Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
PLoS One. 2013 Apr 30;8(4):e62493. doi: 10.1371/journal.pone.0062493. Print 2013.
The glycolytic response of hypoxic cells is primarily mediated by the hypoxia inducible factor alpha (HIF-1α) but even in the presence of abundant oxygen tumours typically show high rates of glycolysis. Higher levels of HIF-1α in tumours are associated with a poorer prognosis and up-regulation of markers of epithelial mesenchymal transition (EMT) due to HIF-1α actions. We have recently shown that EMT occurs within the CD44(high) cancer stem cell (CSC) fraction and that epithelial and EMT CSCs are distinguished by high and low ESA expression, respectively. We here show that hypoxia induces a marked shift of the CSC fraction towards EMT leading to altered cell morphology, an increased proportion of CD44(high)/ESA(low) cells, patterns of gene expression typical of EMT, and enhanced sphere-forming ability. The size of EMT fractions returned to control levels in normoxia indicating a reversible process. Surprisingly, however, even under normoxic conditions a fraction of EMT CSCs was present and maintained high levels of HIF-1α, apparently due to actions of cytokines such as TNFα. Functionally, this EMT CSC fraction showed decreased mitochondrial mass and membrane potential, consumed far less oxygen per cell, and produced markedly reduced levels of reactive oxygen species (ROS). These differences in the patterns of oxygen metabolism of sub-fractions of tumour cells provide an explanation for the general therapeutic resistance of CSCs and for the even greater resistance of EMT CSCs. They also identify potential mechanisms for manipulation of CSCs.
缺氧细胞的糖酵解反应主要由缺氧诱导因子 alpha (HIF-1α)介导，但即使在氧气充足的情况下，肿瘤通常也表现出高糖酵解率。肿瘤中 HIF-1α水平较高与预后较差相关，并由于 HIF-1α的作用而上调上皮间质转化 (EMT)的标志物。我们最近表明，EMT 发生在 CD44(high)癌症干细胞 (CSC) 亚群中，并且上皮和 EMT CSC 分别通过高和低 ESA 表达来区分。我们在这里表明，缺氧诱导 CSC 亚群向 EMT 发生明显转变，导致细胞形态改变、CD44(high)/ESA(low)细胞比例增加、典型的 EMT 基因表达模式以及增强的球体形成能力。在常氧条件下，EMT 亚群的大小恢复到对照水平，表明这是一个可逆过程。然而，令人惊讶的是，即使在常氧条件下，也存在一部分 EMT CSC 并维持高水平的 HIF-1α，显然是由于 TNFα 等细胞因子的作用。功能上，这个 EMT CSC 亚群显示出线粒体质量和膜电位减少，每个细胞消耗的氧气明显减少，产生的活性氧 (ROS)水平明显降低。肿瘤细胞亚群在氧气代谢模式上的这些差异为 CSC 的普遍治疗抵抗以及 EMT CSC 更大的抵抗提供了解释。它们还确定了操纵 CSC 的潜在机制。
