Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm 171 77, Sweden; Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China.
Cell Metab. 2018 Jul 3;28(1):104-117.e5. doi: 10.1016/j.cmet.2018.05.005. Epub 2018 May 31.
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.
内在和逃避性抗血管生成药物 (AAD) 耐药性在癌症患者中经常发生，而 AAD 耐药性的分子机制在很大程度上尚不清楚。在这里，我们描述了 AAD 触发的、依赖脂质的代谢重编程作为 AAD 耐药性的另一种机制。出乎意料的是，脂肪和非脂肪环境中的肿瘤血管生成对 AAD 治疗同样敏感。在微血管数量最少的情况下，在脂肪环境中接受 AAD 治疗的肿瘤表现出更快的生长速度。在机制上，AAD 诱导的肿瘤缺氧引发脂肪酸氧化代谢重编程，并增加游离脂肪酸 (FFA) 的摄取，从而刺激癌细胞增殖。抑制肉碱棕榈酰转移酶 1A (CPT1) 可显著削弱 FFA 诱导的细胞增殖。CPT1 功能的遗传和药理学丧失使 AAD 治疗效果敏感，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。
