Public Laboratory, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
Laboratory Animal Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
J Exp Clin Cancer Res. 2023 Jul 28;42(1):184. doi: 10.1186/s13046-023-02765-3.
Fructose is a very common sugar found in natural foods, while current studies demonstrate that high fructose intake is significantly associated with increased risk of multiple cancers and more aggressive tumor behavior, but the relevant mechanisms are not fully understood.
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).
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.
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.
果糖是天然食物中一种非常常见的糖，而目前的研究表明，高果糖摄入与多种癌症风险增加和肿瘤侵袭性增强显著相关，但相关机制尚未完全阐明。
通过肿瘤移植实验和体外血管生成实验，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（VEC）和血管生成的生物学功能的影响。利用 448 例结直肠癌标本分析 VEC 和肿瘤细胞中 Glut5 表达水平与微血管密度（MVD）之间的关系。
我们发现，果糖可被 VEC 代谢，并激活 Akt 和 Src 信号通路，从而增强 VEC 的增殖、迁移和管状形成能力，进而促进血管生成。此外，果糖还可以通过上调结直肠癌细胞中活性氧（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 VEC 的生物学功能。此外，果糖代谢的这种促血管生成作用在临床结直肠癌组织和小鼠模型中也得到了很好的验证。果糖有助于小鼠皮下肿瘤移植中的血管生成，MVD 与结直肠癌标本中内皮细胞和肿瘤细胞的 Glut5 表达水平呈正相关。
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了可靠的证据。
