胃癌化学预防: 阿司匹林、二甲双胍等经典药物的希望与挑战

Gastric cancer chemoprevention: hopes and challenges of aspirin, metformin, and other classic drugs

摘要

胃癌是全球范围内常见的恶性肿瘤之一, 每年有近一半的胃癌新发病例和死亡病例发生在中国。幽门螺杆菌(Hp)感染是胃癌的主要危险因素, 但根除Hp并不能完全预防胃癌的发生。近年来, 阿司匹林、环氧化酶2抑制剂、二甲双胍及他汀类药物与胃癌风险的关系受到广泛关注。系统梳理上述药物与胃癌风险的流行病学证据、潜在作用机制及临床转化前景, 并对未来研究方向提出展望。

Abstract

Gastric cancer is one of the most common malignant neoplasms worldwide, with nearly half of all new cases and deaths occurring in China annually. Helicobacter pylori (Hp) infection is a major risk factor for gastric cancer; however, Hp eradication does not completely prevent the occurrence of gastric cancer. In recent years, the relationship between aspirin, cyclooxygenase-2 inhibitors, metformin, and statins and the risk of gastric cancer has garnered substantial attention. The epidemiological evidence, potential mechanisms of action, and clinical translation prospects of these drugs in relation to gastric cancer risk are systematically reviewed, and future research directions are proposed.

关键词

胃肿瘤 / 化学预防 / 阿司匹林 / 环氧化酶2抑制剂 / 二甲双胍 / 羟甲基戊二酰辅酶A还原酶抑制剂 / 幽门螺杆菌 / 危险因素

Key words

stomach neoplasms / chemoprevention / aspirin / cyclooxygenase-2 inhibitors / metformin / hydroxymethylglutaryl-CoA reductase inhibitors / Helicobacter pylori / risk factors

参考文献

[1] BRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263. DOI: 10.3322/caac.21834.

[2] KATAI H, ISHIKAWA T, AKAZAWA K, et al. Five-year survival analysis of surgically resected gastric cancer cases in Japan: a retrospective analysis of more than 100,000 patients from the nationwide registry of the Japanese Gastric Cancer Association (2001-2007)[J]. Gastric Cancer, 2018, 21(1): 144-154. DOI: 10.1007/s10120-017-0716-7.

[3] FORD A C, YUAN Y H, PARK J Y, et al. Eradication therapy to prevent gastric cancer in Helicobacter pylori-positive individuals: systematic review and meta-analysis of randomized controlled trials and observational studies[J]. Gastroenterology, 2025, 169(2): 261-276. DOI: 10.1053/j.gastro.2024.12.033.

[4] XING X F, ZHAO R J, CUI Z X, et al. Changes of Helicobacter pylori infection status and risk of precancerous lesions: a prospective cohort study in Chinese population[J]. Helicobacter, 2026, 31(2): e70114. DOI: 10.1111/hel.70114.

[5] SIKAVI D R, WANG K, MA W J, et al. Aspirin use and incidence of colorectal cancer according to lifestyle risk[J]. JAMA Oncol, 2024, 10(10): 1354-1361. DOI: 10.1001/jamaoncol.2024.2503.

[6] CHEUNG K S, CHAN E W, WONG A Y S, et al. Aspirin and risk of gastric cancer after Helicobacter pylori eradication: a territory-wide study[J]. J Natl Cancer Inst, 2018, 110(7): 743-749. DOI: 10.1093/jnci/djx267.

[7] YE X H, FU J J, YANG Y, et al. Frequency-risk and duration-risk relationships between aspirin use and gastric cancer: a systematic review and meta-analysis[J]. PLoS One, 2013, 8(7): e71522. DOI: 10.1371/journal.pone.0071522.

[8] PASTORINO R, PIRES MARAFON D, SASSANO M, et al. Aspirin but not statins is inversely related to gastric cancer with a duration-risk effect: results from the Stomach Cancer Pooling Project Consortium[J]. Cancer, 2024, 130(24): 4276-4286. DOI: 10.1002/cncr.35510.

[9] ZHANG S, WANG H W, JI J J, et al. Dose-response relationship between aspirin and gastric cancer risk: a systematic review and meta-analysis[J]. Cancer Epidemiol, 2025, 97: 102873. DOI: 10.1016/j.canep.2025.102873.

[10] BAI X, DING S Q, ZHANG X P, et al. Exposure to commonly used drugs and the risk of gastric cancer: an umbrella review of meta-analyses[J]. Cancers, 2023, 15(2): 372. DOI: 10.3390/cancers15020372.

[11] ZHENG S L, RODDICK A J. Association of aspirin use for primary prevention with cardiovascular events and bleeding events: a systematic review and meta-analysis[J]. JAMA, 2019, 321(3): 277-287. DOI: 10.1001/jama.2018.20578.

[12] SUN M, YU J, WAN J, et al. Role of aspirin in cancer prevention[J]. Cancer Treat Res Commun, 2025, 43: 100884. DOI: 10.1016/j.ctarc.2025.100884.

[13] DAI X Y, YAN J, FU X H, et al. Aspirin inhibits cancer metastasis and angiogenesis via targeting heparanase[J]. Clin Cancer Res, 2017, 23(20): 6267-6278. DOI: 10.1158/1078-0432.CCR-17-0242.

[14] JOSEFSSON E C. Platelets and megakaryocytes in cancer[J]. J Thromb Haemost, 2025, 23(3): 804-816. DOI: 10.1016/j.jtha.2024.12.016.

[15] PATRONO C, BURN J, PATRIGNANI P, et al. Platelet activation, aspirin, and cancer: from basic science to clinical trials[J]. Pharmacol Rev, 2026, 78(1): 100109. DOI: 10.1016/j.pharmr.2025.100109.

[16] UNVER N. Aspirin's effect on macrophages beyond its chemopreventive role in inflammation and cancer[J]. Inflammopharmacology, 2025, 33(10): 5735-5743. DOI: 10.1007/s10787-025-01945-1.

[17] CHENG J, FAN X M. Role of cyclooxygenase-2 in gastric cancer development and progression[J]. World J Gastroenterol, 2013, 19(42): 7361-7368. DOI: 10.3748/wjg.v19.i42.7361.

[18] WELTERMANN T, SCHULZ C, MACKE L. Effect of frequently prescribed drugs on gastric cancer risk[J]. Best Pract Res Clin Gastroenterol, 2021, 50/51: 101741. DOI: 10.1016/j.bpg.2021.101741.

[19] WANG W H, WONG W M, DAILIDIENE D, et al. Aspirin inhibits the growth of Helicobacter pylori and enhances its susceptibility to antimicrobial agents[J]. Gut, 2003, 52(4): 490-495. DOI: 10.1136/gut.52.4.490.

[20] KWON S, MA W J, DREW D A, et al. Association between aspirin use and gastric adenocarcinoma: a prospective cohort study[J]. Cancer Prev Res (Phila), 2022, 15(4): 265-272. DOI: 10.1158/1940-6207.CAPR-21-0413.

[21] 刘霖. 胃癌前病变患者幽门螺杆菌感染与COX-2表达相关性分析[J]. 陕西医学杂志, 2010, 39(11): 1463-1465.

[22] 范力宏, 张军, 苏保山, 等. 环氧合酶2在食管癌、胃癌、贲门癌的表达比较[J]. 西安交通大学学报(医学版), 2005, 26(2): 145-148. DOI: 10.3969/j.issn.1671-8259.2005.02.014.

[23] KONG P F, WU R Y, LIU X C, et al. The effects of anti-inflammatory drug treatment in gastric cancer prevention: an update of a meta-analysis[J]. J Cancer, 2016, 7(15): 2247-2257. DOI: 10.7150/jca.16524.

[24] JIANG Y X, CHEN Y, SUN H H, et al. Effects of cyclooxygenase-2 inhibitors on gastrointestinal malignancies: a systematic review and meta-analysis[J]. Indian J Surg Oncol, 2022, 13(2): 348-355. DOI: 10.1007/s13193-022-01547-1.

[25] WONG B C Y, ZHANG L, MA J L, et al. Effects of selective COX-2 inhibitor and Helicobacter pylori eradication on precancerous gastric lesions[J]. Gut, 2012, 61(6): 812-818. DOI: 10.1136/gutjnl-2011-300154.

[26] HUNG K H, YANG H B, CHENG H C, et al. Short-term celecoxib to regress long-term persistent gastric intestinal metaplasia after Helicobacter pylori eradication[J]. J Gastroenterol Hepatol, 2010, 25(1): 48-53. DOI: 10.1111/j.1440-1746.2009.05974.x.

[27] SHEU B S, TSAI Y C, WU C T, et al. Long-term celecoxib can prevent the progression of persistent gastric intestinal metaplasia After H. pylori eradication[J]. Helicobacter, 2013, 18(2): 117-123. DOI: 10.1111/hel.12013.

[28] YANG H B, CHENG H C, SHEU B S, et al. Chronic celecoxib users more often show regression of gastric intestinal metaplasia after Helicobacter pylori eradication[J]. Aliment Pharmacol Ther, 2007, 25(4): 455-461. DOI: 10.1111/j.1365-2036.2006.03224.x.

[29] 朱晓静, 李嵩博, 刘洁, 等. 塞来昔布治疗胃黏膜肠化生患者的疗效分析[J]. 现代肿瘤医学, 2023, 31(19): 3615-3621. DOI: 10.3969/j.issn.1672-4992.2023.19.015.

[30] LIU K S, WONG I O, LEUNG W K. Helicobacter pylori associated gastric intestinal metaplasia: treatment and surveillance[J]. World J Gastroenterol, 2016, 22(3): 1311-1320. DOI: 10.3748/wjg.v22.i3.1311.

[31] WANG D Z, CABALAG C S, CLEMONS N J, et al. Cyclooxygenases and prostaglandins in tumor immunology and microenvironment of gastrointestinal cancer[J]. Gastroenterology, 2021, 161(6): 1813-1829. DOI: 10.1053/j.gastro.2021.09.059.

[32] KASSAB A E. Recent advances in targeting COX-2 for cancer therapy: a review[J]. RSC Med Chem, 2025, 16(7): 2974-3002.

[33] XU Y Q, WANG J, HE Z H, et al. A review on the effect of COX-2-mediated mechanisms on development and progression of gastric cancer induced by nicotine[J]. Biochem Pharmacol, 2024, 220: 115980. DOI: 10.1016/j.bcp.2023.115980.

[34] KUANG B Y, YANG K, ZHONG X T, et al. Celecoxib in oncology: targeting the COX-2/PGE₂ axis to reprogram the tumor immune microenvironment and enhance multimodal therapy[J]. Front Pharmacol, 2025, 16: 1691392. DOI: 10.3389/fphar.2025.1691392.

[35] WANG L, ZHANG Z. Diabetes mellitus and gastric cancer: correlation and potential mechanisms[J]. J Diabetes Res, 2023, 2023: 4388437. DOI: 10.1155/2023/4388437.

[36] SHUAI Y, LI C, ZHOU X. The effect of metformin on gastric cancer in patients with type 2 diabetes: a systematic review and meta-analysis[J]. Clin Transl Oncol, 2020, 22(9): 1580-1590. DOI: 10.1007/s12094-020-02304-y.

[37] CHEUNG K S, CHAN E W, WONG A Y S, et al. Metformin use and gastric cancer risk in diabetic patients after Helicobacter pylori eradication[J]. J Natl Cancer Inst, 2019, 111(5): 484-489. DOI: 10.1093/jnci/djy144.

[38] TSENG C H. Metformin reduces gastric cancer risk in patients with type 2 diabetes mellitus[J]. Aging, 2016, 8(8): 1636-1649. DOI: 10.18632/aging.101019.

[39] HUANG D C, ZHANG F J, HUANG T. Metformin treatment and reduction of gastrointestinal cancer risk: a 2-sample Mendelian randomization study[J]. Medicine, 2026, 105(4): e47322. DOI: 10.1097/MD.0000000000047322.

[40] LI S B, LI X Z, ZHU X J, et al. Therapeutic effect of metformin on reversing gastric intestinal metaplasia[J]. Chin Med J, 2025. Online ahead of print. DOI: 10.1097/CM9.0000000000003675.

[41] SUISSA S, AZOULAY L. Metformin and the risk of cancer: time-related biases in observational studies[J]. Diabetes Care, 2012, 35(12): 2665-2673. DOI: 10.2337/dc12-0788.

[42] WANG Y B, TAN L M, LUO L S, et al. Immortal time bias exaggerates the effect of metformin on the risk of gastric cancer: a meta-analysis[J]. Pharmacol Res, 2021, 165: 105425. DOI: 10.1016/j.phrs.2021.105425.

[43] VUJOVIC S, PEROVIC S, VLAOVIC M, et al. From metabolism to longevity: molecular mechanisms underlying metformin's anticancer and anti-aging effects[J]. Curr Issues Mol Biol, 2026, 48(3): 286. DOI: 10.3390/cimb48030286.

[44] HAN G, GONG H J, WANG Y D, et al. AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell[J]. Cancer Biol Ther, 2015, 16(1): 77-87. DOI: 10.4161/15384047.2014.987021.

[45] RYAN B M, O'DONOVAN N, DUFFY M J. Survivin: a new target for anti-cancer therapy[J]. Cancer Treat Rev, 2009, 35(7): 553-562. DOI: 10.1016/j.ctrv.2009.05.003.

[46] CHANG H R, NAM S, KOOK M C, et al. HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer[J]. Gut, 2016, 65(1): 19-32. DOI: 10.1136/gutjnl-2014-307918.

[47] JACOBO-TOVAR E, MEDEL-SÁNCHEZ A, DURÁN-CASTILLO C, et al. Insulin resistance in cancer risk and prognosis[J]. Semin Cancer Biol, 2025, 114: 73-87. DOI: 10.1016/j.semcancer.2025.06.006.

[48] KATO K, GONG J, IWAMA H, et al. The antidiabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo[J]. Mol Cancer Ther, 2012, 11(3): 549-560. DOI: 10.1158/1535-7163.MCT-11-0594.

[49] WANG K Q, CHEN Y Y, ZHANG M M, et al. Metformin suppresses gastric cancer progression by disrupting the STAT1-PRMT1 axis[J]. Biochem Pharmacol, 2024, 226: 116367. DOI: 10.1016/j.bcp.2024.116367.

[50] CHIURILLO M A. Role of the Wnt/β-catenin pathway in gastric cancer: an in-depth literature review[J]. World J Exp Med, 2015, 5(2): 84-102. DOI: 10.5493/wjem.v5.i2.84.

[51] VALAEE S, YAGHOOBI M M, SHAMSARA M. Metformin inhibits gastric cancer cells metastatic traits through suppression of epithelial-mesenchymal transition in a glucose-independent manner[J]. PLoS One, 2017, 12(3): e0174486. DOI: 10.1371/journal.pone.0174486.

[52] JUN K H, LEE J E, KIM S H, et al. Clinicopathological significance of N-cadherin and VEGF in advanced gastric cancer brain metastasis and the effects of metformin in preclinical models[J]. Oncol Rep, 2015, 34(4): 2047-2053. DOI: 10.3892/or.2015.4191.

[53] COURTOIS S, DURÁN R V, GIRAUD J, et al. Metformin targets gastric cancer stem cells[J]. Eur J Cancer, 2017, 84: 193-201. DOI: 10.1016/j.ejca.2017.07.020.

[54] MAHBOOB A, SHIN C, ALMUGHANNI S, et al. The gut nexus: unraveling microbiota-mediated links between type 2 diabetes and colorectal cancer[J]. Nutrients, 2025, 17(23): 3803. DOI: 10.3390/nu17233803.

[55] ABDELHAMID A, NASRALLAH D, AHMED E, et al. Beyond cardiovascular health: the pharmacotherapeutic potential of statins in oncology[J]. Semin Cancer Biol, 2025, 117: 1-22. DOI: 10.1016/j.semcancer.2025.10.003.

[56] LOU D D, FU R R, GU L H, et al. Association between statins' exposure with incidence and prognosis of gastric cancer: an updated meta-analysis[J]. Expert Rev Clin Pharmacol, 2022, 15(9): 1127-1138. DOI: 10.1080/17512433.2022.2112178.

[57] SU C H, ISLAM M M, JIA G H, et al. Statins and the risk of gastric cancer: a systematic review and meta-analysis[J]. J Clin Med, 2022, 11(23): 7180. DOI: 10.3390/jcm11237180.

[58] LI Y F, FENG Q Z, GAO W Q, et al. The difference between Asian and Western in the effect of LDL-C lowering therapy on coronary atherosclerotic plaque: a meta-analysis report[J]. BMC Cardiovasc Disord, 2015, 15: 6. DOI: 10.1186/1471-2261-15-6.

[59] SHAH R R, GAEDIGK A. Precision medicine: does ethnicity information complement genotype-based prescribing decisions?[J]. Ther Adv Drug Saf, 2018, 9(1): 45-62. DOI: 10.1177/2042098617743393.

[60] WOO H I, KIM S R, HUH W, et al. Association of genetic variations with pharmacokinetics and lipid-lowering response to atorvastatin in healthy Korean subjects[J]. Drug Des Devel Ther, 2017, 11: 1135-1146. DOI: 10.2147/DDDT.S131487.

[61] WANG J Z, CAO G, LIU Y, et al. Mendelian randomization study on simvastatin and gastric cancer: exploring the therapeutic potential of statins in oncology[J]. Transl Cancer Res, 2024, 13(9): 4671-4677. DOI: 10.21037/tcr-24-576.

[62] LEE J, LEE S H, HUR K Y, et al. Statins and the risk of gastric cancer in diabetes patients[J]. BMC Cancer, 2012, 12: 596. DOI: 10.1186/1471-2407-12-596.

[63] KWON T J, KIM T J, LEE H, et al. Statin use decreases the risk of metachronous gastric cancer in patients without Helicobacter pylori infection[J]. Cancers, 2021, 13(5): 1020. DOI: 10.3390/cancers13051020.

[64] KWON M J, KANG H S, KIM J H, et al. Association between statin use and gastric cancer: a nested case-control study using a national health screening cohort in Korea[J]. Pharmaceuticals (Basel), 2021, 14(12): 1283. DOI: 10.3390/ph14121283.

[65] MARCHEGGIANI F, CIRILLI I, ORLANDO P, et al. Modulation of Coenzyme Q10 content and oxidative status in human dermal fibroblasts using HMG-CoA reductase inhibitor over a broad range of concentrations. From mitohormesis to mitochondrial dysfunction and accelerated aging[J]. Aging, 2019, 11(9): 2565-2582. DOI: 10.18632/aging.101926.

[66] PEREIRA M, MATUSZEWSKA K, GLOGOVA A, et al. Mutant p53, the mevalonate pathway and the tumor microenvironment regulate tumor response to statin therapy[J]. Cancers, 2022, 14(14): 3500. DOI: 10.3390/cancers14143500.

[67] GÖBEL A, RAUNER M, HOFBAUER L C, et al. Cholesterol and beyond-the role of the mevalonate pathway in cancer biology[J]. Biochim Biophys Acta BBA Rev Cancer, 2020, 1873(2): 188351. DOI: 10.1016/j.bbcan.2020.188351.

[68] LIKUS W, SIEMIANOWICZ K, BIE K K, et al. Could drugs inhibiting the mevalonate pathway also target cancer stem cells?[J]. Drug Resist Updat, 2016, 25: 13-25. DOI: 10.1016/j.drup.2016.02.001.

[69] WONG W W, DIMITROULAKOS J, MINDEN M D, et al. HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis[J]. Leukemia, 2002, 16(4): 508-519. DOI: 10.1038/sj.leu.2402476.

[70] RAO S, PORTER D C, CHEN X, et al. Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase[J]. Proc Natl Acad Sci U S A, 1999, 96(14): 7797-7802. DOI: 10.1073/pnas.96.14.7797.

[71] KIM D, YOON M S, LEE J, et al. Effects of phospholipase D1-inhibitory peptide on the growth and metastasis of gastric cancer cells[J]. Mol Cells, 2024, 47(11): 100128. DOI: 10.1016/j.mocell.2024.100128.

[72] CHAN J E, SHANMUGHAM S, KUMAR S, et al. Chemoprevention of gastrointestinal cancers: an umbrella review of meta-analyses of randomized controlled trials and cohort studies[J]. Clin Transl Sci, 2025, 18(5): e70235. DOI: 10.1111/cts.70235.

[73] US PREVENTIVE SERVICES TASK FORCE, DAVIDSON K W, BARRY M J, et al. Aspirin use to prevent cardiovascular disease: US Preventive Services Task Force Recommendation Statement[J]. JAMA, 2022, 327(16): 1577-1584. DOI: 10.1001/jama.2022.4983.

[74] SOLOMON S D, MCMURRAY J J, PFEFFER M A, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention[J]. N Engl J Med, 2005, 352(11): 1071-1080. DOI: 10.1056/NEJMoa050405.

[75] NABRDALIK K, HENDEL M, IRLIK K, et al. Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: a systematic review and meta-analysis with meta-regression of observational studies[J]. BMC Endocr Disord, 2024, 24(1): 206. DOI: 10.1186/s12902-024-01727-w.

[76] ORLOFF J, MIN J Y, MUSHLIN A, et al. Safety and effectiveness of metformin in patients with reduced renal function: a systematic review[J]. Diabetes Obes Metab, 2021, 23(9): 2035-2047. DOI: 10.1111/dom.14440.

[77] CHOLESTEROL TREATMENT TRIALISTS' COLLABORATION. Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials[J]. Lancet, 2022, 400(10355): 832-845. DOI: 10.1016/S0140-6736(22)01545-8.

[78] ZENG W W, DENG H, LUO Y N, et al. Advances in statin adverse reactions and the potential mechanisms: a systematic review[J]. J Adv Res, 2025, 76: 781-797. DOI: 10.1016/j.jare.2024.12.020.

基金资助

国家科技重大专项(2025ZD0545301)

陕西省卫生健康科研创新能力提升计划团队支持项目(2024TD-06)