Skip to main content

Advertisement

Log in

Extracellular acidity, a “reappreciated” trait of tumor environment driving malignancy: perspectives in diagnosis and therapy

  • CLINICAL
  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Tumors are ecosystems which develop from stem cells endowed with unlimited self-renewal capability and genetic instability, under the effects of mutagenesis and natural selection imposed by environmental changes. Abnormal vascularization, reduced lymphatic network, uncontrolled cell growth frequently associated with hypoxia, and extracellular accumulation of glucose metabolites even in the presence of an adequate oxygen level are all factors contributing to reduce pH in the extracellular space of tumors. Evidence is accumulating that acidity is associated with a poor prognosis and participates actively to tumor progression. This review addresses some of the most experimental evidences providing that acidity of tumor environment facilitates local invasiveness and metastatic dissemination, independently from hypoxia, with which acidity is often but not always associated. Clinical investigations have also shown that tumors with acidic environment are associated with resistance to chemotherapy and radiation-induced apoptosis, suppression of cytotoxic lymphocytes, and natural killer cells tumoricidal activity. Therefore, new technologies for functional and molecular imaging as well as strategies directed to target low extracellular pH and low pH-adapted tumor cells might represent important issues in oncology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Nicolson, G. L. (1984). Tumor progression, oncogenes and the evolution of metastatic phenotypic diversity. Clinical and Experimental Metastasis, 2, 85–105.

    CAS  PubMed  Google Scholar 

  2. Miller, F. R., & Heppner, G. H. (1990). Cellular interactions in metastasis. Cancer and Metastasis Reviews, 9, 21–34.

    CAS  PubMed  Google Scholar 

  3. Witz, I. P. (2008). Tumor-microenvironment interactions: dangerous liaisons. Advances in Cancer Research, 100, 203–229.

    CAS  PubMed  Google Scholar 

  4. Nguyen, D. X., Bos, P. D., & Massague, J. (2009). Metastasis: from dissemination to organ-specific colonization. Nature Reviews Cancer, 9, 274–284.

    CAS  PubMed  Google Scholar 

  5. Joyce, J. A., & Pollard, J. W. (2009). Microenvironmental regulation of metastasis. Nature Reviews Cancer, 9, 239–252.

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Aguirre-Ghiso, J. A. (2007). Models, mechanisms and clinical evidence for cancer dormancy. Nature Reviews Cancer, 7, 834–846.

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Rubin, H. (2008). Contact interactions between cells that suppress neoplastic development: can they also explain metastatic dormancy? Advances in Cancer Research, 100, 159–202.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  9. Tammela, T., & Alitalo, K. (2010). Lymphangiogenesis: molecular mechanisms and future promise. Cell, 140, 460–476.

    CAS  PubMed  Google Scholar 

  10. Karkkainen, M. J., Haiko, P., Sainio, K., Partanen, J., Taipale, J., Petrova, T. V., et al. (2004). Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nature Immunology, 5, 74–80.

    CAS  PubMed  Google Scholar 

  11. Fukumura, D., & Jain, R. K. (2007). Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. Journal of Cellular Biochemistry, 101, 937–949.

    CAS  PubMed  Google Scholar 

  12. Racker, E. (1974). History of the Pasteur effect and its pathobiology. Molecular and Cellular Biochemistry, 5, 17–23.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Klement, R. J., & Kämmerer, U. (2011). Is there a role for carbohydrate restriction in the treatment and prevention of cancer? Nutrition & Metabolism (London), 8, 75.

    CAS  Google Scholar 

  16. Denko, N. C. (2008). Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nature Reviews Cancer, 8, 705–713.

    CAS  PubMed  Google Scholar 

  17. DeBerardinis, R. J. (2008). Is cancer a disease of abnormal cellular metabolism? New angles on an old idea. Genetics in Medicine, 10, 767–777.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Hirschhaeuser, F., Sattler, U. G., & Mueller-Klieser, W. (2011). Lactate: a metabolic key player in cancer. Cancer Research, 71(22), 6921–6925.

    CAS  PubMed  Google Scholar 

  19. Lu, H., Forbes, R. A., & Verma, A. (2002). Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. Journal of Biological Chemistry, 277, 23111–23115.

    CAS  PubMed  Google Scholar 

  20. Ebert, B. L., Firth, J. D., & Ratcliffe, P. J. (1995). Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences. Journal of Biological Chemistry, 270(49), 29083–29089.

    CAS  PubMed  Google Scholar 

  21. Kim, J. W., Tchernyshyov, I., Semenza, G. L., & Dang, C. V. (2006). HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switchrequired for cellular adaptation to hypoxia. Cell Metabolism, 3, 177–185.

    PubMed  Google Scholar 

  22. Semenza, G. L., Jiang, B. H., Leung, S. W., Passantino, R., Concordet, J. P., Maire, P., et al. (1996). Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. Journal of Biological Chemistry, 271(51), 32529–32537.

    CAS  PubMed  Google Scholar 

  23. Cairns, R. A., Harris, I., McCracken, S., & Mak, T. W. (2011). Cancer cell metabolism. Cold Spring Harbor Symposia on Quantitative Biology, 76, 299–311.

    CAS  PubMed  Google Scholar 

  24. Sonveaux, P., Vegran, F., Schroeder, T., Wergin, M. C., Verrax, J., Rabbani, Z. N., et al. (2008). Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. Journal of Clinical Investigation, 118, 3930–3942.

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Feron, O. (2009). Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiotherapy and Oncology, 92, 329–333.

    CAS  PubMed  Google Scholar 

  26. Whitaker-Menezes, D., Martinez-Outschoorn, U. E., Lin, Z., Ertel, A., Flomenberg, N., Witkiewicz, A. K., et al. (2011). Evidence for a stromal-epithelial ‘lactate shuttle’ in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle, 10, 1772–1783.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Brooks, G. A. (2009). Cell-cell and intracellular lactate shuttles. Journal of Physiology, 587, 5591–5600.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Gladden, L. B. (2004). Lactate metabolism: a new paradigm for the third millennium. Journal of Physiology, 558, 5–30.

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Guido, C., Whitaker-Menezes, D., Capparelli, C., Balliet, R., Lin, Z., Pestell, R. G., et al. (2012). Metabolic reprogramming of cancer-associated fibroblasts by TGF-β drives tumor growth: connecting TGF-β signaling with “Warburg-like” cancer metabolism and l-lactate production. Cell Cycle, 11(16), 3019–3035.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Fiaschi, T., Marini, A., Giannoni, E., Taddei, M. L., Gandellini, P., De Donatis, A., et al. (2012). Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Research, 72, 5130–5140.

    CAS  PubMed  Google Scholar 

  31. Roos, A., & Boron, W. F. (1981). Intracellular pH. Physiological Reviews, 61, 296–434.

    CAS  PubMed  Google Scholar 

  32. Parks, S. K., Chiche, J., & Pouysségur, J. (2013). Disrupting proton dynamics and energy metabolism for cancer therapy. Nature Reviews Cancer, 13(9), 611–623.

    CAS  PubMed  Google Scholar 

  33. Calorini, L., Peppicelli, S., & Bianchini, F. (2012). Extracellular acidity as favouring factor of tumor progression and metastatic dissemination. Experimental Oncology, 34(2), 79–84.

    CAS  PubMed  Google Scholar 

  34. Walenta, S., Wetterling, M., Lehrke, M., Schwickert, G., Sundfør, K., Rofstad, E. K., et al. (2000). High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Research, 60, 916–921.

    CAS  PubMed  Google Scholar 

  35. Morita, T., Nagaki, T., Fukuda, I., & Okumura, K. (1992). Clastogenicity of low pH to various cultured mammalian cells. Mutation Research, 268, 297–305.

    CAS  PubMed  Google Scholar 

  36. Raghunand, N., Mahoney, B., van Sluis, R., Baggett, B., & Gillies, R. J. (2001). Acute metabolic alkalosis enhances response of C3H mouse mammary tumors to the weak base mitoxantrone. Neoplasia, 3, 227–235.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Rottinger, E. M., & Mendonca, M. (1982). Radioresistance secondary to low pH in human glial cells and Chinese hamster ovary cells. International Journal of Radiation Oncology, Biology, and Physics, 8, 1309–1314.

    CAS  Google Scholar 

  38. Webb, B. A., Chimenti, M., Jacobson, M. P., & Barber, D. L. (2011). Dysregulated pH: a perfect storm for cancer progression. Nature Reviews Cancer, 11, 671–677.

    CAS  PubMed  Google Scholar 

  39. Provent, P., Benito, M., Hiba, B., Farion, R., López-Larrubia, P., Ballesteros, P., et al. (2007). Serial in vivo spectroscopic nuclear magnetic resonance imaging of lactate and extracellular pH in rat gliomas shows redistribution of protons away from sites of glycolysis. Cancer Research, 67, 7638–7645.

    CAS  PubMed  Google Scholar 

  40. Pouyssegur, J., Dayan, F., & Mazure, N. M. (2006). Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature, 441, 437–443.

    CAS  PubMed  Google Scholar 

  41. Helmlinger, G., Yuan, F., Dellian, M., & Jain, R. K. (1997). Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nature Medicine, 3, 177–182.

    CAS  PubMed  Google Scholar 

  42. Ridley, A. J., Schwartz, M. A., Burridge, K., Firtel, R. A., Ginsberg, M. H., Borisy, G., et al. (2003). Cell migration: integrating signals from front to back. Science, 302, 1704–1709.

    CAS  PubMed  Google Scholar 

  43. Pope, B. J., Zierler-Gould, K. M., Kühne, R., Weeds, A. G., & Ball, L. J. (2004). Solution structure of human cofilin: actin binding, pH sensitivity, and relationship to actin-depolymerizing factor. Journal of Biological Chemistry, 279(6), 4840–4848.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  45. Moseley, J. B., Okada, K., Balcer, H. I., Kovar, D. R., Pollard, T. D., & Goode, B. L. (2006). Twinfilin is an actin-filament-severing protein and promotes rapid turnover of actin structures in vivo. Journal of Cell Science, 119, 1547–1557.

    CAS  PubMed  Google Scholar 

  46. Grey, M. J., Tang, Y., Alexov, E., McKnight, C. J., Raleigh, D. P., & Palmer, A. G., III. (2006). Characterizing a partially folded intermediate of the villin headpiece domain under non-denaturing conditions: contribution of His41 to the pHdependent stability of the N-terminal subdomain. Journal of Molecular Biology, 355, 1078–1094.

    CAS  PubMed  Google Scholar 

  47. Srivastava, J., Barreiro, G., Groscurth, S., Gingras, A. R., Goult, B. T., Critchley, D. R., et al. (2008). Structural model and functional significance of pH-dependent talin-actin binding for focal adhesion remodeling. Proceedings of the National Academy of Sciences of the United States of America, 105, 14436–14441.

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Stock, C., Cardone, R. A., Busco, G., Krähling, H., Schwab, A., & Reshkin, S. J. (2008). Protons extruded by NHE1: digestive or glue? European Journal of Cell Biology, 87, 591–599.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Brisson, L., Reshkin, S. J., Goré, J., & Roger, S. (2012). pH regulators in invadosomal functioning: proton delivery for matrix tasting. European Journal of Cell Biology, 91, 847–860.

    CAS  PubMed  Google Scholar 

  52. Lucien, F., Brochu-Gaudreau, K., Arsenault, D., Harper, K., & Dubois, C. M. (2011). Hypoxia-induced invadopodia formation involves activation of NHE-1 by the p90 ribosomal S6 kinase (p90RSK). PLoS One, 6, e28851.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Attanasio, F., Caldieri, G., Giacchetti, G., van Horssen, R., Wieringa, B., & Buccione, R. (2011). Novel invadopodia components revealed by differential proteomic analysis. European Journal of Cell Biology, 90, 115–127.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  55. Webb, S. D., Sherratt, J. A., & Fish, R. G. (1999). Alterations in proteolytic activity at low pH and its association with invasion: a theoretical model. Clinical and Experimental Metastasis, 17, 397–407.

    CAS  PubMed  Google Scholar 

  56. Goretzki, L., Schmitt, M., Mann, K., Calvete, J., Chucholowski, N., Kramer, M., et al. (1992). Effective activation of the proenzyme form of the urokinase-type plasminogen activator (pro-uPA) by the cysteine protease cathepsin L. FEBS Letters, 297, 112–118.

    CAS  PubMed  Google Scholar 

  57. Mignatti, P., & Rifkin, D. B. (1996). Plasminogen activators and matrix metalloproteinases in angiogenesis. Enzyme and Protein, 49, 117–137.

    CAS  PubMed  Google Scholar 

  58. Lyons, R. M., Keski-Oja, J., & Moses, H. L. (1988). Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium. Journal of Cell Biology, 106, 1659–1665.

    CAS  PubMed  Google Scholar 

  59. Ellis, V., Pyke, C., Eriksen, J., Solberg, H., & Danø, K. (1992). The urokinase receptor: involvement in cell surface proteolysis and cancer invasion. Annals of the New York Academy of Sciences, 667, 13–31.

    CAS  PubMed  Google Scholar 

  60. Nagase, H., & Woessner, J. F. (1999). Matrix metalloproteinases. Journal of Biological Chemistry, 274, 21491–21494.

    CAS  PubMed  Google Scholar 

  61. Vihinen, P., & Kähäri, V. M. (2002). Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets. International Journal of Cancer, 99(2), 157–166.

    CAS  Google Scholar 

  62. Itoh, T., Tanioka, M., Matsuda, H., Nishimoto, H., Yoshioka, T., Suzuki, R., et al. (1999). Experimental metastasis is suppressed in MMP-9-deficient mice. Clinical and Experimental Metastasis, 17(2), 177–181.

    CAS  PubMed  Google Scholar 

  63. Itoh, T., Tanioka, M., Yoshida, H., Yoshioka, T., Nishimoto, H., & Itohara, S. (1998). Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Research, 58(5), 1048–1051.

    CAS  PubMed  Google Scholar 

  64. Kato, Y., Nakayama, Y., Umeda, M., & Miyazaki, K. (1992). Induction of 103-kDa gelatinase/type IV collagenase by acidic culture conditions in mouse metastatic melanoma cell lines. Journal of Biological Chemistry, 267(16), 11424–11430.

    CAS  PubMed  Google Scholar 

  65. Toyoshima, M., & Nakajima, M. (1999). Human heparanase. Purification, characterization, cloning, and expression. Journal of Biological Chemistry, 274, 24153–24160.

    CAS  PubMed  Google Scholar 

  66. Shi, Q., Le, X., Wang, B., Abbruzzese, J. L., Xiong, Q., He, Y., et al. (2001). Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells. Oncogene, 20, 3751–3756.

    CAS  PubMed  Google Scholar 

  67. Fukumura, D., Xu, L., Chen, Y., Gohongi, T., Seed, B., & Jain, R. K. (2000). Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Research, 61, 6020–6024.

    Google Scholar 

  68. Xu, L., & Fidler, I. J. (2000). Acidic pH-induced elevation in interleukin 8 expression by human ovarian carcinoma cells. Cancer Research, 60(16), 4610–4616.

    CAS  PubMed  Google Scholar 

  69. Peppicelli, S., Bianchini, F., Contena, C., Tombaccini, D., & Calorini, L. (2013). Acidic pH via NF-κB favours VEGF-C expression in human melanoma cells. Clinical and Experimental Metastasis, 30(8), 957–967.

    CAS  PubMed  Google Scholar 

  70. Su, J. L., Yang, P. C., Shih, J. Y., Yang, C. Y., Wei, L. H., Hsieh, C. Y., et al. (2006). The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. Cancer Cell, 9, 209–223.

    CAS  PubMed  Google Scholar 

  71. Radisky, D. C. (2005). Epithelial-mesenchymal transition. Journal of Cell Science, 118(Pt 19), 4325–4326.

    CAS  PubMed  Google Scholar 

  72. Kalluri, R., & Neilson, E. G. (2003). Epithelial-mesenchymal transition and its implications for fibrosis. The Journal of Clinical Investigation, 112(12), 1776–1784.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Kalluri, R. (2009). EMT: when epithelial cells decide to become mesenchymal-like cells. The Journal of Clinical Investigation, 119(6), 1417–1419.

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Peppicelli, S., Bianchini, F., Torre, E., Calorini, L. (2014). Contribution of acidic melanoma cells undergoing epithelial-to-mesenchymal transition to aggressiveness of non-acidic melanoma cells. Clinical and Experimental Metastasis.

  75. Xue, L., & Lucocq, J. M. (1997). Low extracellular pH induces activation of ERK 2, JNK, and p38 in A431 and Swiss 3 T3 cells. Biochemical and Biophysical Research Communications, 241(2), 236–242.

    CAS  PubMed  Google Scholar 

  76. Sarosi, G. A., Jr., Jaiswal, K., Herndon, E., Lopez-Guzman, C., Spechler, S. J., & Souza, R. F. (2005). Acid increases MAPK-mediated proliferation in Barrett’s esophageal adenocarcinoma cells via intracellular acidification through a Cl-/HCO3- exchanger. American Journal of Physiology - Gastrointestinal and Liver Physiology, 289(6), G991–G997.

    CAS  PubMed  Google Scholar 

  77. Kumar, S., Reusch, H. P., & Ladilov, Y. (2008). Acidic pre-conditioning suppresses apoptosis and increases expression of Bcl-xL in coronary endothelial cells under simulated ischaemia. Journal of Cellular and Molecular Medicine, 12(5A), 1584–1592.

    CAS  PubMed  Google Scholar 

  78. Ryder, C., McColl, K., Zhong, F., & Distelhorst, C. W. (2012). Acidosis promotes Bcl-2 family-mediated evasion of apoptosis: involvement of acid-sensing G protein-coupled receptor Gpr65 signaling to Mek/Erk. Journal of Biological Chemistry, 287(33), 27863–27875.

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Wojtkowiak, J. W., Rothberg, J. M., Kumar, V., Schramm, K. J., Haller, E., Proemsey, J. B., et al. (2012). Chronic autophagy is a cellular adaptation to tumor acidic pH microenvironments. Cancer Research, 72(16), 3938–3947.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Mizushima, N., & Klionsky, D. J. (2007). Protein turnover via autophagy: implications for metabolism. Annual Review of Nutrition, 27, 19–40.

    CAS  PubMed  Google Scholar 

  81. Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., et al. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133, 704–715.

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Celià-Terrassa, T., Meca-Cortés, O., Mateo, F., de Paz, A. M., Rubio, N., Arnal-Estapé, A., et al. (2012). Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumorinitiating cells. The Journal of Clinical Investigation, 122, 1849–1868.

    PubMed Central  PubMed  Google Scholar 

  83. Hjelmeland, A. B., Wu, Q., Heddleston, J. M., Choudhary, G. S., MacSwords, J., Lathia, J. D., et al. (2011). Acidic stress promotes a glioma stem cell phenotype. Cell Death and Differentiation, 18, 829–840.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Choi, S. Y., Collins, C. C., Gout, P. W., & Wang, Y. (2013). Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite? The Journal of Pathology, 230(4), 350–355.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Lardner, A. (2001). The effects of extracellular pH on immune function. Journal of Leukocyte Biology, 69, 522–530.

    CAS  PubMed  Google Scholar 

  86. Gottfried, E., Kunz-Schughart, L. A., Ebner, S., Mueller-Klieser, W., Hoves, S., Andreesen, R., et al. (2006). Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood, 107, 2013–2021.

    CAS  PubMed  Google Scholar 

  87. Calcinotto, A., Filipazzi, P., Grioni, M., Iero, M., De Milito, A., Ricupito, A., et al. (2012). Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Research, 72, 2746–2756.

    CAS  PubMed  Google Scholar 

  88. Mendler, A. N., Hu, B., Prinz, P. U., Kreutz, M., Gottfried, E., & Noessner, E. (2012). Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. International Journal of Cancer, 131, 633–640.

    CAS  Google Scholar 

  89. Ohashi, T., Akazawa, T., Aoki, M., Kuze, B., Mizuta, K., Ito, Y., et al. (2013). Dichloroacetate improves immune dysfunction caused by tumor-secreted lactic acid and increases antitumor immunoreactivity. International Journal of Cancer, 133, 1107–1118.

    CAS  Google Scholar 

  90. Dhup, S., Dadhich, R. K., Porporato, P. E., & Sonveaux, P. (2012). Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Current Pharmaceutical Design, 18, 1319–1330.

    CAS  PubMed  Google Scholar 

  91. Goetze, K., Walenta, S., Ksiazkiewicz, M., Kunz-Schughart, L. A., & Mueller-Klieser, W. (2011). Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release. International Journal of Oncology, 9, 453–463.

    Google Scholar 

  92. Beckert, S., Farrahi, F., Aslam, R. S., Scheuenstuhl, H., Königsrainer, A., Hussain, M. Z., et al. (2006). Lactate stimulates endothelial cell migration. Wound Repair and Regeneration, 14, 321–324.

    PubMed  Google Scholar 

  93. Végran, F., Boidot, R., Michiels, C., Sonveaux, P., & Feron, O. (2011). Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis. Cancer Research, 71(7), 2550–2560.

    PubMed  Google Scholar 

  94. Chen, J. L., Lucas, J. E., Schroeder, T., Mori, S., Wu, J., Nevins, J., et al. (2008). The genomic analysis of lactic acidosis and acidosis response in human cancers. PLoS Genetics, 4, e1000293.

    PubMed Central  PubMed  Google Scholar 

  95. Thews, O., Gassner, B., Kelleher, D. K., Schwerdt, G., & Gekle, M. (2006). Impact of extracellular acidity on the activity of P-glycoprotein and the cytotoxicity of chemotherapeutic drugs. Neoplasia, 8, 14352.

    Google Scholar 

  96. Raghunand, N., & Gillies, R. J. (2002). pH and drug resistance in tumors. Drug Resistance Updates, 3, 39–47.

    Google Scholar 

  97. Newell, K., Wood, P., Stratford, I., & Tannock, I. (1992). Effects of agents which inhibit the regulation of intracellular pH on murine solid tumours. British Journal of Cancer, 66, 311–317.

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Ohtsubo, T., Igawa, H., Saito, T., Matsumoto, H., Park, H. J., Song, C. W., et al. (2001). Acidic environment modifies heat- or radiation-induced apoptosis in human maxillary cancer cells. International Journal of Radiation Oncology, Biology, and Physics, 49, 1391–8131.

    CAS  Google Scholar 

  99. Trowell, O. A. (1953). The effect of environmental factors on the radiosensitivity of lymph nodes cultured in vitro. British Journal of Radiology, 306, 302–309.

    Google Scholar 

  100. Haveman, J. (1980). The influence of pH on the survival after X-irradiation of cultured malignant cells. Effects of carbonylcyanide-3-chlorophenylhydrazone. International Journal of Radiation Biology, 37, 201–205.

    CAS  Google Scholar 

  101. Ohtsubo, T., Wang, X., Takahashi, A., Ohnishi, K., Saito, H., Song, C. W., et al. (1997). p53-dependent induction of WAF1 by a low-pH culture condition in human glioblastoma cells. Cancer Research, 57(18), 3910–3913.

    CAS  PubMed  Google Scholar 

  102. Lee, H. S., Park, H. J., Lyons, J. C., Griffin, R. J., Auger, E. A., & Song, C. W. (1997). Radiation-induced apoptosis in different pH environments in vitro. International Journal of Radiation Oncology, Biology, and Physics, 38(5), 1079–1087.

    CAS  Google Scholar 

  103. Choi, E. K., Roberts, K. P., Griffin, R. J., Han, T., Park, H. J., Song, C. W., et al. (2004). Effect of pH on radiation-induced p53 expression. International Journal of Radiation Oncology, Biology, and Physics, 60, 1264–1271.

    CAS  Google Scholar 

  104. Park, H. J., Lee, S. H., Chung, H., Rhee, Y. H., Lim, B. U., Ha, S. W., et al. (2003). Influence of environmental pH on G2-phase arrest caused by ionizing radiation. Radiation Research, 159, 86–93.

    CAS  PubMed  Google Scholar 

  105. Zhang, X., Lin, Y., & Gillies, R. J. (2010). Tumor pH and its measurement. Journal of Nuclear Medicine, 51(8), 1167–1170.

    CAS  PubMed  Google Scholar 

  106. Delbeke, D., Coleman, R. E., Guiberteau, M. J., Brown, M. L., Royal, H. D., Siegel, B. A., et al. (2006). Procedure guideline for tumor imaging with 18F-FDG PET/CT 1.0. Journal of Nuclear Medicine, 47(5), 885–895.

    PubMed  Google Scholar 

  107. Reshetnyak, Y. K., Andreev, O. A., Lehnert, U., & Engelman, D. M. (2006). Translocation of a molecules into cells by pH-dependent insertion of a transmembrane helix. Proceedings of the National Academy of Sciences of the United States of America, 103, 6460–6465.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Reshetnyak, Y. K., Segala, M., Andreev, O. A., & Engelman, D. M. (2007). A monomeric membrane peptide that lives in three worlds: in solution, attached to, and inserted across lipid bilayers. Biophysical Journal, 93, 2363–2372.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Andreev, O. A., Dupuy, A. D., Segala, M., Sandugu, S., Serra, D. A., Chichester, C. O., et al. (2007). Mechanism and uses of a membrane peptide that targets tumors and other acidic tissues in vivo. Proceedings of the National Academy of Sciences of the United States of America, 104, 7893–7898.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Vāvere, A. L., Biddlecombe, G. B., Spees, W. M., Garbow, J. R., Wijesinghe, D., Andreev, O. A., et al. (2009). A novel technology for the imaging of acidic prostate tumors by positron emission tomography. Cancer Research, 69(10), 4510–4516.

    PubMed  Google Scholar 

  111. Aime, S., Botta, M., Crich, S. G., Giovenzana, G., Palmisano, G., & Sisti, M. (1999). A macromolecular Gd(III) complex as pH-responsive relaxometric probe for MRI applications. Chemical communications (Cambridge), 16, 1577–1578.

    Google Scholar 

  112. Zhang, S., Wu, K., & Sherry, A. D. (1999). A novel pH-sensitive MRI contrast agent. Angewandte Chemie International Edition in English, 38, 3192–3194.

    CAS  Google Scholar 

  113. Garcia-Martin, M. L., Martinez, G. V., Raghunand, N., Sherry, A. D., Zhang, S. R., & Gillies, R. J. (2006). High resolution pH(e) imaging of rat glioma using pH-dependent relaxivity. Magnetic Resonance in Medicine, 55, 309–315.

    CAS  PubMed  Google Scholar 

  114. Robey, I. F., Baggett, B. K., Kirkpatrick, N. D., Roe, D. J., Dosescu, J., Sloane, B. F., et al. (2009). Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Research, 69, 2260–2268.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Silva, A. S., Yunes, J. A., Gillies, R. J., & Gatenby, R. A. (2009). The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion. Cancer Research, 69, 2677–2684.

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Ibrahim Hashim, A., Cornnell, H. H., Coelho Ribeiro Mde, L., Abrahams, D., Cunningham, J., Lloyd, M., et al. (2011). Reduction of metastasis using a non-volatile buffer. Clinical and Experimental Metastasis, 28, 841–849.

    PubMed Central  PubMed  Google Scholar 

  117. Fais, S., De Milito, A., You, H., & Qin, W. (2007). Targeting vacuolar H+-ATPases as a new strategy against cancer. Cancer Research, 67, 10627–10630.

    CAS  PubMed  Google Scholar 

  118. De Milito, A., Canese, R., Marino, M. L., Borghi, M., Iero, M., Villa, A., et al. (2010). pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. International Journal of Cancer, 127, 207–219.

    Google Scholar 

  119. Yeo, M., Kim, D. K., Park, H. J., Cho, S. W., Cheong, J. Y., & Lee, K. J. (2008). Retraction: blockage of intracellular proton extrusion with proton pump inhibitor induces apoptosis in gastric cancer. Cancer Science, 99, 185.

    CAS  Google Scholar 

  120. Supino, R., Scovassi, A. I., Croce, A. C., Dal Bo, L., Favini, E., Corbelli, A., et al. (2009). Biological effects of a new vacuolar-H,-ATPase inhibitor in colon carcinoma cell lines. Annals of the New York Academy of Sciences, 1171, 606–616.

    CAS  PubMed  Google Scholar 

  121. Lauritzen, G., Stock, C. M., Lemaire, J., Lund, S. F., Jensen, M. F., Damsgaard, B., et al. (2012). The Na+/H+ exchanger NHE1, but not the Na+, HCO3(−) cotransporter NBCn1, regulates motility of MCF7 breast cancer cells expressing constitutively active ErbB2. Cancer Letters, 317, 172–183.

    CAS  PubMed  Google Scholar 

  122. He, B., Deng, C., Zhang, M., Zou, D., & Xu, M. (2007). Reduction of intracellular pH inhibits the expression of VEGF in K562 cells after targeted inhibition of the Na+/H+ exchanger. Leukemia Research, 2007(31), 507–514.

    Google Scholar 

  123. Provost, J. J., Rastedt, D., Canine, J., Ngyuen, T., Haak, A., Kutz, C., et al. (2012). Urokinase plasminogen activator receptor induced non-small cell lung cancer invasion and metastasis requires NHE1 transporter expression and transport activity. Cellular Oncology, 2012(35), 95–110.

    Google Scholar 

  124. Commisso, C., Davidson, S. M., Soydaner-Azeloglu, R. G., Parker, S. J., Kamphorst, J. J., Hackett, S., et al. (2013). Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature, 497, 633–637.

    CAS  PubMed  Google Scholar 

  125. Wong, P., Kleemann, H. W., & Tannock, I. F. (2002). Cytostatic potential of novel agents that inhibit the regulation of intracellular pH. British Journal of Cancer, 87(2), 238–245.

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Harguindey, S., Arranz, J. L., Polo Orozco, J. D., Rauch, C., Fais, S., Cardone, R. A., et al. (2013). Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs—an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research. Journal of Translational Medicine, 11(1), 282.

    PubMed Central  PubMed  Google Scholar 

  127. Gao, W., Chang, G., Wang, J., Jin, W., Wang, L., Lin, Y., et al. (2011). Inhibition of K562 leukemia angiogenesis and growth by selective Na+/H+ exchanger inhibitor cariporide through down-regulation of pro-angiogenesis factor VEGF. Leukemia Research, 11, 1506–1511.

    Google Scholar 

  128. Sennoune, S. R., Luo, D., & Martínez-Zaguilán, R. (2004). Plasmalemmal vacuolar-type H+-ATPase in cancer biology. Cell Biochemistry and Biophysics, 40(2), 185–206.

    CAS  PubMed  Google Scholar 

  129. Luciani, F., Spada, M., De Milito, A., Molinari, A., Rivoltini, L., Montinaro, A., et al. (2004). Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. Journal of the National Cancer Institute, 96, 1702–1713.

    CAS  PubMed  Google Scholar 

  130. Shen, Y., Wu, Y., Chen, M., Shen, W., Huang, S., Zhang, L., et al. (2012). Effects of pantoprazole as a HIF-1α inhibitor on human gastric adenocarcinoma sgc-7901 cells. Neoplasma, 59, 142–149.

    CAS  PubMed  Google Scholar 

  131. Wahl, M. L., Owen, J. A., Burd, R., Herlands, R. A., Nogami, S. S., Rodeck, U., et al. (2002). Regulation of intracellular pH in human melanoma: potential therapeutic implications. Molecular Cancer Therapeutics, 1(8), 617–628.

    CAS  PubMed  Google Scholar 

  132. Supuran, C. T. (2008). Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nature Reviews Drug Discovery, 7, 168–181.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge the “Istituto Toscano Tumori” and Ente Cassa di Risparmio di Firenze for their financial support.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lido Calorini.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peppicelli, S., Bianchini, F. & Calorini, L. Extracellular acidity, a “reappreciated” trait of tumor environment driving malignancy: perspectives in diagnosis and therapy. Cancer Metastasis Rev 33, 823–832 (2014). https://doi.org/10.1007/s10555-014-9506-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-014-9506-4

Keywords

Navigation