Contributions of cell metabolism and H+ diffusion to the acidic pH of tumors
Contributions of cell metabolism and H+ diffusion to the acidic pH of tumors
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DOI：
10.1016/s1476-5586(03)80005-2
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发表时间：
2003-03-01
期刊：
影响因子：
4.8
通讯作者：
Gillies, RJ
中科院分区：
文献类型：
--
作者：
Schornack, PA;Gillies, RJ
肿瘤微环境是缺氧和酸性的。这些疾病对肿瘤进展和对治疗的反应有显著影响。有强有力的证据表明，肿瘤缺氧是由于混乱的血管系统造成的灌注不足。因此，一些肿瘤区域氧合良好，而另一些则缺氧。通常认为，缺氧区域是酸性的，这是由于通过缺氧刺激糖酵解，但这还没有得到证实。目前的研究调查肿瘤酸性的原因，通过确定酸的生产率和H+当量通过模型系统的扩散机制。研究了具有不同代谢特征的两种乳腺癌细胞系：非转移性MCF-7/s和高转移性MDA-mb-435细胞。糖酵解和酸的产生在MCF-7/s细胞中被氧抑制，但在MDA-mb-435细胞中不被抑制。MDA-mb-435细胞的肿瘤比MCF-7/s细胞的肿瘤明显更酸性，这表明肿瘤酸性主要是由内源性代谢引起的，而不是缺氧。代谢产生的质子与移动的缓冲液一起扩散，与先前的研究一致。使用反应-扩散模型分析代谢和扩散数据，以证明随后的pH曲线与这两种细胞系肿瘤的测量pH值完全一致。
The tumor microenvironment is hypoxic and acidic. These conditions have a significant impact on tumor progression and response to therapies. There is strong evidence that tumor hypoxia results from inefficient perfusion due to a chaotic vasculature. Consequently, some tumor regions are well oxygenated and others are hypoxic. It is commonly believed that hypoxic regions are acidic due to a stimulation of glycolysis through hypoxia, yet this is not yet demonstrated. The current study investigates the causes of tumor acidity by determining acid production rates and the mechanism of diffusion for H+ equivalents through model systems. Two breast cancer cell lines were investigated with divergent metabolic profiles: nonmetastatic MCF-7/s and highly metastatic MDA-mb-435 cells. Glycolysis and acid production are inhibited by oxygen in MCF-7/s cells, but not in MDA-mb-435 cells. Tumors of MDA-mb-435 cells are significantly more acidic than are tumors of MCF-7/s cells, suggesting that tumor acidity is primarily caused by endogenous metabolism, and not the lack of oxygen. Metabolically produced protons are shown to diffuse in association with mobile buffers, in concordance with previous studies. The metabolic and diffusion data were analyzed using a reaction-diffusion model to demonstrate that the consequent pH profiles conform well to measured pH values for tumors of these two cell lines.