Intrinsic and evasive antiangiogenic drug (AAD) resistance is frequently developed in cancer patients, and molecular mechanisms underlying AAD resistance remain largely unknown. Here we describe AAD-triggered, lipid-dependent metabolic reprogramming as an alternative mechanism of AAD resistance. Unexpectedly, tumor angiogenesis in adipose and non-adipose environments is equally sensitive to AAD treatment. AAD-treated tumors in adipose environment show accelerated growth rates in the presence of a minimal number of microvessels. Mechanistically, AAD-induced tumor hypoxia initiates the fatty acid oxidation metabolic reprogramming and increases uptake of free fatty acid (FFA) that stimulates cancer cell proliferation. Inhibition of carnitine palmitoyl transferase 1A (CPT1) significantly compromises the FFA-induced cell proliferation. Genetic and pharmacological loss of CPT1 function sensitizes AAD therapeutic efficacy and enhances its anti-tumor effects. Together, we propose an effective cancer therapy concept by combining drugs that target angiogenesis and lipid metabolism.

中文翻译：

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癌症脂质代谢赋予抗血管生成药物抗性。

内源性和逃避性抗血管生成药物（AAD）耐药性在癌症患者中经常出现，而引起AAD耐药性的分子机制仍然未知。在这里，我们描述了AAD触发的脂质依赖性代谢重编程，作为AAD耐药性的替代机制。出乎意料的是，在脂肪和非脂肪环境中的肿瘤血管生成对AAD治疗同样敏感。在最小数量的微血管存在下，在脂肪环境中经AAD处理的肿瘤显示出加速的生长速度。从机理上讲，AAD诱导的肿瘤缺氧启动了脂肪酸氧化代谢的重新编程，并增加了刺激癌细胞增殖的游离脂肪酸（FFA）的吸收。肉碱棕榈酰转移酶1A（CPT1）的抑制作用大大削弱了FFA诱导的细胞增殖。CPT1功能的遗传和药理作用丧失可增强AAD的治疗功效，并增强其抗肿瘤作用。总之，我们通过结合靶向血管生成和脂质代谢的药物，提出了一种有效的癌症治疗概念。