Metabolic plasticity in CLL: adaptation to the hypoxic niche
Metabolic plasticity in CLL: adaptation to the hypoxic niche
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DOI：
10.1038/leu.2015.187
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发表时间：
2016-01-01
期刊：
影响因子：
11.4
通讯作者：
Guenther, U. L.
中科院分区：
文献类型：
--
作者：
Koczula, K. M.;Ludwig, C.;Guenther, U. L.
癌症中的代谢转化越来越被人们所了解。然而，人们对癌细胞的代谢反应知之甚少，这些反应使它们能够在不同的微环境中生存。我们已经使用了一种基于核磁共振的方法来监测在生活的原发性慢性淋巴细胞白血病（CLL）细胞的代谢，并询问他们的实时代谢反应缺氧。我们的研究表明CLL细胞具有相当大的代谢可塑性。尽管处于含氧血液中，但循环CLL细胞被引发缺氧，如通过组成性低水平缺氧诱导因子（HIF-1 α）活性和来自糖酵解的适度乳酸产生所测量的。进入缺氧后，我们观察到代谢率的快速上调。已经适应缺氧的CLL细胞在再充氧时返回到“启动”状态，并且在二次暴露于缺氧时再次显示出相同的适应性反应。我们还观察到在氧合和缺氧条件下不依赖HIF-1 α的丙酮酸盐的差异利用。当充氧时，CLL细胞释放丙酮酸，但在缺氧中进口丙酮酸以防止缺氧相关的氧化应激。最后，我们确定了与Binet A0期样本相关的静息葡萄糖和谷氨酰胺消耗较慢，丙氨酸和乳酸产生较低，表明CLL可分为反映疾病阶段的较高和较低代谢状态的肿瘤。
Metabolic transformation in cancer is increasingly well understood. However, little is known about the metabolic responses of cancer cells that permit their survival in different microenvironments. We have used a nuclear magnetic resonance based approach to monitor metabolism in living primary chronic lymphoid leukemia (CLL) cells and to interrogate their real-time metabolic responses to hypoxia. Our studies demonstrate considerable metabolic plasticity in CLL cells. Despite being in oxygenated blood, circulating CLL cells are primed for hypoxia as measured by constitutively low level hypoxia-inducible factor (HIF-1 alpha) activity and modest lactate production from glycolysis. Upon entry to hypoxia we observed rapid upregulation of metabolic rates. CLL cells that had adapted to hypoxia returned to the 'primed' state when re-oxygenated and again showed the same adaptive response upon secondary exposure to hypoxia. We also observed HIF-1 alpha independent differential utilization of pyruvate in oxygenated and hypoxic conditions. When oxygenated, CLL cells released pyruvate, but in hypoxia imported pyruvate to protect against hypoxia-associated oxidative stress. Finally, we identified a marked association of slower resting glucose and glutamine consumption, and lower alanine and lactate production with Binet A0 stage samples indicating that CLL may be divided into tumors with higher and lower metabolic states that reflect disease stage.