Intersections between innate immune response and gastric cancer development

Table 1 Expression of Toll-like receptors in esophageal and gastric epitheliums

PRR	Organ	Model	Method	Ligand	Observation	Reference
TLR1/2	Esophagus	Esophageal carcinoma and premalignant lesions	IHQ	Triacyl lipopeptide	Receptor upregulation in tumor and dysplasia	[22,171]
TLR2	Stomach; esophagus	Human ADC and premalignant lesions; H. pylori infection mice model andin vitro culture	IHQ; RT-qPCR	Microbial lipopeptide	Receptor upregulation in tumor cores. Increased tumorigenesis; constitutive expression in TE-1 cell line	[21,22,27,32,172-174]
TLR3	Stomach; esophagus	Human gastric and esophageal carcinoma	IHQ; RT-qPCR	dsRNA	Increased receptor levels correlate with poor prognosis; increased expression on EAC-derived cell lines	[25,174-176]
TLR4	Stomach; esophagus	Human ADC and premalignant lesions; H. pylori infection; esophageal carcinoma	IHQ; RT-qPCR	LPS	Upregulation in tumor cores; weak association with clinicopathologic variables; high expression correlates with poor prognosis; upregulation of IL-8 and COX-2 in BE	[21,24,25,27,32,171,173-179,182]
TLR5	Stomach; esophagus	Human ADC and premalignant lesions; H pylori infection	IHQ	Flagellin	Highly expressed; upregulation in tumor and older patients; association with necrosis and tumor growth in the stomach; overexpression in dysplastic lesions of BE; no association with EAC prognosis	[26,27,32,177]
TLR6	Esophagus	Esophageal carcinoma and human dysplasia	IHQ; IF	Diacyl lipopeptide	Upregulated in tumor tissue	[22,171]
TLR7	Stomach; esophagus	Human ADC and normal tissue	IHQ; WB; RT-qPCR	ssRNA	Downregulated in gastric tumors; high levels correlate with a better outcome in GC; constitutive expression in TE-1 cell line; association between expression and tumor grade in ESCC	[22,32,173,174,176,180,183]
TLR9	Stomach; esophagus	Human ADC	IHQ; RT-qPCR	ssDNA; dsDNA	Upregulated in early tumors; correlation with better prognosis in GC; association with histopathological grade in ESCC and dysplasia; high expression in EAC correlates with advanced tumor stage and metastasis	[24,25,32-34,173,175,176,181,184]
TLR10	Stomach	Human biopsy	RT-qPCR	ssDNA; dsDNA	Upregulated by H. pylori	[35]

ADC: Adenocarcinoma; BE: Barrett’s esophagus; EAC: Esophageal adenocarcinoma; ESCC: Esophageal squamous cell carcinoma; GC: Gastric cancer; H. pylori: Helicobacter pylori; IF: Immunofluorescence; IHQ: Immunohistochemistry; PRR: Pattern recognition receptor; RT-qPCR: Reverse transcription and quantitative PCR; TE-1: Human cell line derived from esophageal cancer; TLR: Toll-like receptors; WB: Western blot.

Table 2 Gastric cancer incidence and socioeconomic indicators per country

Country	Estimated cases	Crude rate	ASR, world1	Cum. risk	HDI classification
Japan	138470	109.5	31.6	9.35	Very high
Korea	28713	56	27.9	6.51	Very high
Brunei Darussalam	55	12.6	13.5	5.93	Very high
Russia	37364	25.6	13.5	3.29	Very high
Chile	4208	22	13.1	4.17	Very high
Lithuania	864	31.7	13	3.4	Very high
Estonia	379	28.6	12.3	3.2	Very high
Latvia	530	28.1	12	3.01	Very high
Portugal	2950	28.9	11	2.99	Very high
Slovakia	1210	22.2	10.7	3.12	Very high
Mongolia	860	26.2	32.5	7.71	High
China	478508	33.1	20.6	5.24	High
Iran	14656	17.4	17.5	6.58	High
Kazakhstan	3357	17.9	15.8	3.47	High
Belarus	2739	29	15.4	3.5	High
Peru	6300	19.1	15.2	5.16	High
Colombia	8214	16.1	12.8	3.61	High
Costa Rica	952	18.7	12.8	4.12	High
Samoa	20	10.1	12.8	3.75	High
Azerbaijan	1453	14.3	12.7	3.42	High
Tajikistan	1301	13.6	23.4	6.96	Medium
Kyrgyzstan	1027	15.7	19.7	5.01	Medium
Cabo Verde	82	14.7	18.4	5.88	Medium
Bhutan	118	15.3	17.7	3.88	Medium
Viet Nam	17906	18.4	15.5	3.57	Medium
Sao Tome and Principe	18	8.2	14.7	2.06	Medium
Myanmar	7235	13.3	13.7	3.58	Medium
Lao	675	9.3	12.9	3.17	Medium
Guatemala	1637	9.1	12.2	3.93	Medium
Turkmenistan	583	9.7	11.8	2.37	Medium
Haiti	1184	10.4	13.5	4.58	Low
Mali	1097	5.4	12.8	2.96	Low
Afghanistan	2149	5.5	12.4	3.18	Low
Zimbabwe	641	4.3	9.4	3.24	Low
Papua New Guinea	474	5.3	9.2	3.17	Low
Rwanda	587	4.5	8.1	1.61	Low
Yemen	966	3.2	7.1	2.68	Low
Senegal	597	3.6	7	1.66	Low
Benin	429	3.5	7	2.29	Low
Mauritania	143	3.1	5.6	1.46	Low

¹Top 10 countries with the highest age-standardized incidence rates per 100000 inhabitants, per each human development index classification. Source: Globocan 2020, access by https://gco.iarc.fr. ASR: Age-standardized incidence rate; HDI: Human development index.