文章：

pH动力学紊乱和Na+/H+交换剂在转移中的作用

The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis

原文发布日期：2005-09-20

DOI: 10.1038/nrc1713

类型: Review Article

开放获取: 否

要点：

1. The gradient from the extracellular pH (pHe) to the intracellular pH (pHi) is reversed in tumours. That is, tumours become more acidic extracellularly and more alkaline intracellularly.
2. This reversed pH gradient arises early in transformation and is driven primarily by oncogene-dependent stimulation of the Na⁺/H⁺ exchanger NHE1, which results in cellular alkalinization and subsequent aerobic glycolysis and H⁺/lactate symport.
3. Cellular alkalinization induces cell proliferation that is independent of serum and substrate anchorage, which results in dense disorganized cell masses that are poorly vascularized.
4. Poor vascularization, together with the increased proton-extrusion ability of the tumour cell, produces the tumour-specific metabolic microenvironment. Owing to positive-feedback interactions between the tumour cell and this microenvironment, an ever higher reversed pH gradient is achieved as the disease progresses.
5. Both the acidic pHe and the constitutive activity of NHE1 have roles in driving protease-mediated digestion and remodelling of the extracellular matrix. They also stimulate the invasive phenotypes of the cell — actin remodelling for increased motility and the formation of invasive structures such as leading-edge pseudopodia and invadopodia.
6. Little is known about the signal-transduction systems that regulate NHE1 activity and that are associated with invasion.
7. The formation of a tumour-microenvironment model of invasion and metastasis that integrates the interaction of cell structure with the biochemistry, physiology and regulation of NHE1 will lead to a better understanding of the dynamics of the invasive response of the tumour cell to the microenvironment.

要点翻译：

1. 肿瘤中细胞外pH值（pHe）到细胞内pH值（pHi）的梯度发生逆转。即肿瘤细胞外环境变得更酸，而细胞内环境变得更碱。
2. 这种反向pH梯度在转化早期即出现，主要由癌基因依赖性刺激Na+/H+交换体NHE1驱动，导致细胞碱化，继而引发有氧糖酵解和H+/乳酸同向转运。
3. 细胞碱化诱导不依赖于血清和基质锚定的细胞增殖，从而形成血管化程度低的致密无序细胞团块。
4. 血管化不良与肿瘤细胞增强的质子外排能力共同形成了肿瘤特异性代谢微环境。由于肿瘤细胞与该微环境之间的正反馈相互作用，随着疾病进展，反向pH梯度会持续升高。
5. 酸性pHe和NHE1的组成性活性共同驱动蛋白酶介导的细胞外基质消化和重塑，并刺激细胞的侵袭表型——肌动蛋白重塑以增强运动性，以及形成前沿伪足和侵袭伪足等侵袭结构。
6. 目前对调控NHE1活性并与侵袭相关的信号转导系统知之甚少。
7. 构建一个整合细胞结构与NHE1生化特性、生理功能及调控的肿瘤微环境侵袭和转移模型，将有助于更好地理解肿瘤细胞对微环境侵袭反应的动态过程。

英文摘要：

Recent research has highlighted the fundamental role of the tumour's extracellular metabolic microenvironment in malignant invasion. This microenvironment is acidified primarily by the tumour-cell Na+/H+ exchanger NHE1 and the H+/lactate cotransporter, which are activated in cancer cells. NHE1 also regulates formation of invadopodia — cell structures that mediate tumour cell migration and invasion. How do these alterations of the metabolic microenvironment and cell invasiveness contribute to tumour formation and progression?

摘要翻译： 

最新研究强调了肿瘤胞外代谢微环境在恶性侵袭中的基础性作用。该微环境的酸化主要由肿瘤细胞中的Na+/H+交换体NHE1和H+/乳酸共转运体介导，二者在癌细胞中被激活。NHE1还调控侵袭伪足的形成——这是一种介导肿瘤细胞迁移与侵袭的细胞结构。这些代谢微环境的改变与细胞侵袭性如何共同促进肿瘤的发生与进展？

原文链接：

The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis