BACKGROUND Epidemiologic studies suggest that diabetes is associated with an increased risk of cancer. Concurrently, clinical trials have shown that metformin, which is a first-line antidiabetic drug, displays anticancer activity. The underlying mechanisms for these effects are, however, still not well recognized. METHODS Methods based on atomic force microscopy (AFM) were used to directly evaluate the influence of metformin on the nanomechanical and adhesive properties of endothelial and cancer cells in chronic hyperglycemia. AFM single-cell force spectroscopy (SCFS) was used to measure the total adhesion force and the work of detachment between EA.hy926 endothelial cells and A549 lung carcinoma cells. Nanoindentation with a spherical AFM probe provided information about the nanomechanical properties of cells, particularly the length and grafting density of the glycocalyx layer. Fluorescence imaging was used for glycocalyx visualization and monitoring of E-selectin and ICAM-1 expression. RESULTS SCFS demonstrated that metformin attenuates adhesive interactions between EA.hy926 endothelial cells and A549 lung carcinoma cells in chronic hyperglycemia. Nanoindentation experiments, confirmed by confocal microscopy imaging, revealed metformin-induced recovery of endothelial glycocalyx length and density. The recovery of endothelial glycocalyx was correlated with a decrease in the surface expression of E-selectin and ICAM-1. CONCLUSION Our results identify metformin-induced endothelial glycocalyx restoration as a key factor responsible for the attenuation of adhesion between EA.hy926 endothelial cells and A549 lung carcinoma cells. GENERAL SIGNIFICANCE Metformin-induced glycocalyx restoration and the resulting attenuation of adhesive interactions between the endothelium and cancer cells may account for the antimetastatic properties of this drug.

中文翻译：

---

二甲双胍可通过恢复内皮糖萼屏障来减轻慢性高血糖中癌症与内皮细胞之间的粘附。

背景技术流行病学研究表明，糖尿病与罹患癌症的风险增加有关。同时，临床试验表明二甲双胍是一线抗糖尿病药，具有抗癌活性。但是，仍然没有很好地认识到这些影响的潜在机制。方法采用原子力显微镜（AFM）方法直接评估二甲双胍对慢性高血糖患者内皮细胞和癌细胞的纳米力学和粘附特性的影响。原子力显微镜单细胞力光谱法（SCFS）用于测量总粘附力和EA.hy926内皮细胞与A549肺癌细胞之间的分离作用。使用球形AFM探针进行纳米压痕可提供有关细胞纳米机械特性的信息，特别是糖萼层的长度和接枝密度。荧光成像用于糖萼可视化和监测E-选择蛋白和ICAM-1表达。结果SCFS证实二甲双胍可减轻EA.hy926内皮细胞与A549肺癌细胞在慢性高血糖症中的粘附相互作用。通过共聚焦显微镜成像证实的纳米压痕实验揭示了二甲双胍诱导的内皮糖萼长度和密度的恢复。内皮糖萼的恢复与E-选择蛋白和ICAM-1的表面表达下降有关。结论我们的研究结果表明，二甲双胍诱导的内皮糖萼修复是导致EA.hy926内皮细胞与A549肺癌细胞之间粘附减弱的关键因素。