Asgharzadeh Mohammad Reza, Barar Jaleh, Pourseif Mohammad M, Eskandani Morteza, Jafari Niya Mojtaba, Mashayekhi Mohammad Reza, Omidi Yadollah
Department of Biology, Fars Science and Research Branch, Islamic Azad University, Marvdasht, Iran.
Department of Biology, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran.
Bioimpacts. 2017;7(2):115-133. doi: 10.15171/bi.2017.15. Epub 2017 Jun 7.
Cancer is an intricate disorder/dysfunction of cells that can be defined as a genetic heterogeneity in human disease. Therefore, it is characterized by several adaptive complex hallmarks. Among them, the pH dysregulation appears as a symbol of aberrant functions within the tumor microenvironment (TME). In comparison with normal tissues, in the solid tumors, we face with an irregular acidification and alkalinization of the extracellular and intracellular fluids. In this study, we comprehensively discussed the most recent reports on the hallmarks of solid tumors to provide deep insights upon the molecular machineries involved in the pH dysregulation of solid tumors and their impacts on the initiation and progression of cancer. The dysregulation of pH in solid tumors is fundamentally related to the Warburg effect and hypoxia, leading to expression of a number of molecular machineries, including: NHE1, H+ pump V-ATPase, CA-9, CA-12, MCT-1, GLUT-1. Activation of proton exchangers and transporters (PETs) gives rise to formation of TME. This condition favors the cancer cells to evade from the anoikis and apoptosis, granting them aggressive and metastasis phenotype, as well as resistance to chemotherapy and radiation therapy. This review aimed to discuss the key molecular changes of tumor cells in terms of bio-energetics and cancer metabolism in relation with pH dysregulation. During this phenomenon, the intra- and extracellular metabolites are altered and/or disrupted. Such molecular alterations provide molecular hallmarks for direct targeting of the PETs by potent relevant inhibitors in combination with conventional cancer therapies as ultimate therapy against solid tumors. Taken all, along with other treatment strategies, targeting the key molecular machineries related to intra- and extracellular metabolisms within the TME is proposed as a novel strategy to inhibit or block PETs that are involved in the pH dysregulation of solid tumors.
癌症是一种复杂的细胞紊乱/功能失调，可被定义为人类疾病中的一种基因异质性。因此，它具有几个适应性复杂特征。其中，pH失调表现为肿瘤微环境（TME）内异常功能的一个标志。与正常组织相比，在实体瘤中，我们面临细胞外液和细胞内液的不规则酸化和碱化。在本研究中，我们全面讨论了关于实体瘤特征的最新报告，以深入了解参与实体瘤pH失调的分子机制及其对癌症发生和发展的影响。实体瘤中pH的失调与瓦伯格效应和缺氧密切相关，导致多种分子机制的表达，包括：NHE1、H⁺泵V-ATP酶、CA-9、CA-12、MCT-1、GLUT-1。质子交换体和转运体（PETs）的激活导致TME的形成。这种情况有利于癌细胞逃避失巢凋亡和凋亡，赋予它们侵袭性和转移表型，以及对化疗和放疗的抗性。本综述旨在讨论肿瘤细胞在生物能量学和癌症代谢方面与pH失调相关的关键分子变化。在这一现象中，细胞内和细胞外代谢物会发生改变和/或破坏。这种分子改变为通过有效的相关抑制剂与传统癌症疗法联合直接靶向PETs提供了分子标志，作为对抗实体瘤的最终疗法。综上所述，连同其他治疗策略，针对TME内与细胞内和细胞外代谢相关的关键分子机制被提议作为一种新策略，以抑制或阻断参与实体瘤pH失调的PETs。
