Display options
Cite
Barar J, Omidi Y. Dysregulated pH in Tumor Microenvironment Checkmates Cancer Therapy. Bioimpacts. 2013;3(4):149-62doi: 10.5681/bi.2013.036.
Barar, J., & Omidi, Y. (2013). Dysregulated pH in Tumor Microenvironment Checkmates Cancer Therapy. BioImpacts : BI, 3(4), 149-62. https://doi.org/10.5681/bi.2013.036
Barar, Jaleh, and Omidi, Yadollah. "Dysregulated pH in Tumor Microenvironment Checkmates Cancer Therapy." BioImpacts : BI vol. 3,4 (2013): 149-62. doi: https://doi.org/10.5681/bi.2013.036
Barar J, Omidi Y. Dysregulated pH in Tumor Microenvironment Checkmates Cancer Therapy. Bioimpacts. 2013;3(4):149-62. doi: 10.5681/bi.2013.036. Epub 2013 Dec 10. PMID: 24455478; PMCID: PMC3892734.
Copy Download .nbib Format: NLM
Share it on

Bioimpacts. 2013;3(4):149-62. doi: 10.5681/bi.2013.036. Epub 2013 Dec 10.

Dysregulated pH in Tumor Microenvironment Checkmates Cancer Therapy.

BioImpacts : BI

Jaleh Barar, Yadollah Omidi

Affiliations

  1. Research Center for Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.

PMID: 24455478 PMCID: PMC3892734 DOI: 10.5681/bi.2013.036

Abstract

INTRODUCTION: The dysregulation of pH by cancerous cells of solid tumors is able to create a unique milieu that is in favor of progression, invasion and metastasis as well as chemo-/immuno-resistance traits of solid tumors. Bioelements involved in pH dysregulation provide new set of oncotargets, inhibition of which may result in better clinical outcome.

METHODS: To study the impacts of pH dysregulation, we investigated the tumor development and progression in relation with Warburg effect, glycolysis and formation of aberrant tumor microenvironment.

RESULTS: The upregulation of glucose transporter GLUT-1 and several enzymes involve in glycolysis exacerbates this phenomenon. The accumulation of lactic acids in cancer cells provokes upregulation of several transport machineries (MCT-1, NHE-1, CA IX and H(+) pump V-ATPase) resulting in reinforced efflux of proton into extracellular fluid. This deviant event makes pH to be settled at 7.4 and 6.6 respectively in cancer cells cytoplasm and extracellular fluid within the tumor microenvironment, which in return triggers secretion of lysosomal components (various enzymes in acidic milieu with pH 5) into cytoplasm. All these anomalous phenomena make tumor microenvironment (TME) to be exposed to cocktail of various enzymes with acidic pH, upon which extracellular matrix (ECM) can be remodeled and even deformed, resulting in emergence of a complex viscose TME with high interstitial fluid pressure.

CONCLUSION: It seems that pH dysregulation is able to remodel various physiologic functions and make solid tumors to become much more invasive and metastatic. It also can cause undesired resistance to chemotherapy and immunotherapy. Hence, cancer therapy needs to be reinforced using specific inhibitors of bioelements involved in pH dysregulation of TME in solid tumors.

Keywords: Glycolysis; Tumor microenvironment; Warburg effect; pH dysregulation

References

  1. Semin Cancer Biol. 2012 Oct;22(5-6):396-403 - PubMed
  2. Life Sci. 2006 Apr 18;78(21):2419-25 - PubMed
  3. FEBS J. 2011 Jul;278(14):2436-59 - PubMed
  4. Nat Rev Cancer. 2003 Oct;3(10):721-32 - PubMed
  5. J Biol Chem. 2005 Jun 24;280(25):24238-44 - PubMed
  6. J Nutr Biochem. 2010 Sep;21(9):809-17 - PubMed
  7. Histol Histopathol. 2011 Oct;26(10):1279-86 - PubMed
  8. FEBS Lett. 2002 Feb 13;512(1-3):52-8 - PubMed
  9. Neoplasma. 2012;59(2):142-9 - PubMed
  10. Nat Rev Cancer. 2012 Nov;12(11):741-52 - PubMed
  11. Traffic. 2009 Jun;10(6):737-53 - PubMed
  12. Cancer Treat Rev. 2009 Dec;35(8):707-13 - PubMed
  13. Nat Immunol. 2007 Jan;8(1):11-3 - PubMed
  14. J Med Chem. 2012 Jun 14;55(11):5506-17 - PubMed
  15. Int J Biol Markers. 2011 Jul-Sep;26(3):166-72 - PubMed
  16. Physiology (Bethesda). 2010 Dec;25(6):364-77 - PubMed
  17. Int J Cancer. 2008 Mar 1;122(5):990-8 - PubMed
  18. Clin Cancer Res. 2005 May 1;11(9):3553-7 - PubMed
  19. Nat Rev Cancer. 2004 Nov;4(11):891-9 - PubMed
  20. Mol Cells. 2006 Dec 31;22(3):291-9 - PubMed
  21. Curr Cancer Drug Targets. 2002 Sep;2(3):227-42 - PubMed
  22. Clin Cancer Res. 2009 Oct 1;15(19):6128-36 - PubMed
  23. Oncogene. 2008 Mar 6;27(11):1501-10 - PubMed
  24. Mol Cancer Ther. 2008 Jan;7(1):90-100 - PubMed
  25. Histopathology. 2005 Jan;46(1):31-6 - PubMed
  26. Toxicol Mech Methods. 2008;18(4):369-78 - PubMed
  27. Cell Cycle. 2011 Nov 1;10(21):3692-700 - PubMed
  28. Nat Rev Cancer. 2004 Oct;4(10):806-13 - PubMed
  29. Biochem Biophys Res Commun. 2003 Jan 3;300(1):241-6 - PubMed
  30. Int J Toxicol. 2009 Mar-Apr;28(2):113-22 - PubMed
  31. J Clin Invest. 2008 Dec;118(12):3835-7 - PubMed
  32. Curr Pharm Des. 2012;18(10):1345-71 - PubMed
  33. Anticancer Agents Med Chem. 2008 Apr;8(3):305-12 - PubMed
  34. BioDrugs. 2013 Feb;27(1):55-67 - PubMed
  35. Cancer Lett. 2002 Jul 8;181(1):31-8 - PubMed
  36. Blood. 2009 Apr 2;113(14):3276-86 - PubMed
  37. Oncogene. 2009 Feb 12;28(6):781-91 - PubMed
  38. Nat Genet. 2013 Jan;45(1):104-8 - PubMed
  39. BJU Int. 2012 Oct;110(7):1062-9 - PubMed
  40. Cancer Lett. 2007 Sep 18;255(1):107-16 - PubMed
  41. Exp Cell Res. 2002 Sep 10;279(1):128-40 - PubMed
  42. J Biol Chem. 2011 Dec 2;286(48):41600-41615 - PubMed
  43. Anticancer Res. 2003 Nov-Dec;23(6C):4853-8 - PubMed
  44. J Drug Target. 2007 Jan;15(1):83-8 - PubMed
  45. Oncogene. 2008 Jan 24;27(5):684-93 - PubMed
  46. Int J Mol Med. 1999 Oct;4(4):333-50 - PubMed
  47. Hum Antibodies. 2009;18(3):81-100 - PubMed
  48. Int J Biochem Cell Biol. 2011 Jul;43(7):981-9 - PubMed
  49. J Cell Physiol. 2011 Feb;226(2):511-9 - PubMed
  50. Cancer Res. 2006 Mar 15;66(6):3197-204 - PubMed
  51. J Drug Target. 2003 Jul;11(6):311-23 - PubMed
  52. Nat Rev Urol. 2011 Sep 08;8(9):471 - PubMed
  53. Curr Drug Deliv. 2005 Oct;2(4):429-41 - PubMed
  54. Int J Cancer. 2010 Jun 15;126(12):2773-89 - PubMed
  55. J Biol Chem. 2010 Mar 26;285(13):9780-9791 - PubMed
  56. Cancer. 2009 Jun 15;115(12):2732-43 - PubMed
  57. Int J Radiat Biol. 2013 Jan;89(1):9-15 - PubMed
  58. Immunotherapy. 2009 May;1(3):483-93 - PubMed
  59. Clin Cancer Res. 2003 Jun;9(6):2366-73 - PubMed
  60. Recent Pat Anticancer Drug Discov. 2013 Jan 1;8(1):85-99 - PubMed
  61. Curr Pharm Des. 2012;18(10):1372-82 - PubMed
  62. Pflugers Arch. 2008 Feb;455(5):799-810 - PubMed
  63. Hum Antibodies. 2010;19(2-3):63-70 - PubMed
  64. Bioimpacts. 2013;3(3):105-9 - PubMed
  65. Cell Cycle. 2012 Mar 15;11(6):1108-17 - PubMed
  66. Cancer Sci. 2011 May;102(5):1007-13 - PubMed
  67. Blood. 2008 Sep 1;112(5):2013-6 - PubMed
  68. Curr Opin Oncol. 2012 Nov;24(6):650-4 - PubMed
  69. J Cell Biochem. 2008 Jun 1;104(3):985-94 - PubMed
  70. Mol Oncol. 2014 Feb;8(1):9-19 - PubMed
  71. Nat Rev Cancer. 2003 Aug;3(8):615-22 - PubMed
  72. Cell. 2000 Jan 7;100(1):57-70 - PubMed
  73. Nat Cell Biol. 2008 May;10(5):593-601 - PubMed
  74. Oncology. 2004;66(5):404-10 - PubMed
  75. Cell Cycle. 2012 Nov 15;11(22):4152-66 - PubMed
  76. J Biol Chem. 2008 May 30;283(22):14910-4 - PubMed
  77. Curr Pharm Des. 2010;16(29):3288-99 - PubMed
  78. Am J Physiol. 1992 Sep;263(3 Pt 1):G312-8 - PubMed
  79. Arch Pharm Res. 2011 Oct;34(10):1583-5 - PubMed
  80. J Exp Clin Cancer Res. 2003 Mar;22(1):117-23 - PubMed
  81. Bioimpacts. 2011;1(1):23-30 - PubMed
  82. Cell Physiol Biochem. 2012;30(5):1241-53 - PubMed
  83. Oncogene. 2006 Jan 12;25(2):176-85 - PubMed
  84. Prostate Cancer Prostatic Dis. 2010 Jun;13(2):178-81 - PubMed
  85. Cell Cycle. 2012 Mar 15;11(6):1059 - PubMed
  86. Curr Top Med Chem. 2007;7(9):865-78 - PubMed
  87. Am J Clin Pathol. 2003 Nov;120(5):691-8 - PubMed
  88. Cancer Res. 2003 Sep 1;63(17):5513-20 - PubMed
  89. Surg Oncol. 2012 Sep;21(3):172-7 - PubMed
  90. Eur J Cancer. 2009 Sep;45(13):2418-24 - PubMed
  91. Hum Antibodies. 2009;18(1-2):11-6 - PubMed

Publication Types