Mouse models of colorectal cancer: Past, present and future perspectives

Table 1 Overview of genetically engineered mouse models

Link to Figure 1	Ref.	Methods	Results
1	[127]	loxP flanked Apc exon 14 (Apc580S)	Adenoma formation in the distal rectum in most of the Apc580S homozygotes. 50% of animals show invasive adenocarcinoma after 1 yr without lymphatic or distant metastases
		Colorectal tumor induction by rectal infection with Cre-delivering Adenovirus (AxSRαCre)
2	[109]	ApcΔ242/+	Adenomas: Higher in numbers but smaller in size and no differences in histology compared to ApcMin/+ mice
3	[110]	ApcΔ14/+	Shift of tumor distribution, more severe phenotype, invasion of muscularis propria, 50% dead after 12 mo
4	[120]	Fabpl-Cre; Apc15lox/+	Increased survival due to lower number of tumors, but larger tumors predominantly in the colon, 91% at least low-grade adenoma, 50% carcinoma; invasiveness and metastases not reported
5	[108]	Apc+/Δ716 (C57BL/6J background)	Intestinal polyposis with emphasis on the small intestine
6	[126]	Cac; Apc580S/+	Transgene expression limited to the large intestine. Adenoma formation without malignancy
7	[125]	CDX2P9.5-G22Cre	Frameshifted Cre-recombinase with a long guanine nucleotide tract under control of the homeobox promotor CDX2P9.5 leads to limited activation of Cre by spontaneous somatic mutations in the large intestine: Apcflox/flox homozygotes dye rapidly from florid polyposis of proximal colon and cecum
		Apcflox/flox
8	[374]	Apc+/Δ716 Cdx2+/−	Increased adenoma formation in the colon, reduced number of polyps in the small intestine
9	[132]	Apc+/fle1−15; Villin-Cre mice (conditional) and ApcΔe1−15 constitutive null allele	More severe polyposis compared to ApcMin/+ mice
10	[375]	BubR1+/–ApcMin/+	Increased tumor formation in the large intestine and higher malignancy through increased chromosomal instability (invasiveness and metastases not reported). Note, that BUBR1 mutations are uncommon in CRC[376]
11	[377]	ΔcyEphb2;ApcMin/+	Reduced tumor formation in the small intestine, but large adenocarcinomas of the colorectum
		Ephb3+/-;ApcMin/+
		Ephb3-/-;ApcMin/+
12	[133]	CDX2P-CreERT2Apcflox/flox	Tamoxifen inducible Apc-knockout in the distal intestine
13	[378]	long living ApcMin/+ mice	Some adenomas progress to adenocarcinomas
14	[104]	C57BL/6J ApcMin/+ × SWR/J or C57BR/cdcJ	Hybrid ApcMin/+ mice survive longer due to decreased adenoma frequency. After one-year high amount of invasive adenocarcinomas. 3% metastasis to lymph nodes
15	[105]	Change of the ApcMin/+ genetic background from C57Bl6/J to A/J mice	Increased tumor formation in the intestine. 50% adenocarcinomas in the small intestine and 20% in the colon
16	[131]	AhCre+; Apcflox/flox	β-naphthoflavone-inducible Cyp1A promoter Cre-transgene (AhCre). Rapid death upon induction due to disruption of intestinal architecture
17	[98]	ApcMin/+ + AOM	6-fold increase of colonic tumor formation compared to ApcMin/+ mice
18	[379]	ApcMin/+ + AOM	Increased incidence of colonic adenocarcinomas
19	[52]	ApcMin/+ + DSS	High incidence of well differentiated colonic carcinomas
20	[380]	ApcMin/+ + PhIP	2- to 3-fold increase of tumor formation compared to ApcMin/+ mice
21	[99]	ApcMin/+ + AOM + DSS	Mainly small intestinal tumor formation
22	[111]	ApcMin/+P53-/-	No increased adenoma formation or malignancy compared to ApcMin/+ 53-/+ - and ApcMin/+P53+/+ -mice
23	[112]	ApcMin/+P53-/-	No increased malignancy or adenoma formation compared to ApcMin/+ mice
24	[381]	ApcMin/+P53-/-	Slight, but not significant, increase in malignancy
25	[113]	ApcMin/+Mom1R/RP53−/−	P53 deficiency increases intestinal adenoma multiplicity and malignancy
		ApcMin/+Mom1R/SP53−/−
26	[139]	ApcΔ716Trp53+/LSL•R270HVillin-CreER	Homozygotes die rapidly from lymphoma while heterozygous P53R270H leads to invasive adenocarcinomas with features of EMT
		ApcΔ716Trp53LSL•R270H/LSL•R270HVillin-CreER
27	[128]	Deletion of Apc and P53 by viral delivery of corresponding sgRNA into Rosa26LSL-Cas9-eGFP/+; VillinCreER	In vivo editing of Apc alone or in combination with P53 via Cre mediated Cas9-expression and provision of sgRNA by viral infection of the colonic epithelium leads to tumor formation without metastatic properties
28	[382]	Fabpl:Cre+/oTdgflox/-ApcMin/+	TDG knockout increases adenoma formation, no carcinomas
29	[122]	AhCre+/T; Kras+/LSLV12	Cytochrome p450 mediated Cre expression in the liver and intestine induced by β-naphthoflavone (AhCre). KrasV12 mutation does not alter the intestinal epithelium, but combined with APC-loss, accelerates tumorigenesis in the intestine. 17% of the tumors are invasive adenocarcinomas
		AhCre+/T; Kras+/LSLV12, Apc+/fl
30	[383]	CDX2P9.5-G22Cre; Apcflox/flox; LSL-KrasG12D	Severe debilities in mice with reduced weight and lifespan and anal bulging. Kras mutation does not increase malignancy
31	[136]	Fapbl-Cre; Apc2lox14/+; KrasLSL-G12D/+	KrasG12D, but not NrasG12D drives colon cancer progression. Nras indistinct from ApcMin/+ mice
		Fapbl-Cre; Apc2lox14/+; NrasLSL-G12D/+
32	[143]	shApc/KrasG12D/P53fl/fl/Lgr5	Mice with inducible and reversible Apc deletion via short hairpin RNA show duodenal and colonic tumor formation. Additional, conditional mutations drive cancer progression, but upon Apc restoration by withdrawal of doxycycline rapid tumor regression can be induced
33	[130,384]	ApcCKO/LSL-Kras	Cre-mediated knockout of Apc and KrasG12D activation by surgical application of AdenoCre to the colonic epithelium leads to adenocarcinomas with 20% liver metastases after 20 weeks
34	[385]	Apc+/580S, Kras+/LSL, CAC+	Only adenomas
35	[116]	CMV-cre × LSL- KrasG12D	Germline embryonic expression of an endogenous KrasG12D allele is uniformly lethal. Diffuse colonic hyper- and dysplasia
		LSL-KrasG12D; Fabpl-Cre
36	[117]	Kras+/V12 × CMV-Cre+/T	High embryonic lethality; adult animals succumb to pulmonary neoplasia, no phenotypic changes in the intestine
37	[134]	LSL-KrasG12D/Villin-cre +AOM	Increased number of microadenomas in the proximal colon
38	[198]	Villin-Cre/K-rasG12Dint/Ink4a/Arf−/−	Within 12 wk progression to invasive adenocarcinomas (79%) with 60% lung metastases
39	[165]	ApcΔ716 Tgfbr2flox/flox; villin-CreER	Disruption of TGFβ-signaling leads to locally invasive adenocarcinomas
40	[164]	AOM-treatment of Fabpl4xat-132Cre; Tgfbr2flx/flx mice	Higher incidence of colonic adenomas and adenocarcinomas
41	[167]	Villin-Cre; Apc1638N/wt; Tgfbr2flx/flx	Compared to Apc1638N/wt similar tumor incidence but increased progression to locally invasive adenocarcinoma
42	[163]	Tgfb1−/−Rag2−/−	Rapid formation of adenomas and adenocarcinomas
43	[166]	LSL-KrasG12D/wt; Villin-Cre; Tgfbr2E2flx/E2flx	Wnt-independent induction of invasive carcinomas in the intestine with 15% distant metastases
44	[153]	Villin-Cre; Ptenflx/flx; Tgfbr2flx/flx	Mice with inactivation of TGFβR2 combined with loss of PTEN show high number of mucinous adenocarcinomas throughout the intestine. 8% show distant metastases (not Wnt, but deregulation of CDK inhibitor expression). Pten loss without mutation has no effect
45	[152]	Villin-CreERT; Apcfl/+; Ptenfl/fl; KrasLSL/+	Villin-CreERT; Apcfl/+; Ptenfl/fl; KrasLSL/+ mice show rapid morbidity due to invasive small intestinal tumors
46	[151]	AhCre; Ptenf/f	PTEN is dispensable in the intestinal epithelium, but increases tumorigenesis in the context of APC deficiency
47	[386]	ApcMin/+Pld1−/− vs ApcMin/+Pld1+/+ +AOM/DSS	Pld1-knockout/suppression leads to decreased tumor burden
48	[157]	Dpc4+/-: Apc+/Δ716	Dpc4 and ApcΔ716 cis-compound heterozygote mice show adenoma to carcinoma progression in the small intestine and colon with submucosal infiltration
49	[159]	Smad2+/-; Apc+/Δ716	Combination of Apc mutation and loss of Smad2 leads to no changes in tumor size or properties compared to Apc+/Δ716 mice
50	[161]	ApcMin/+; Smad3−/−	Reduced lifespan of 2 months due to rapid tumor development in the distal colon with mixed histology but no metastases
51	[156]	Apc+/1638N/Smad4+/E6sad (cis and trans)	Smad4 mutation leads to intestinal tumors without malignant properties. Both mutations lead to high tumor burden in the upper GI (cis>trans); some show invasion of the submucosa
52	[387]	cis-Apc+/-/Smad4+/- Mmp7−/−	Mmp7 knockout reduces tumor size but does not affect invasiveness
53	[388]	Smad2+/-; Apc580D/+ (cis)	Larger tumors, higher incidence of malignant phenotype (compared to Apc580D/+mice)
54	[160]	Smad3-/- (129/Sv genetic background)	Adenocarcinomas of the intestine with penetration of the whole intestinal wall and lymphatic spread. Lower tumor burden in C57/BL6 × 129/Sv Smad3-/- hybrids. Note, that Smad3 mutations occur only in 2% of CRC (Fleming et al[162], 2013)
55	[179]	Smad4f/f;Catnblox(ex3)/+;Lgr5-CreERT2-IRES-GFP	Mosaic Cre-expression leads to adenoma formation
56	[178]	Catnb+/lox(ex3): Krt1-19+/creCatnb+/lox(ex3): Tg·Fabplcre	Constitutional Cre-mediated excision of ß-catenin phosphorylation site leads to a plethora of small intestine adenomas
57	[177]	Villin-creERT2/CatnbloxEx3/WT	Expression of GSK3β-resistant β-catenin leads to substitution of enterocytes by highly proliferative crypt stem cells (rapid death)
58	[142]	Nicd/Apc+/1638N	NOTCH-signaling does not influence adenoma formation
59	[141]	Nicd/P53−/−	Villin-CreERT2 tamoxifen-dependent P53 deletion in constitutively active NOTCH-signaling background leads to intestinal tumor formation and metastasis
60	[158]	Car1CreER/+; Apcfl/fl; KrasLSL–G12D/+; P53KO; Smad4fl/fl	Rapid tumor formation in cecum and proximal colon, but high mortality in triple and quadruple mutants
61	[192]	Msh2Δ7N/Δ7N /Apc+/1638N. Msh2Δ7N/Δ7N /ApcMin/+	Rapid tumor formation in the small intestine, early death (2-3 months), more tumors in Msh2Δ7N/Δ7N /ApcMin/+
62	[191]	ApcMin/+/Msh2+/+; ApcMin/+/Msh2+/-; ApcMin/+/Msh2-/-	Accelerated tumor formation in the small intestine in MSH2-deficient mice. Mice homozygous for Msh2-/- dye rapidly from lymphomas
63	[389]	KrasV12/Cre/Msh2−/−	β-naphthoflavone inducible Kras mutation (AhCre+/T, Kras+/LSLV12) combined with homozygous Msh2-knockout leads to increased number of intestinal adenomas. No carcinomas, relevant number of thymic lymphomas
64	[197]	VCMsh2LoxP/LoxP	Villin-controlled Cre-expression leads to intestinal MMR-deficiency, similar to Lynch syndrome. 50% of tumors in the small intestine are malignant. A high proportion of carcinomas in VCMsh2LoxP/null mice are resistant to cisplatin and FOLFOX
		VCMsh2LoxP/G674D
		VCMsh2LoxP/null
65	[185,186]	Msh2-/-	Death due to lymphoma
66	[194]	Apc1638N/+ Exo1 +/− Fen1+/−	Increased tumor multiplicity and incidence, higher progression to malignancy, high incidence of hematopoietic cancers
67	[193]	Fen1null/Apc1638N	Increased malignancy of intestinal tumors compared to Apc1638N mice through MSI
68	[184]	Mlh1-/-/Apc1638N	Increased tumor incidence and multiplicity, 30% adenocarcinomas, reduced lifespan of 3.3 mo. High amount of extraintestinal tumors
69	[187]	Msh6-/+	Reduced life span in hetero- and homozygotes due to lymphomas and gastrointestinal tumors. Tumors show no signs of MSI
		Msh6-/-
70	[390]	Msh3−/−; Msh6−/−	Decreased life span, death due to intestinal adenocarcinomas or lymphomas
71	[190]	Msh6TD/TD; Msh6TD/+	B or T cell non-Hodgkin lymphomas, adenomas of the small intestine, basal cell carcinomas
72	[388]	Pms2-/-; Pms1-/-	Pms2-deficient mice develop lymphomas and sarcomas, but no intestinal tumors; Pms1 deficiency does not cause tumor development
73	[150]	Fc+; Pik3ca*+ (FVB/N-Tg(Fabp1-Cre)1Jig; Gt(ROSA)26Sortm7(Pik3ca*,EGFP)Rsky	Constitutively active PI3K causes mucinous adenocarcinomas of the proximal colon with infiltration of the whole intestinal wall
74	[129]	Apcfl/fl KrasG12D/+ Pik3cap110*+ Cre-Adenovirus via coloscopic injection	Additional driver mutations do not increase tumor proliferation, but cause progression to adenocarcinoma and metastatic disease
75	[172]	ApcCKO/CKO; BrafCA/+, AdenoCre delivery via colonoscopy	Cre-mediated Apc-knockout combined with latent BrafV600E cause neoplasia of the distal colon (50% adenocarcinomas)
76	[174]	Villin-Cre;BrafLSL-V637E/+	Some invasive adenocarcinomas (13%), dominant negative P53 mutation leads to 60% cancers with 2% metastases. Also, p16ink4a mutation causes carcinomas in a Braf mutational background
		Villin-Cre;BrafLSL-V637E/+;P53LSL-R172H/+
		Villin-Cre;BrafLSL-V637E/+;p16Ink4∗
77	[171]	Braf+/LSL-V600E; AhCreERT+/o x	CypA1-promotor-driven, tamoxifen-inducible Cre-recombinase facilitates BrafV600E expression in the small intestine with consecutive crypt hyperplasia. Repression of p16Ink4A leads to tumor formation in various tissues and decreased survival (6 wk)
		Cdkn2a (Ink4a/ArfΔEx2,3) = VE;Cdkn2aΔEx2,3/ΔEx2,3
78	[140]	ApcΔ716 (A), Kras+/LSL-G12D (K), Tgfbr2flox/flox (T), Trp53+/LSL-R270H (P), Fbxw7flox/flox (F), and Villin-CreER	Kras mutation increases multiplicity of tumors, whilst P53 gain-of-function mutation and Tgfβr-knockout leads to invasiveness, no spontaneous metastases
79	[147]	ApcMin/+; Fbw7ΔG	Reduced survival for Fbw7 deficient mice, also in heterozygous setting
80	[148]	Fbw7flox/flox; P53flox/flox; Villin-Cre	Aggressive carcinomas with metastatic spread to lymph nodes and liver
81	[391]	Mutyh-/-	Spontaneous adenoma and adenocarcinoma development in the intestine; predominantly in the upper small intestine. Tumorigenesis increased by oxidative stress (KBrO3)