Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism
Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism
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DOI：
10.4161/cc.11.2.19006
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发表时间：
2012-01-15
期刊：
影响因子：
4.3
通讯作者：
Lisanti, Michael P.
中科院分区：
文献类型：
--
作者：
Ertel, Adam;Tsirigos, Aristotelis;Lisanti, Michael P.
衰老导致线粒体氧化功能的大量系统性降低，使整个身体的代谢转向有氧糖酵解，也就是瓦尔堡效应。衰老也是人类癌症（包括乳腺癌）发展的最重要风险因素之一。这两个发现是如何联系起来的？一个简单的想法是，癌细胞通过增加其氧化线粒体代谢（OXPHOS）的能力来反抗衰老过程。然后，衰老宿主中的局部和全身有氧糖酵解将提供富含能量的线粒体燃料（如L-乳酸盐和酮），以直接“燃料”肿瘤细胞生长和转移。这将建立一种寄生虫-宿主关系或“二室肿瘤代谢”，具有糖酵解/氧化代谢偶联。癌细胞（“种子”）将在这种营养丰富的微环境（“土壤”）中蓬勃发展，这种微环境已被宿主老化所滋养。在这种情况下，癌细胞只是试图通过放大线粒体代谢来设计代谢叛乱，从而使自己免受衰老的影响。我们讨论罗恩DePinho博士（MD安德森）和克雷格斯普森博士（斯隆-凯特琳）的最新发现，这些发现也与这一新假设相一致，将癌症进展与代谢衰老联系起来。利用数据挖掘和生物信息学方法，我们还提供了PGC 1a/NRF 1信号传导在（1）两室肿瘤代谢和（2）人类乳腺癌细胞线粒体生物发生发病机制中作用的关键证据。
Aging drives large systemic reductions in oxidative mitochondrial function, shifting the entire body metabolically toward aerobic glycolysis, a.k.a, the Warburg effect. Aging is also one of the most significant risk factors for the development of human cancers, including breast tumors. How are these two findings connected? One simplistic idea is that cancer cells rebel against the aging process by increasing their capacity for oxidative mitochondrial metabolism (OXPHOS). Then, local and systemic aerobic glycolysis in the aging host would provide energy-rich mitochondrial fuels (such as L-lactate and ketones) to directly "fuel" tumor cell growth and metastasis. This would establish a type of parasite-host relationship or "two-compartment tumor metabolism," with glycolytic/oxidative metabolic-coupling. The cancer cells ("the seeds") would flourish in this nutrient-rich microenvironment ("the soil"), which has been fertilized by host aging. In this scenario, cancer cells are only trying to save themselves from the consequences of aging, by engineering a metabolic mutiny, through the amplification of mitochondrial metabolism. We discuss the recent findings of Drs. Ron DePinho (MD Anderson) and Craig Thomspson (Sloan-Kettering) that are also consistent with this new hypothesis, linking cancer progression with metabolic aging. Using data mining and bioinformatics approaches, we also provide key evidence of a role for PGC1a/NRF1 signaling in the pathogenesis of (1) two-compartment tumor metabolism and (2) mitochondrial biogenesis in human breast cancer cells.