Metformin and Gastric Carcinogenesis: Stage-Specific Effects?

Metformin has been investigated for its potential anticancer effects across various malignancies; however, the findings have been inconsistent across both cancer types and study designs. [1][2]2][3][4][5] Observational studies have yielded inconsistent findings regarding the association between metformin use and gastric cancer risk.A nationwide cohort study reported that long-term metformin use, particularly among patients not receiving insulin therapy, was associated with a reduced risk of gastric cancer, 6 whereas a Swedish population-based cohort study found no significant association between metformin use and gastric adenocarcinoma risk. 7Experimental studies have demonstrated that metformin inhibits gastric cancer cell proliferation and induces apoptosis through AMPK/mTORmediated pathways, 8,9 and may also suppress epithelial-mesenchymal transition, thereby attenuating metastatic potential. 10In addition, metformin has been shown to inhibit the growth of Helicobacter pylori, suggesting a potential role in modulating gastric carcinogenesis. 11ee et al. 12 examined the association between metformin and insulin use, alone or in combination, and different stages of gastric carcinogenesis.Gastric cancer was less frequent in metformin-treated patients who were not receiving insulin, whereas a higher prevalence of gastric cancer was observed in insulin-treated patients regardless of metformin use.In contrast, the prevalence of dysplasia did not differ according to treatment groups.These findings do not allow a definitive conclusion regarding a chemoprotective effect of metformin.The higher prevalence of gastric cancer in insulin-treated patients, including those receiving metformin, may reflect the effects of insulin itself, prolonged exposure to chronic hyperglycemia, 13 or the underlying metabolic milieu associated with insulin resistance and metabolic syndrome, rather than the absence of a protective effect of metformin alone.The lack of association between antidiabetic treatment and dysplasia is also notable.This pattern raises the possibility that metformin may act at a later stage of gastric carcinogenesis, rather than during earlier precancerous stages.However, mechanistic evidence supporting such stage-specific effects remains limited.Molecular studies have suggested distinct stage-related pathways in intestinal-type gastric carcinogenesis, with APC mutations predominating in low-grade intraepithelial neoplasia and TP53 alterations more commonly observed in high-grade dysplasia and minute gastric cancer. 14Whether metformin differentially influences these pathways remains unclear.One possible explanation is that adenocarcinoma cells may be more sensitive to the