变基因 Mutant gene	参考文献 Reference
HCT116	人源	MSI	KRAS、PIK3CA	[40]
LIM1215	人源	-	-	-
HT29	人源	MSS	APC、BRAF、PIK3CA、TP53	[40]
SW480	人源	MSS	APC、KRAS、TP53	[40]
SW620	人源	MSS	APC、KRAS、TP53	[40]
HCT15	人源	MSI	APC^[41]、KRAS、PIK3CA、TP53	[40]
Colo320DM	人源	MSS	APC、TP53	[40]
Co115	人源	MSI	BRAF、PTEN	[40]
CaCo2	人源	MSS	APC、TP53	[40]
WiDr	人源	MSS	APC、BRAF、PIK3CA、TP53	[40]
COLO205	人源	MSS^[42]	BRAF^[43]	-
DLD-1	人源	MSI	KRAS、PIK3CA、TP53	[40]
CT26	BALB/c小鼠	MSS^[44]	KRAS^[45]	[44-45]
MC38	C57BL/6J小鼠	MSI^[44]	-	[44]

肿瘤细胞系名称 Tumor cell line names	来源 Source	MSI状态 MSI status	突变基因 Mutant gene	参考文献 Reference
HCT116	人源	MSI	KRAS、PIK3CA	[40]
LIM1215	人源	-	-	-
HT29	人源	MSS	APC、BRAF、PIK3CA、TP53	[40]
SW480	人源	MSS	APC、KRAS、TP53	[40]
SW620	人源	MSS	APC、KRAS、TP53	[40]
HCT15	人源	MSI	APC^[41]、KRAS、PIK3CA、TP53	[40]
Colo320DM	人源	MSS	APC、TP53	[40]
Co115	人源	MSI	BRAF、PTEN	[40]
CaCo2	人源	MSS	APC、TP53	[40]
WiDr	人源	MSS	APC、BRAF、PIK3CA、TP53	[40]
COLO205	人源	MSS^[42]	BRAF^[43]	-
DLD-1	人源	MSI	KRAS、PIK3CA、TP53	[40]
CT26	BALB/c小鼠	MSS^[44]	KRAS^[45]	[44-45]
MC38	C57BL/6J小鼠	MSI^[44]	-	[44]

模型分类 Model classification	诱导方式 Induction mode	动物品种品系 Species	涉及化合物及细胞系 Relates to compounds and cell lines	突变基因Mutant gene	局限性 Limitation	有无转移 Metastasis	应用范围 Application	参考文献 Reference
自发性肠道肿瘤模型	自发性	C57BL、 BALB/c-nu小鼠	-	-	发生率极低	无	老龄化研究	[16-17]
自发性肠道肿瘤模型	单纯饮食诱导	C57BL/6小鼠	-	-	诱导时间长	无	饮食对肿瘤的影响	[18]
化合物诱导模型	致癌物诱导模型	F344大鼠	PhIP、IQ	Apc	PhIP诱导未发现Kras和Tp53基因突变	无	化合物预防和风险因素识别	[81]
		F344大鼠	MNNG、MNU	Apc、Kras	引起多器官恶性肿瘤	-		[24]
		F344大鼠	DMBA	Apc、Kras	引起多器官恶性肿瘤	-		[22]
		F344大鼠、A/J小鼠	DMH、AOM	Apc、Kras	诱导时间长，极少转移	无		[27]
		F344大鼠、ICR小鼠	AOM/DSS	Apc、Kras	极少转移	无		[24, 31]
移植瘤模型	CDX模型	BALB/c、C57BL/6小鼠	C T26、MC38	-	不能准确反映人类CRC发病过程	可发生转移	发现新的肿瘤标志物，测试化合物，手术模型	[33]
移植瘤模型	PDX模型	免疫缺陷小鼠、人源化小鼠	HCT116、HT29、LIM1215、SW480、SW620	-	建立周期长（2～4个月），成本高，过程中存在发生突变的可能	可发生转移	发现新的肿瘤标志物，测试化合物，手术模型	[38-39]
基因工程模型	Apc突变相关模型	Apc^min小鼠	-	Apc	缺乏转移，肿瘤集中在小肠	缺乏转移	研究特定基因，化合物预防，风险因素识别	[56]
		Apc^Δ716、Apc^Δ14和Apc^1638N小鼠	-	Apc	缺乏转移，肿瘤集中在小肠	缺乏转移		[7, 29]
		Apc CKO/LSL-Kras小鼠	-	Apc、Kras		肝转移		[60]
		Apc^minSmad3^-/-、Apc^∆716/+Smad4^+/-小鼠	-	Apc、Smad3或者Smad4	寿命短，缺乏转移	缺乏转移		[29]
		Apc^fl/+p53^fl/+、Apc^fl/+p53^R172H/+小鼠	-	Apc、p53	缺乏转移	无		[57]
		iKAP小鼠	-	Apc、Kras、p53	寿命短	肝和肺		[61]
	其他基因突变模型	Kras^G12DTgfbr2^-/-小鼠	-	Kras、Tgfbr2	-	12%～25%的小鼠肿瘤转移到局部淋巴结、胰腺或肺		[62]
	其他基因突变模型	Vil-Cre；Braf^V637E/+；p53^{LSL-R172H/+-/-}小鼠	-	BRAF、p53	-	15%转移到淋巴结和肺部		[63]
	HNPCC	Mlh1^-/-、Msh2^-/-、Msh6^-/-小鼠	-	-	过早死于侵袭性淋巴瘤	无		[21]
	IBD-CRC	Il-10^-/-、Il-2^-/-、Muc2^-/-小鼠	-	-	较低肿瘤发生率，受肠道菌群影响	无		[64-65]
	Apc突变模型	Pirc:F344/NTac-Apcam¹¹³⁷大鼠	-	Apc	4个月自发肠道腺瘤，缺乏转移	无	化合物预防	[69-70, 63]
	Apc突变模型	KAD大鼠	-	Apc	不自发肿瘤，经过AOM/DSS联合诱导发生肿瘤	无	化合物预防	[71]
	Apc突变模型	Apc¹³¹¹猪	-	Apc	肠道肿瘤为腺瘤	无	转化医学研究	[73]

模型分类 Model classification	诱导方式 Induction mode	动物品种品系 Species	涉及化合物及细胞系 Relates to compounds and cell lines	突变基因Mutant gene	局限性 Limitation	有无转移 Metastasis	应用范围 Application	参考文献 Reference
自发性肠道肿瘤模型	自发性	C57BL、 BALB/c-nu小鼠	-	-	发生率极低	无	老龄化研究	[16-17]
自发性肠道肿瘤模型	单纯饮食诱导	C57BL/6小鼠	-	-	诱导时间长	无	饮食对肿瘤的影响	[18]
化合物诱导模型	致癌物诱导模型	F344大鼠	PhIP、IQ	Apc	PhIP诱导未发现Kras和Tp53基因突变	无	化合物预防和风险因素识别	[81]
		F344大鼠	MNNG、MNU	Apc、Kras	引起多器官恶性肿瘤	-		[24]
		F344大鼠	DMBA	Apc、Kras	引起多器官恶性肿瘤	-		[22]
		F344大鼠、A/J小鼠	DMH、AOM	Apc、Kras	诱导时间长，极少转移	无		[27]
		F344大鼠、ICR小鼠	AOM/DSS	Apc、Kras	极少转移	无		[24, 31]
移植瘤模型	CDX模型	BALB/c、C57BL/6小鼠	C T26、MC38	-	不能准确反映人类CRC发病过程	可发生转移	发现新的肿瘤标志物，测试化合物，手术模型	[33]
移植瘤模型	PDX模型	免疫缺陷小鼠、人源化小鼠	HCT116、HT29、LIM1215、SW480、SW620	-	建立周期长（2～4个月），成本高，过程中存在发生突变的可能	可发生转移	发现新的肿瘤标志物，测试化合物，手术模型	[38-39]
基因工程模型	Apc突变相关模型	Apc^min小鼠	-	Apc	缺乏转移，肿瘤集中在小肠	缺乏转移	研究特定基因，化合物预防，风险因素识别	[56]
		Apc^Δ716、Apc^Δ14和Apc^1638N小鼠	-	Apc	缺乏转移，肿瘤集中在小肠	缺乏转移		[7, 29]
		Apc CKO/LSL-Kras小鼠	-	Apc、Kras		肝转移		[60]
		Apc^minSmad3^-/-、Apc^∆716/+Smad4^+/-小鼠	-	Apc、Smad3或者Smad4	寿命短，缺乏转移	缺乏转移		[29]
		Apc^fl/+p53^fl/+、Apc^fl/+p53^R172H/+小鼠	-	Apc、p53	缺乏转移	无		[57]
		iKAP小鼠	-	Apc、Kras、p53	寿命短	肝和肺		[61]
	其他基因突变模型	Kras^G12DTgfbr2^-/-小鼠	-	Kras、Tgfbr2	-	12%～25%的小鼠肿瘤转移到局部淋巴结、胰腺或肺		[62]
	其他基因突变模型	Vil-Cre；Braf^V637E/+；p53^{LSL-R172H/+-/-}小鼠	-	BRAF、p53	-	15%转移到淋巴结和肺部		[63]
	HNPCC	Mlh1^-/-、Msh2^-/-、Msh6^-/-小鼠	-	-	过早死于侵袭性淋巴瘤	无		[21]
	IBD-CRC	Il-10^-/-、Il-2^-/-、Muc2^-/-小鼠	-	-	较低肿瘤发生率，受肠道菌群影响	无		[64-65]
	Apc突变模型	Pirc:F344/NTac-Apcam¹¹³⁷大鼠	-	Apc	4个月自发肠道腺瘤，缺乏转移	无	化合物预防	[69-70, 63]
	Apc突变模型	KAD大鼠	-	Apc	不自发肿瘤，经过AOM/DSS联合诱导发生肿瘤	无	化合物预防	[71]
	Apc突变模型	Apc¹³¹¹猪	-	Apc	肠道肿瘤为腺瘤	无	转化医学研究	[73]

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[4]	. Guidelines for the Selection of Animal Models and Preclinical Drug Trials for Spontaneous Intracerebral Hemorrhage (2024 Edition) [J]. Laboratory Animal and Comparative Medicine, 2024, 44(1): 3-30.
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