Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Dysregulated pH: a perfect storm for cancer progression

Abstract

Although cancer is a diverse set of diseases, cancer cells share a number of adaptive hallmarks. Dysregulated pH is emerging as a hallmark of cancer because cancers show a 'reversed' pH gradient with a constitutively increased intracellular pH that is higher than the extracellular pH. This gradient enables cancer progression by promoting proliferation, the evasion of apoptosis, metabolic adaptation, migration and invasion. Several new advances, including an increased understanding of pH sensors, have provided insight into the molecular basis for pH-dependent cell behaviours that are relevant to cancer cell biology. We highlight the central role of pH sensors in cancer cell adaptations and suggest how dysregulated pH could be exploited to develop cancer-specific therapeutics.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Dysregulated pH creates a perfect storm for cancer progression.
Figure 2: Mechanisms for pH sensing by glycolytic enzymes.
Figure 3: Molecular mechanisms of pH sensors in cell migration and invasion.
Figure 4: Protonation of weakly basic pharmaceuticals reduces cellular uptake.

References

  1. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  Article  PubMed  Google Scholar 

  2. Gillies, R. J., Raghunand, N., Karczmar, G. S. & Bhujwalla, Z. M. MRI of the tumor microenvironment. J. Magn. Reson. Imaging 16, 430–450 (2002).

    PubMed  Article  Google Scholar 

  3. Stüwe, L. et al. pH dependence of melanoma cell migration: protons extruded by NHE1 dominate protons of the bulk solution. J. Physiol. 585, 351–360 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  4. Busco, G. et al. NHE1 promotes invadopodial ECM proteolysis through acidification of the peri-invadopodial space. FASEB J. 24, 3903–3915 (2010).

    CAS  PubMed  Article  Google Scholar 

  5. Gallagher, F. A. et al. Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature 453, 940–943 (2008).

    CAS  PubMed  Article  Google Scholar 

  6. Martinez-Zaguilan, R., Lynch, R. M., Martinez, G. M. & Gillies, R. J. Vacuolar-type H+-ATPases are functionally expressed in plasma membranes of human tumor cells. Am. J. Physiol. 265, C1015–C1029 (1993).

    CAS  PubMed  Article  Google Scholar 

  7. Sennoune, S. R. et al. Vacuolar H+-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity. Am. J. Physiol. Cell Physiol. 286, C1443–C1452 (2004).

    CAS  PubMed  Article  Google Scholar 

  8. Hinton, A. et al. Function of a subunit isoforms of the V-ATPase in pH homeostasis and in vitro invasion of MDA-MB231 human breast cancer cells. J. Biol. Chem. 284, 16400–16408 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. McLean, L. A., Roscoe, J., Jorgensen, N. K., Gorin, F. A. & Cala, P. M. Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes. Am. J. Physiol. Cell Physiol. 278, C676–C688 (2000).

    CAS  PubMed  Article  Google Scholar 

  10. Kumar, A. P. et al. Repression of NHE1 expression by PPARγ activation is a potential new approach for specific inhibition of the growth of tumor cells in vitro and in vivo. Cancer Res. 69, 8636–8644 (2009).

    CAS  PubMed  Article  Google Scholar 

  11. Miraglia, E. et al. Na+/H+ exchanger activity is increased in doxorubicin-resistant human colon cancer cells and its modulation modifies the sensitivity of the cells to doxorubicin. Int. J. Cancer 115, 924–929 (2005).

    CAS  PubMed  Article  Google Scholar 

  12. Chiang, Y., Chou, C.-Y., Hsu, K.-F., Huang, Y.-F. & Shen, M.-R. EGF upregulates Na+/H+ exchanger NHE1 by post-translational regulation that is important for cervical cancer cell invasiveness. J. Cell. Physiol. 214, 810–819 (2008).

    CAS  PubMed  Article  Google Scholar 

  13. Pinheiro, C. et al. Increasing expression of monocarboxylate transporters 1 and 4 along progression to invasive cervical carcinoma. Int. J. Gynecol. Pathol. 27, 568–574 (2008).

    PubMed  Article  Google Scholar 

  14. Pinheiro, C. et al. Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Arch. 452, 139–146 (2008).

    CAS  PubMed  Article  Google Scholar 

  15. Pinheiro, C. et al. Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44. J. Biomed. Biotechnol. 2010, 427694 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. Kennedy, K. M. & Dewhirst, M. W. Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol. 6, 127–148 (2010).

    CAS  PubMed  Article  Google Scholar 

  17. Chiche, J. et al. In vivo pH in metabolic-defective Ras-transformed fibroblast tumors: key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH. Int. J. Cancer 30 May 2011 (doi:10.1002/ijc.26125).

  18. Halestrap, A. P. & Price, N. T. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem. J. 343, 281–299 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Harris, T., Eliyahu, G., Frydman, L. & Degani, H. Kinetics of hyperpolarized 13C1-pyruvate transport and metabolism in living human breast cancer cells. Proc. Natl Acad. Sci. USA 106, 18131–18136 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. Denker, S. P. & Barber, D. L. Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. J. Cell Biol. 159, 1087–1096 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Patel, H. & Barber, D. L. A developmentally regulated Na-H exchanger in Dictyostelium discoideum is necessary for cell polarity during chemotaxis. J. Cell Biol. 169, 321–329 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Grillon, E. et al. The spatial organization of proton and lactate transport in a rat brain tumor. PLoS ONE 6, e17416 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Martin, C., Pedersen, S. F., Schwab, A. & Stock, C. Intracellular pH gradients in migrating cells. Am. J. Physiol. Cell Physiol. 300, C490–C495 (2011).

    CAS  PubMed  Article  Google Scholar 

  24. Wykoff, C. C. et al. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 60, 7075–7083 (2000).

    CAS  PubMed  Google Scholar 

  25. Loncaster, J. A. et al. Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res. 61, 6394–6399 (2001).

    CAS  PubMed  Google Scholar 

  26. Swietach, P., Patiar, S., Supuran, C. T., Harris, A. L. & Vaughan-Jones, R. D. The role of carbonic anhydrase 9 in regulating extracellular and intracellular pH in three-dimensional tumor cell growths. J. Biol. Chem. 284, 20299–20310 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Chiche, J. et al. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res. 69, 358–368 (2009).

    CAS  PubMed  Article  Google Scholar 

  28. Ilie, M. et al. High levels of carbonic anhydrase IX in tumour tissue and plasma are biomarkers of poor prognostic in patients with non-small cell lung cancer. Br. J. Cancer 102, 1627–1635 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Pastorekova, S., Parkkila, S. & Zavada, J. Tumor-associated carbonic anhydrases and their clinical significance. Adv. Clin. Chem. 42, 167–216 (2006).

    CAS  PubMed  Article  Google Scholar 

  30. Cardone, R. A., Casavola, V. & Reshkin, S. J. The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nature Rev. Cancer 5, 786–795 (2005).

    CAS  Article  Google Scholar 

  31. Harguindey, S., Orive, G., Luis Pedraz, J., Paradiso, A. & Reshkin, S. J. The role of pH dynamics and the Na+/H+ antiporter in the etiopathogenesis and treatment of cancer. Two faces of the same coin — one single nature. Biochim. Biophys. Acta 1756, 1–24 (2005).

    CAS  PubMed  Google Scholar 

  32. Gatenby, R. A., Gawlinski, E. T., Gmitro, A. F., Kaylor, B. & Gillies, R. J. Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res. 66, 5216–5223 (2006).

    CAS  PubMed  Article  Google Scholar 

  33. Stock, C. & Schwab, A. Protons make tumor cells move like clockwork. Pflugers Arch. 458, 981–992 (2009).

    CAS  PubMed  Article  Google Scholar 

  34. Srivastava, J., Barber, D. L. & Jacobson, M. P. Intracellular pH sensors: design principles and functional significance. Physiology 22, 30–39 (2007).

    CAS  PubMed  Article  Google Scholar 

  35. Pouysségur, J., Franchi, A., L'Allemain, G. & Paris, S. Cytoplasmic pH, a key determinant of growth factor-induced DNA synthesis in quiescent fibroblasts. FEBS Lett. 190, 115–119 (1985).

    PubMed  Article  Google Scholar 

  36. Moolenaar, W. H. Effects of growth factors on intracellular pH regulation. Annu. Rev. Physiol. 48, 363–376 (1986).

    CAS  PubMed  Article  Google Scholar 

  37. Kapus, A., Romanek, R., Qu, A. Y., Rotstein, O. D. & Grinstein, S. A pH-sensitive and voltage-dependent proton conductance in the plasma membrane of macrophages. J. Gen. Physiol. 102, 729–760 (1993).

    CAS  PubMed  Article  Google Scholar 

  38. Denker, S. P., Huang, D. C., Orlowski, J., Furthmayr, H. & Barber, D. L. Direct binding of the Na-H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H+ translocation. Mol. Cell 6, 1425–1436 (2000).

    CAS  PubMed  Article  Google Scholar 

  39. Lagadic-Gossmann, D., Huc, L. & Lecureur, V. Alterations of intracellular pH homeostasis in apoptosis: origins and roles. Cell Death Differ. 11, 953–961 (2004).

    CAS  PubMed  Article  Google Scholar 

  40. Matsuyama, S., Llopis, J., Deveraux, Q. L., Tsien, R. Y. & Reed, J. C. Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis. Nature Cell Biol. 2, 318–325 (2000).

    CAS  PubMed  Article  Google Scholar 

  41. Putney, L. K. & Barber, D. L. Na-H exchange-dependent increase in intracellular pH times G2/M entry and transition. J. Biol. Chem. 278, 44645–44649 (2003).

    CAS  PubMed  Article  Google Scholar 

  42. Harada, K., Oita, E. & Chiba, K. Metaphase I arrest of starfish oocytes induced via the MAP kinase pathway is released by an increase of intracellular pH. Development 130, 4581–4586 (2003).

    CAS  PubMed  Article  Google Scholar 

  43. Sellier, C. et al. Intracellular acidification delays hormonal G2/M transition and inhibits G2/M transition triggered by thiophosphorylated MAPK in Xenopus oocytes. J. Cell. Biochem. 98, 287–300 (2006).

    CAS  PubMed  Article  Google Scholar 

  44. Park, H. J., Lyons, J. C., Ohtsubo, T. & Song, C. W. Cell cycle progression and apoptosis after irradiation in an acidic environment. Cell Death Differ. 7, 729–738 (2000).

    CAS  PubMed  Article  Google Scholar 

  45. Zhao, R. et al. DNA damage-induced Bcl-xL deamidation is mediated by NHE-1 antiport regulated intracellular pH. PLoS Biol. 5, e1 (2007).

    PubMed  Article  CAS  Google Scholar 

  46. Liao, C., Hu, B., Arno, M. J. & Panaretou, B. Genomic screening in vivo reveals the role played by vacuolar H+ ATPase and cytosolic acidification in sensitivity to DNA-damaging agents such as cisplatin. Mol. Pharmacol. 71, 416–425 (2007).

    CAS  PubMed  Article  Google Scholar 

  47. Khaled, A. R., Kim, K., Hofmeister, R., Muegge, K. & Durum, S. K. Withdrawal of IL-7 induces Bax translocation from cytosol to mitochondria through a rise in intracellular pH. Proc. Natl Acad. Sci. USA 96, 14476–14481 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nature Rev. Cancer 4, 891–899 (2004).

    CAS  Article  Google Scholar 

  49. Tennant, D. A., Durán, R. V. & Gottlieb, E. Targeting metabolic transformation for cancer therapy. Nature Rev. Cancer 10, 267–277 (2010).

    CAS  Article  Google Scholar 

  50. Kroemer, G. & Pouyssegur, J. Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 13, 472–482 (2008).

    CAS  Article  PubMed  Google Scholar 

  51. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Kuwata, F. et al. Enzymatic regulation of glycolysis and gluconeogenesis in rabbit periodontal ligament under various physiological pH conditions. J. Nihon Univ. Sch. Dent. 33, 81–90 (1991).

    CAS  PubMed  Article  Google Scholar 

  53. al-Habori, M., Peak, M., Thomas, T. H. & Agius, L. The role of cell swelling in the stimulation of glycogen synthesis by insulin. Biochem. J. 282, 789–796 (1992).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Dietl, K. et al. Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes. J. Immunol. 184, 1200–1209 (2010).

    CAS  PubMed  Article  Google Scholar 

  55. Gray, J. A. Kinetics of enamel dissolution during formation of incipient caries-like lesions. Arch. Oral Biol. 11, 397–422 (1966).

    CAS  PubMed  Article  Google Scholar 

  56. Trivedi, B. & Danforth, W. H. Effect of pH on the kinetics of frog muscle phosphofructokinase. J. Biol. Chem. 241, 4110–4112 (1966).

    CAS  PubMed  Google Scholar 

  57. Frieden, C., Gilbert, H. R. & Bock, P. E. Phosphofructokinase III. Correlation of the regulatory kinetic and molecular properties of the rabbit muscle enzyme. J. Biol. Chem. 251, 5644–5647 (1976).

    CAS  PubMed  Google Scholar 

  58. Andrés, V., Carreras, J. & Cussó, R. Regulation of muscle phosphofructokinase by physiological concentrations of bisphosphorylated hexoses: effect of alkalinization. Biochem. Biophys. Res. Commun. 172, 328–334 (1990).

    PubMed  Article  Google Scholar 

  59. Banaszak, K. et al. The crystal structures of eukaryotic phosphofructokinases from baker's yeast and rabbit skeletal muscle. J. Mol. Biol. 407, 284–297 (2011).

    CAS  PubMed  Article  Google Scholar 

  60. Schering, B., Eigenbrodt, E., Linder, D. & Schoner, W. Purification and properties of pyruvate kinase type M2 from rat lung. Biochim. Biophys. Acta 717, 337–347 (1982).

    CAS  PubMed  Article  Google Scholar 

  61. Akhtar, K. et al. Differential behavior of missense mutations in the intersubunit contact domain of the human pyruvate kinase M2 isozyme. J. Biol. Chem. 284, 11971–11981 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M. & Cantley, L. C. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452, 181–186 (2008).

    CAS  Article  PubMed  Google Scholar 

  63. Hitosugi, T. et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci. Signal. 2, ra73 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. Deberardinis, R. J., Sayed, N., Ditsworth, D. & Thompson, C. B. Brick by brick: metabolism and tumor cell growth. Curr. Opin. Genet. Dev. 18, 54–61 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Putney, L. & Barber, D. Expression profile of genes regulated by activity of the Na-H exchanger NHE1. BMC Genomics 5, 46 (2004).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. Chen, J. L. et al. The genomic analysis of lactic acidosis and acidosis response in human cancers. PLoS Genet. 4, e1000293 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. Attanasio, F. et al. Novel invadopodia components revealed by differential proteomic analysis. Eur. J. Cell Biol. 90, 115–127 (2011).

    CAS  PubMed  Article  Google Scholar 

  68. Campanella, M. E., Chu, H. & Low, P. S. Assembly and regulation of a glycolytic enzyme complex on the human erythrocyte membrane. Proc. Natl Acad. Sci. USA 102, 2402–2407 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. Chu, H. & Low, P. S. Mapping of glycolytic enzyme-binding sites on human erythrocyte band 3. Biochem. J. 400, 143–151 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. van Horssen, R. et al. Modulation of cell motility by spatial repositioning of enzymatic ATP/ADP exchange capacity. J. Biol. Chem. 284, 1620–1627 (2009).

    CAS  PubMed  Article  Google Scholar 

  71. Frantz, C., Karydis, A., Nalbant, P., Hahn, K. M. & Barber, D. L. Positive feedback between Cdc42 activity and H+ efflux by the Na-H exchanger NHE1 for polarity of migrating cells. J. Cell Biol. 179, 403–410 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. Koivusalo, M. et al. Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling. J. Cell Biol. 188, 547–563 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. Frantz, C. et al. Cofilin is a pH sensor for actin free barbed end formation: role of phosphoinositide binding. J. Cell Biol. 183, 865–879 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Pope, B. J., Zierler-Gould, K. M., Kühne, R., Weeds, A. G. & Ball, L. J. Solution structure of human cofilin: actin binding, pH sensitivity, and relationship to actin-depolymerizing factor. J. Biol. Chem. 279, 4840–4848 (2004).

    CAS  PubMed  Article  Google Scholar 

  75. McLachlan, G. D., Cahill, S. M., Girvin, M. E. & Almo, S. C. Acid-induced equilibrium folding intermediate of human platelet profilin. Biochemistry 46, 6931–6943 (2007).

    CAS  PubMed  Article  Google Scholar 

  76. Moseley, J. B. et al. Twinfilin is an actin-filament- severing protein and promotes rapid turnover of actin structures in vivo. J. Cell Sci. 119, 1547–1557 (2006).

    CAS  PubMed  Article  Google Scholar 

  77. Grey, M. J. et al. Characterizing a partially folded intermediate of the villin headpiece domain under non-denaturing conditions: contribution of His41 to the pH-dependent stability of the N-terminal subdomain. J. Mol. Biol. 355, 1078–1094 (2006).

    CAS  PubMed  Article  Google Scholar 

  78. Srivastava, J. et al. Structural model and functional significance of pH-dependent talin-actin binding for focal adhesion remodeling. Proc. Natl Acad. Sci. USA 105, 14436–14441 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  79. Lee, H.-S. et al. Characterization of an actin-binding site within the talin FERM domain. J. Mol. Biol. 343, 771–784 (2004).

    CAS  PubMed  Article  Google Scholar 

  80. Goldmann, W. H., Hess, D. & Isenberg, G. The effect of intact talin and talin tail fragment on actin filament dynamics and structure depends on pH and ionic strength. Eur. J. Biochem. 260, 439–445 (1999).

    CAS  PubMed  Article  Google Scholar 

  81. Schmidt, J. M., Zhang, J., Lee, H. S., Stromer, M. H. & Robson, R. M. Interaction of talin with actin: sensitive modulation of filament crosslinking activity. Arch. Biochem. Biophys. 366, 139–150 (1999).

    CAS  PubMed  Article  Google Scholar 

  82. Sidani, M. et al. Cofilin determines the migration behavior and turning frequency of metastatic cancer cells. J. Cell Biol. 179, 777–791 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. van Rheenen, J., Condeelis, J. & Glogauer, M. A common cofilin activity cycle in invasive tumor cells and inflammatory cells. J. Cell Sci. 122, 305–311 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. Lee, S. A. et al. Targeting of the FYVE domain to endosomal membranes is regulated by a histidine switch. Proc. Natl Acad. Sci. USA 102, 13052–13057 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  85. Wymann, M. P. & Schneiter, R. Lipid signalling in disease. Nature Rev. Mol. Cell Biol. 9, 162–176 (2008).

    CAS  Article  Google Scholar 

  86. Stock, C. et al. Protons extruded by NHE1: digestive or glue? Eur. J. Cell Biol. 87, 591–599 (2008).

    CAS  PubMed  Article  Google Scholar 

  87. Stock, C. et al. Migration of human melanoma cells depends on extracellular pH and Na+/H+ exchange. J. Physiol. 567, 225–238 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Karydis, A., Jimenez-Vidal, M., Denker, S. P. & Barber, D. L. Mislocalized scaffolding by the Na-H exchanger NHE1 dominantly inhibits fibronectin production and TGF-β activation. Mol. Biol. Cell 20, 2327–2336 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Paradise, R. K., Lauffenburger, D. A. & Van Vliet, K. J. Acidic extracellular pH promotes activation of integrin αvβ3 . PLoS ONE 6, e15746 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. Martin, N. K., Gaffney, E. A., Gatenby, R. A. & Maini, P. K. Tumour–stromal interactions in acid-mediated invasion: a mathematical model. J. Theor. Biol. 267, 461–470 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  91. Saadoun, S., Papadopoulos, M. C., Hara-Chikuma, M. & Verkman, A. S. Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption. Nature 434, 786–792 (2005).

    CAS  Article  PubMed  Google Scholar 

  92. Charras, G. T., Yarrow, J. C., Horton, M. A., Mahadevan, L. & Mitchison, T. J. Non-equilibration of hydrostatic pressure in blebbing cells. Nature 435, 365–369 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Rozhin, J., Sameni, M., Ziegler, G. & Sloane, B. F. Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. Cancer Res. 54, 6517–6525 (1994).

    CAS  PubMed  Google Scholar 

  94. Johnson, L. L. et al. A rationalization of the acidic pH dependence for stromelysin-1 (Matrix metalloproteinase-3) catalysis and inhibition. J. Biol. Chem. 275, 11026–11033 (2000).

    CAS  PubMed  Article  Google Scholar 

  95. Wilhelm, S. M. et al. Matrix metalloproteinase-3 (stromelysin-1). Identification as the cartilage acid metalloprotease and effect of pH on catalytic properties and calcium affinity. J. Biol. Chem. 268, 21906–21913 (1993).

    CAS  PubMed  Google Scholar 

  96. Bourguignon, L. Y. W., Singleton, P. A., Diedrich, F., Stern, R. & Gilad, E. CD44 interaction with Na+-H+ exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion. J. Biol. Chem. 279, 26991–27007 (2004).

    CAS  PubMed  Article  Google Scholar 

  97. Giusti, I. et al. Cathepsin B mediates the pH-dependent proinvasive activity of tumor-shed microvesicles. Neoplasia 10, 481–488 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Robey, I. F. et al. Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Res. 69, 2260–2268 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Gerweck, L. E., Vijayappa, S. & Kozin, S. Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics. Mol. Cancer Ther. 5, 1275–1279 (2006).

    CAS  PubMed  Article  Google Scholar 

  100. Mahoney, B. P., Raghunand, N., Baggett, B. & Gillies, R. J. Tumor acidity, ion trapping and chemotherapeutics: I. acid pH affects the distribution of chemotherapeutic agents in vitro. Biochem. Pharmacol. 66, 1207–1218 (2003).

    CAS  PubMed  Article  Google Scholar 

  101. Raghunand, N., Mahoney, B. P. & Gillies, R. J. Tumor acidity, ion trapping and chemotherapeutics: II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents. Biochem. Pharmacol. 66, 1219–1229 (2003).

    CAS  PubMed  Article  Google Scholar 

  102. Thews, O., Gassner, B., Kelleher, D. K., Schwerdt, G. & Gekle, M. Impact of extracellular acidity on the activity of P-glycoprotein and the cytotoxicity of chemotherapeutic drugs. Neoplasia 8, 143–152 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Frézard, F., Pereira-Maia, E., Quidu, P., Priebe, W. & Garnier-Suillerot, A. P-glycoprotein preferentially effluxes anthracyclines containing free basic versus charged amine. Eur. J. Biochem. 268, 1561–1567 (2001).

    PubMed  Article  Google Scholar 

  104. Aller, S. G. et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323, 1718–1722 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Breedveld, P. et al. The effect of low pH on breast cancer resistance protein (ABCG2)-mediated transport of methotrexate, 7-hydroxymethotrexate, methotrexate diglutamate, folic acid, mitoxantrone, topotecan, and resveratrol in in vitro drug transport models. Mol. Pharmacol. 71, 240–249 (2007).

    CAS  PubMed  Article  Google Scholar 

  106. Du, J.-Z., Sun, T.-M., Song, W.-J., Wu, J. & Wang, J. A tumor-acidity-activated charge-conversional nanogel as an intelligent vehicle for promoted tumoral-cell uptake and drug delivery. Angew. Chem. Int. Ed. Engl. 49, 3621–3626 (2010).

    CAS  PubMed  Article  Google Scholar 

  107. Ahmed, F. et al. Shrinkage of a rapidly growing tumor by drug-loaded polymersomes: pH-triggered release through copolymer degradation. Mol. Pharm. 3, 340–350 (2006).

    CAS  PubMed  Article  Google Scholar 

  108. Li, W., Nicol, F. & Szoka, F. C. GALA: a designed synthetic pH-responsive amphipathic peptide with applications in drug and gene delivery. Adv. Drug Deliv. Rev. 56, 967–985 (2004).

    CAS  PubMed  Article  Google Scholar 

  109. Bae, Y., Fukushima, S., Harada, A. & Kataoka, K. Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. Angew. Chem. Int. Ed. Engl. 42, 4640–4643 (2003).

    CAS  PubMed  Article  Google Scholar 

  110. Kan, Z. et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466, 869–873 (2010).

    CAS  PubMed  Article  Google Scholar 

  111. DiGiammarino, E. L. et al. A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nature Struct. Biol. 9, 12–16 (2002).

    CAS  PubMed  Article  Google Scholar 

  112. Iwakuma, T. & Lozano, G. Crippling p53 activities via knock-in mutations in mouse models. Oncogene 26, 2177–2184 (2007).

    CAS  Article  PubMed  Google Scholar 

  113. Olive, K. P. et al. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 119, 847–860 (2004).

    CAS  Article  PubMed  Google Scholar 

  114. Pouysségur, J., Franchi, A. & Pagès, G. pHi, aerobic glycolysis and vascular endothelial growth factor in tumour growth. Novartis Found. Symp. 240, 186–196 (2001).

    PubMed  Google Scholar 

  115. Reshkin, S. J. et al. Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. FASEB J. 14, 2185–2197 (2000).

    CAS  PubMed  Article  Google Scholar 

  116. Matthews, H., Ranson, M. & Kelso, M. J. Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty? Int. J. Cancer 4 May 2011 (doi:10.1002/ijc.26156).

Download references

Acknowledgements

We thank T. Wittmann, S. Oakes and members of the Barber laboratory for helpful suggestions; K. Van Vliet for sharing data on pH-dependent conformational changes in integrin αvβ3; and C. Smith (University of California, San Francisco, USA) for computations on the pH-dependence of PFK1. Work on the structure and function of actin-binding pH sensors was supported by a Canadian Institutes of Health Research Postdoctoral Fellowship to B.A.W. and a US National Institutes of Health grant, GM58642, to D.L.B.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Diane L. Barber.

Ethics declarations

Competing interests

M.P.J. is a consultant to Schrödinger LLC. The other authors declare no competing financial interests.

Related links

Related links

DATABASES

Cancer Institute Drug Dictionary

doxorubicin

FURTHER INFORMATION

Matthew P. Jacobson's homepage

Diane L. Barber's homepage

Ingenuity pathway analysis

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Webb, B., Chimenti, M., Jacobson, M. et al. Dysregulated pH: a perfect storm for cancer progression. Nat Rev Cancer 11, 671–677 (2011). https://doi.org/10.1038/nrc3110

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3110

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing