期刊
CANCER RESEARCH
卷 75, 期 1, 页码 120-133出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-2037
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类别
资金
- AIRC [14295, 14032]
- Progetto d'Ateneo
- PRIN [2009P5JPT4_003, 2010MCLPLB_003]
- Deutsche Forschungsgemeinschaft DFG [Mu 576/15-1, SA 1749/3-1]
- Mainzer Forschungsfoerderungsprogramm MAIFOR [8277000]
- Italian Minister of University: Progetto Premiale Medicina Personalizzata and Sysbionet, (Italian Research Infrastructures of the Italian ESFRI roadmap)
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.
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