Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells
Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells
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DOI：
10.1172/jci.insight.87489
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发表时间：
2017-02-23
期刊：
影响因子：
8
通讯作者：
Muller, Catherine
中科院分区：
文献类型：
--
作者：
Wang, Yuan Yuan;Attane, Camille;Muller, Catherine
在乳腺癌中，瘤周脂肪细胞的一个关键特征是在体外和人类肿瘤中观察到的脂肪含量的丢失。脂肪细胞在肿瘤分泌物诱导脂肪分解后释放的游离脂肪酸(FFAs)以甘油三酯的形式转移并储存在肿瘤细胞中。在肿瘤细胞系中，我们证明了随着时间的推移，游离脂肪酸可以通过脂肪甘油三酯脂肪酶依赖(ATGL依赖)的脂解途径从脂滴中释放出来。在体内，ATGL在人类肿瘤中表达，其表达与肿瘤的侵袭性相关，并通过与脂肪细胞接触而上调。然后，释放的脂肪酸被用于脂肪酸贝塔氧化(FAO)，这是癌症中的一个活跃过程，但不是正常乳腺上皮细胞，并通过与脂肪细胞共培养进行调节。然而，在共培养的细胞中，FAO与ATP的产生是解偶联的，导致AMPK/乙酰辅酶A羧化酶的激活，这一循环维持了这种代谢重塑的状态。通过抑制ATGL依赖的脂解/FAO偶联通路，共培养诱导的肿瘤细胞侵袭能力的增加被完全消除。这些结果表明，肿瘤周围的脂肪细胞和癌细胞之间存在复杂的代谢共生关系，刺激了它们的侵袭性，突显出ATGL是阻止乳腺癌进展的潜在治疗靶点。
In breast cancer, a key feature of peritumoral adipocytes is their loss of lipid content observed both in vitro and in human tumors. The free fatty acids (FFAs), released by adipocytes after lipolysis induced by tumor secretions, are transferred and stored in tumor cells as triglycerides in lipid droplets. In tumor cell lines, we demonstrate that FFAs can be released over time from lipid droplets through an adipose triglyceride lipase-dependent (ATGL-dependent) lipolytic pathway. In vivo, ATGL is expressed in human tumors where its expression correlates with tumor aggressiveness and is upregulated by contact with adipocytes. The released FFAs are then used for fatty acid beta-oxidation (FAO), an active process in cancer but not normal breast epithelial cells, and regulated by coculture with adipocytes. However, in cocultivated cells, FAO is uncoupled from ATP production, leading to AMPK/acetyl-CoA carboxylase activation, a circle that maintains this state of metabolic remodeling. The increased invasive capacities of tumor cells induced by coculture are completely abrogated by inhibition of the coupled ATGL-dependent lipolysis/FAO pathways. These results show a complex metabolic symbiosis between tumor-surrounding adipocytes and cancer cells that stimulate their invasiveness, highlighting ATGL as a potential therapeutic target to impede breast cancer progression.