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2017 ; 7
(2
): 115-133
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Molecular machineries of pH dysregulation in tumor microenvironment: potential
targets for cancer therapy
#MMPMID28752076
Asgharzadeh MR
; Barar J
; Pourseif MM
; Eskandani M
; Jafari Niya M
; Mashayekhi MR
; Omidi Y
Bioimpacts
2017[]; 7
(2
): 115-133
PMID28752076
show ga
Introduction: 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. Methods: 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. Results: 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. Conclusion: 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.