VEGF-Targeted Therapy Stably Modulates the Glycolytic Phenotype of Tumor Cells
VEGF-Targeted Therapy Stably Modulates the Glycolytic Phenotype of Tumor Cells
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DOI：
10.1158/0008-5472.can-13-2037
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发表时间：
2015-01-01
期刊：
影响因子：
11.2
通讯作者：
Indraccolo, Stefano
中科院分区：
文献类型：
--
作者：
Curtarello, Matteo;Zulato, Elisabetta;Indraccolo, Stefano
抗vegf治疗扰乱肿瘤代谢，严重损害氧、葡萄糖和ATP水平。在这项研究中，我们研究了抗vegf治疗在不同糖酵解表型的多种实验性肿瘤模型中的作用，以深入了解这种治疗的代谢特征的最佳调节。在异种肿瘤移植模型中，长时间的治疗诱导血管消退和坏死，糖酵解性强的肿瘤比糖酵解性差的肿瘤更快地产生耐药性。通过PET显像，延长治疗可增加肿瘤缺氧区和增生性区域。在连续移植的小鼠中，高度糖酵解细胞的选择是稳定的，并且与肿瘤侵袭性增加和对VEGF阻断的抵抗有关。我们的研究结果支持一种假设，即在异种移植模型中研究的肿瘤细胞的高度糖酵解表型，无论是原发性还是继发性，都是一种细胞自主特性，赋予对VEGF阻断的抵抗力。肿瘤的代谢特征可以通过抗血管生成治疗来选择，这一发现表明人们对肿瘤代谢的进化动力学有了深入的了解。AACR (C) 2014。
Anti-VEGF therapy perturbs tumor metabolism, severely impairing oxygen, glucose, and ATP levels. In this study, we investigated the effects of anti-VEGF therapy in multiple experimental tumor models that differ in their glycolytic phenotypes to gain insights into optimal modulation of the metabolic features of this therapy. Prolonged treatments induced vascular regression and necrosis in tumor xenograft models, with highly glycolytic tumors becoming treatment resistant more rapidly than poorly glycolytic tumors. By PET imaging, prolonged treatments yielded an increase in both hypoxic and proliferative regions of tumors. A selection for highly glycolytic cells was noted and this metabolic shift was stable and associated with increased tumor aggressiveness and resistance to VEGF blockade in serially transplanted mice. Our results support the hypothesis that the highly glycolytic phenotype of tumor cells studied in xenograft models, either primary or secondary, is a cell-autonomous trait conferring resistance to VEGF blockade. The finding that metabolic traits of tumors can be selected by antiangiogenic therapy suggests insights into the evolutionary dynamics of tumor metabolism. (C)2014 AACR.