Department of Oncology and Surgical Sciences, Oncology Section, University of Padova, Padova, Italy.
Cancer Res. 2011 Jun 15;71(12):4214-25. doi: 10.1158/0008-5472.CAN-11-0242. Epub 2011 May 5.
VEGF antagonists are now widely used cancer therapeutics, but predictive biomarkers of response or toxicity remain unavailable. In this study, we analyzed the effects of anti-VEGF therapy on tumor metabolism and therapeutic response by using an integrated set of imaging techniques, including bioluminescence metabolic imaging, 18-fluorodeoxyglucose positron emission tomography, and MRI imaging and spectroscopy. Our results revealed that anti-VEGF therapy caused a dramatic depletion of glucose and an exhaustion of ATP levels in tumors, although glucose uptake was maintained. These metabolic changes selectively accompanied the presence of large necrotic areas and partial tumor regression in highly glycolytic tumors. In addition, we found that the central metabolic protein kinase AMP-activated protein kinase (AMPK)-a cellular sensor of ATP levels that supports cell viability in response to energy stress-was activated by anti-VEGF therapy in experimental tumors. AMPK-α2 attenuation increased glucose consumption, tumor cell sensitivity to glucose starvation, and tumor necrosis following anti-VEGF therapy. Taken together, our findings reveal functional links between the Warburg effect and the AMPK pathway with therapeutic responses to VEGF neutralization in tumor xenograft models.
VEGF 拮抗剂现已广泛用于癌症治疗，但仍缺乏预测反应或毒性的生物标志物。在这项研究中，我们使用了一组集成的成像技术，包括生物发光代谢成像、18-氟脱氧葡萄糖正电子发射断层扫描和 MRI 成像和光谱分析，来分析抗 VEGF 治疗对肿瘤代谢和治疗反应的影响。我们的结果表明，抗 VEGF 治疗导致肿瘤中葡萄糖的急剧消耗和 ATP 水平的枯竭，尽管葡萄糖摄取得以维持。这些代谢变化选择性地伴随着高糖酵解肿瘤中存在的大坏死区和部分肿瘤消退。此外，我们发现中央代谢蛋白激酶 AMP 激活的蛋白激酶（AMPK）——一种在应对能量应激时支持细胞存活的细胞内 ATP 水平传感器——在实验性肿瘤中被抗 VEGF 治疗激活。AMPK-α2 衰减增加了葡萄糖消耗、肿瘤细胞对葡萄糖饥饿的敏感性以及抗 VEGF 治疗后的肿瘤坏死。总之，我们的研究结果揭示了肿瘤异种移植模型中沃伯格效应和 AMPK 通路与 VEGF 中和治疗反应之间的功能联系。
