METHODS: Tumor-grafting experiments and in vitro angiogenesis assays were conducted to detect the effect of fructose and the conditioned medium of fructose-cultured tumor cells on biological function of vascular endothelial cells (VECs) and angiogenesis. 448 colorectal cancer specimens were utilized to analyze the relationship between Glut5 expression levels in VECs and tumor cells and microvascular density (MVD).
RESULTS: We found that fructose can be metabolized by VECs and activate the Akt and Src signaling pathways, thereby enhancing the proliferation, migration, and tube-forming abilities of VECs and thereby promoting angiogenesis. Moreover, fructose can also improve the expression of vascular endothelial growth factor (VEGF) by upregulating the production of reactive oxygen species (ROS) in colorectal cancer cells, thus indirectly enhancing the biological function of VECs. Furthermore, this pro-angiogenic effect of fructose metabolism has also been well validated in clinical colorectal cancer tissues and mouse models. Fructose contributes to angiogenesis in mouse subcutaneous tumor grafts, and MVD is positively correlated with Glut5 expression levels of both endothelial cells and tumor cells of human colorectal cancer specimens.
CONCLUSIONS: These findings establish the direct role and mechanism by which fructose promotes tumor progression through increased angiogenesis, and provide reliable evidence for a better understanding of tumor metabolic reprogramming.
方法:进行了肿瘤移植实验和体外血管生成实验,以检测果糖和果糖培养的肿瘤细胞条件培养基对血管内皮细胞(VECs)生物学功能和血管生成的影响。利用448例大肠癌标本分析VECs中Glut5表达水平与肿瘤细胞及微血管密度(MVD)的关系。
结果:我们发现果糖可以被VECs代谢并激活Akt和Src信号通路,从而促进扩散,迁移,和VEC的成管能力,从而促进血管生成。此外,果糖还可以通过上调结直肠癌细胞活性氧(ROS)的产生来提高血管内皮生长因子(VEGF)的表达,从而间接增强VECs的生物学功能。此外,果糖代谢的这种促血管生成作用也在临床结直肠癌组织和小鼠模型中得到了很好的验证.果糖有助于小鼠皮下肿瘤移植物中的血管生成,和MVD与人大肠癌标本的内皮细胞和肿瘤细胞的Glut5表达水平呈正相关。
结论:这些发现确立了果糖通过增加血管生成促进肿瘤进展的直接作用和机制。并为更好地理解肿瘤代谢重编程提供可靠的证据。