Comprehensive modeling of the Correa cascade in precancerous lesions of gastric cancer: Leveraging animal, cellular, and organoid systems for translational insights

Table 1 Summary of modeling methods, agents, and animal types used in precancerous lesions of gastric cancer research

Type	Modeling method	Model animals	Modeling time	Observation time	Atrophy	Metaplasia	Dysplasia	Carcinoma	Ref.
MNU	MNU (120 ppm)	C57BL/6 mice	8 weeks	8 weeks	Yes	IM	Yes	No	[19]
	MNU (100-120 ppm)	BALB/c and C57BL/6 mice, Wistar rats	16-30 weeks	31-54 weeks	Yes	Yes	Yes	Yes	[20,72]
	MNU (120 ppm)	db/db mice	20 weeks	30 weeks	No	No	Yes	Yes	[73]
	MNU (300 ppm)	BALB/c mice	16 weeks	16 weeks	No	IM (16 weeks)	No	No	[74]
MNNG	MNNG (200 μg/mL)	SD rats	16 weeks	26 weeks	No	IM (16 weeks)	Yes (16 weeks)	No	[10,75]
	MNNG (200 μg/mL)	SD rats	40 weeks	40 weeks	No	No	Yes (40 weeks)	Yes (40 weeks)	[9]
	MNNG (800 mg/L)	SD rats	10 weeks	34 weeks	Yes (10 weeks)	No	Yes (22 weeks)	Yes (34 weeks)	[11]
	MNNG (150 μg/mL)	BALB/c mice, C57BL/6 mice	6 weeks	14-36 weeks	Yes	IM	Yes	No	[12,13]
CDCA	DCA (0.2%)	INS-GAS mice	6 months	6 months	Yes (5 months)	IM	Yes	No	[23]
	CDCA (20 mmol/L) + 2% sodium salicylate	SD rats	12 weeks	12 weeks	Yes	IM	No	No	[24,25]
	CDCA (20 mmol/L) + 0.1% ammonia + irregular diet	SD rats	16 weeks	16 weeks	Yes				[26]
Acute drug and H. pylori induction	DMP-777	CD-1 rats, C57BL/6 mice	7-14 days	7-14 days	SPEM	No	No	No	[30,76]
	L635	C57BL/6 mice	3 days	3 days	SPEM	No	No	No	[77]
	Tamoxifen (250 mg/kg)	C57BL/6 mice	3 days	3 days	SPEM	Yes	No	No	[31,32]
	Tamoxifen (50 mg/kg)	gp130Y757F/Y757F mice	2 days	16 weeks	SPEM	Yes	Yes	Yes	[33]
	CagA-positive PMSS1	C57BL/6 mice, Tert-/- mice	12 weeks	12 weeks	SPEM	No	No	No	[34]
H. pylori strain	H. felis	C57BL/6 mice	15 months	15 months	Yes	Yes	Yes	Yes	[39]
	H. pylori SS1	C57BL/6 mice	18 months	18 months	Yes	Yes	No	No	[42]
	H. pylori PMSS1	C57BL/6 mice	8 weeks	8 weeks	Yes	Yes	No	No	[43]
	H. pylori HpslyD + strain	C57BL/6 mice	73 weeks	73 weeks	Yes	IM	No	No	[47]
	H. pylori TN2GF4 strain	Mongolian gerbils	18 weeks	18 weeks	Yes (2 weeks)	IM	No	No	[50]
	H. pylori ATCC 43504 strain	Mongolian gerbils	16-18 months	16-18 months	Yes	IM	Yes	Yes	[49]
	H. pylori 7.13 strain	Mongolian gerbils	7-9 weeks	7-9 weeks	Yes	IM (7 weeks)	Yes	Yes (9 weeks)	[52]
Non-H. pylori gastric microbiome	S. anginosus	C57BL/6 mice, germ-free BALB/c mice	48 weeks	48 weeks	Yes (9 months)	Yes (12 months)	Yes (12 months)	No	[53]
	S. anginosus + MNU (240 ppm)	C57BL/6 mice	36 weeks	36 weeks	Yes	Yes	Yes	Yes (9 months)	[53]
MNU + H. pylori	MNU (240 ppm) + HpSS1	C57BL/6 mice	12-16 weeks	50-80 weeks	Yes	IM	Yes	Yes	[55]
	MNU (200 ppm) + H. felis	FVB and B6 mice	36 weeks	36-50 weeks	Yes	Yes	Yes	Yes	[54,78]
	MNU + PMSS1	C57BL/6 mice	12 weeks	40 weeks	Yes	IM	Yes	No	[56]
	MNU (10 ppm) + ATCC 43504	Mongolian gerbil	24 weeks	53 weeks	Yes	IM	Yes	No	[57]
MNU + dietary	MNU (120 ppm) + 10% NaCl	C57BL/6J mice	40 weeks	40 weeks				Yes	[36]
	MNU (120 ppm) + HpSS1 + 10% NaCl	C57BL/6J mice	40 weeks	40 weeks				Yes	[36]
	MNU + DCA	C57BL/6 mice, Lgr5-p53-/- mice	48 weeks	48 weeks		Yes	Yes	No	[59]
	MNU (300 ppm) + irregular diet	BALB/c mice	20 weeks	20 weeks	Yes	IM	Yes	No	[58]
MNNG + H. pylori	MNNG (50 μg/mL) + KMUH-G926	Mongolian gerbil	20 weeks	52 weeks	Yes (32 weeks)	No	Yes	Yes (52 weeks)	[71]
	MNNG (40 μg/mL) + HpSS1	C57BL/6J mice	48 weeks	48 weeks	No	No	Yes (48 weeks)	No	[7]
MNNG composite model	MNNG (200 μg/mL) + saturated salt	Wistar rats	25 weeks	35 weeks	Yes (25 weeks)	IM	Yes (35 weeks)	No	[61]
	MNNG (200 μg/mL) + 0.1% ammonia + irregular fasting	SD rats	20 weeks	20 weeks	Yes	IM	Yes	No	[60]
	MNNG (120 μg/mL) + H. pylori + ammonia	Kunming mice	7 days	120 days	Yes	No	No	No	[16]
	MNNG (170-200 μg/mL) + irregular diet	SD rats, Wistar rats	10-12 weeks	14 weeks	Yes	No	No	No	[62,63]
	MNNG (200 μg/mL) + irregular diet + emotionally stimulated	Wistar rats	24 weeks	24 weeks	Yes	IM	Yes	No	[64]
	MNNG (100 μg/mL) + 2% sodium salicylate	Wistar rats	17 weeks	21 weeks	Yes	IM	Yes	No	[65]
	MNNG (120 μg/mL) + 5% aqueous alcohol solution	Wistar rats	56 weeks	56 weeks	No	No	No	Yes (14 months)	[66]
	MNNG (120-150 μg/mL) + 2% sodium salicylate + irregular fasting + 0.05% ranitidine	Wistar rats	32-40 weeks	32-40 weeks	Yes	Yes	Yes	Yes	[67,68,70]
	MNNG (200 μg/mL) + 40% alcohol + irregular fasting + 0.03% ranitidine	SD rats	40 weeks	40 weeks	Yes	IM	Yes	No	[69]

MNU: N-Nitroso-N-methylurea; MNNG: N-methyl-N’-nitro-N-nitrosoguanidine; CDCA: Chenodeoxycholic acid; H. pylori: Helicobacter pylori; DCA: Deoxycholic acid; H. felis: Helicobacter felis; S. anginosus: Streptococcus anginosus; HpSS1: Helicobacter pylori Sydney strain; INS-GAS: Insulin-gastrin; SD: Sprague-Dawley; Lgr5: Leucine-rich repeat-containing G protein-coupled receptor 5; IM: Intestinal metaplasia.

Table 2 Genetically engineered mouse models of precancerous gastric lesions and their histological characteristics

Type	Mouse model	Observation time	Intervention	SPEM	Atrophy	Metaplasia	Dysplasia	Carcinoma	Ref.
Gastrin-related	Gastrin-/- mice	12 months	No		Yes	IM	Yes	Yes	[79]
	Gastrin-/- mice	28 days	DMP-777	Yes					[76]
	Gastrin-/- mice	36 weeks	MNU + H. felis		Yes	Yes	Yes	Yes	[78]
	INS-GAS mice	36 weeks	MNU		Yes	Yes	Yes	Yes	[78]
	INS-GAS mice	6-18 months	H. pylori SS1		Yes	Yes	Yes	No	[80]
	INS-GAS mice	3-4 months	H. pylori PMSS1, B128, NCTC11637		Yes	IM	Yes	Yes	[81-83]
Inflammatory transmitter induction	H/K-IL-β transgenic mice	12 months	No	Yes	Yes	Yes	Yes	Yes	[87,109]
	H/K-IFN-γ transgenic mice	15 months	No	Yes	Yes	Yes	Yes	Yes	[88]
	TxA23 TCR transgenic mice	12 months	No	Yes	Yes	Yes	Yes	Yes	[89]
	K19-Wnt1/C2mE transgenic mice	30 weeks	No	Yes	No	Yes	Yes	Yes	[110]
Mutations in oncogenes and tumor suppressors	Mist1-Kras transgenic mice	1-4 months	No	Yes	Yes	Yes	Yes	Yes	[90]
	K19-K-ras-V12 transgenic mice	20 months	No		Yes	Yes	Yes	Yes	[93]
	Runx3-/- mice	52 weeks	MNU	Yes	No	IM	Yes	Yes	[94]
	Usf1-/- mice	12 months	H. pylori		Yes	IM	Yes	No	[95]
	p27-/- mice	70 weeks	H. pylori SS1		Yes	Yes	Yes	No	[96]
	MYCR26StopFL/+; Setd2-/-(AMC) mice	10 weeks	No		No	IM	Yes	No	[97]
Glandular cell damage	stCldn18-/- mice	100 weeks	No	Yes	Yes	IM	Yes	Yes	[98]
	Slc26a9-/- mice	18 months	No	Yes	Yes	IM	Yes	Yes	[99]
	Tff1-/- mice	12 months	No		Yes	Yes	Yes	Yes	[100]
	Hip1r-/- mice	5 weeks	No	Yes	No	No	No	No	[110]
	GRIM-19-/- mice	10 weeks	No	Yes	No	No	No	No	[101]
Dysregulation of signalling pathways	PPARD mice	55 weeks	No	Yes	Yes	IM	Yes	Yes	[102]
	Smad3-/- mice	10 months	No	Yes	Yes	Yes	Yes	Yes	[103]
	H/K-noggin mouse	12 weeks	No	Yes	No	No	No	No	[111]
	MyD88-/- mice	47 weeks	H. felis		Yes	IM	Yes	Yes	[104]
	RNF43H292R/H295R mice	6 months	H. pylori; PMSS1		Yes	IM	Yes	Yes	[105]
Multiple gene mutations or deletions in specific glandular cells	Pgc-Cre mice	9 months	No	Yes	Yes	Yes	Yes	Yes	[112]
	Anxa10-Cre mice	10 weeks	No		No	No	Yes	Yes	[106]
	Lgr5-Cre; Smad4fl/fl; PTENfl/fl mice	12 months	No		Yes	IM	Yes	Yes	[107]
	Mist1-Cre; LSL-KrasG12D; Apcfl/fl mice	4 months	No		Yes	IM	Yes	Yes	[91]
	H/K Cre; LKB1L/L; PTENL/L mice	40 weeks	No		No	IM	Yes	Yes	[108]

INS-GAS: Insulin-gastrin; IL-β: Interleukin-β; IFN-γ: Interferon-γ; PPARD: Peroxisome proliferator-activated receptor delta; Lgr5: Leucine-rich repeat-containing G protein-coupled receptor 5; H. pylori: Helicobacter pylori; H. felis: Helicobacter felis; MNU: N-Nitroso-N-methylurea; IM: Intestinal metaplasia.

Table 3 Decision framework for selecting precancerous lesions of gastric cancer research models

Research objective	Model	Induction/approach	Advantages	Limitations
SPEM mechanisms	Mouse (acute drug-induced)	DMP-777 (10-14 days), L635 (10-14 days)	Rapid, reversible, specific parietal cell loss	Lacks chronic inflammatory context
IM	Mouse (bile acid-induced), GES-1 cells, gastric organoids	Mouse: 0.2% DCA in drinking water (6 months); GES-1: 100 μM CDCA for 24 hours. Organoids: BMP activation	In vivo: Recapitulates IM progression. In vitro: Rapid, high-throughput. Organoids: Human-specific, physiologically relevant	In vivo: Long duration. In vitro: Lack tissue complexity. Organoids: Lack full tumor microenvironment
H. pylori pathogenesis	Mongolian gerbil, C57BL/6 mouse	H. pylori inoculation (e.g., TN2GF4, 7.13, PMSS1)	Gerbils: Full Correa cascade to adenocarcinoma. Mice: Genetic tools available, suitable for immune studies	Gerbils: Limited genetic tools. Mice: Resistant to many H. pylori strains
Multifactorial carcinogenesis	Composite rat/mouse models	MNNG/MNU + H. pylori; MNNG/MNU + high-salt diet + ranitidine	Models human synergistic etiology; high clinical relevance	Complex setup, multiple variables to control
Genetic and molecular mechanisms	GEMMs (e.g., INS-GAS, p53KO), CRISPR-edited organoids	Genetic manipulation (e.g., KrasG12D, TP53-/-)	Definitive genotype-phenotype studies; precise temporal control	High cost, technical complexity
Drug screening and toxicity	Cell lines (GES-1, BGC823)	Acute or chronic MNNG/MNU treatment or H. pylori co-culture	High-throughput, low cost, reproducible	Simplified system, lacks in vivo physiology
Immune-microenvironment interactions	Immune-organoid co-culture	Co-culture with macrophages (RAW264.7) or PBMCs	Incorporates human immune components; personalized potential	Technically challenging; not fully vascularized

IM: Intestinal metaplasia; H. pylori: Helicobacter pylori; GES-1: Gastric epithelial cell-1; GEMM: Genetically engineered mouse models; INS-GAS: Insulin-gastrin; CDCA: Chenodeoxycholic acid; DCA: Deoxycholic acid; MNU: N-Nitroso-N-methylurea; MNNG: N-methyl-N’-nitro-N-nitrosoguanidine; TP53: Tumor protein 53; PBMCs: Peripheral blood mononuclear cells.