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.

  • Review
  • Published:

New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation

Subjects

Abstract

In this review, we discuss the role of the tumour-associated carbonic anhydrase isoform IX (CAIX) in the context of pH regulation. We summarise recent experimental findings on the effect of CAIX on cell growth and survival, and present a diffusion-reaction model to help in the assessment of CAIX function under physiological conditions. CAIX emerges as an important facilitator of acid diffusion and acid transport, helping to overcome large cell-to-capillary distances that are characteristic of solid tumours. The source of substrate for CAIX catalysis is likely to be CO2, generated by adequately oxygenated mitochondria or from the titration of metabolic acids with HCO3 taken up from the extracellular milieu. The relative importance of these pathways will depend on oxygen and metabolite availability, the spatiotemporal patterns of the cell's exposure to hypoxia and on the regulation of metabolism by genes. This is now an important avenue for further investigation. The importance of CAIX in regulating tumour pH highlights the protein as a potential target for cancer therapy.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Ahlskog JK, Dumelin CE, Trussel S, Marlind J, Neri D . (2009). In vivo targeting of tumor-associated carbonic anhydrases using acetazolamide derivatives. Bioorg Med Chem Lett 19: 4851–4856.

    Article  CAS  PubMed  Google Scholar 

  • Airley RE, Loncaster J, Raleigh JA, Harris AL, Davidson SE, Hunter RD et al. (2003). GLUT-1 and CAIX as intrinsic markers of hypoxia in carcinoma of the cervix: relationship to pimonidazole binding. Int J Cancer 104: 85–91.

    Article  CAS  PubMed  Google Scholar 

  • Alper SL . (2006). Molecular physiology of SLC4 anion exchangers. Exp Physiol 91: 153–161.

    Article  CAS  PubMed  Google Scholar 

  • Alterio V, Hilvo M, Di Fiore A, Supuran CT, Pan P, Parkkila S et al. (2009). Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX. Proc Natl Acad Sci USA 106: 16233–16238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beasley NJ, Wykoff CC, Watson PH, Leek R, Turley H, Gatter K et al. (2001). Carbonic anhydrase IX, an endogenous hypoxia marker, expression in head and neck squamous cell carcinoma and its relationship to hypoxia, necrosis, and microvessel density. Cancer Res 61: 5262–5267.

    CAS  PubMed  Google Scholar 

  • Boron WF . (2004). Regulation of intracellular pH. Adv Physiol Educ 28: 160–179.

    Article  PubMed  Google Scholar 

  • Boron WF . (2010). Evaluating the role of carbonic anhydrases in the transport of HCO3--related species. Biochim Biophys Acta 1804: 410–421.

    Article  CAS  PubMed  Google Scholar 

  • Chambard JC, Pouyssegur J . (1986). Intracellular pH controls growth factor-induced ribosomal protein S6 phosphorylation and protein synthesis in the G0—G1 transition of fibroblasts. Exp Cell Res 164: 282–294.

    Article  CAS  PubMed  Google Scholar 

  • Chegwidden WR, Dodgson SJ, Spencer IM . (2000). The roles of carbonic anhydrase in metabolism, cell growth and cancer in animals. Exs 90: 343–363.

    CAS  Google Scholar 

  • Chia SK, Wykoff CC, Watson PH, Han C, Leek RD, Pastorek J et al. (2001). Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol 19: 3660–3668.

    Article  CAS  PubMed  Google Scholar 

  • Chiche J, Brahimi-Horn MC, Pouysségur J . (2010). Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J Cell Mol Med 14: 771–794.

    Article  CAS  PubMed  Google Scholar 

  • Chiche J, Ilc K, Laferriere J, Trottier E, Dayan F, Mazure NM et al. (2009). 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.

    Article  CAS  PubMed  Google Scholar 

  • Counillon L, Pouyssegur J . (2000). The expanding family of eucaryotic Na(+)/H(+) exchangers. J Biol Chem 275: 1–4.

    Article  CAS  PubMed  Google Scholar 

  • De Simone G, Supuran CT . (2010). Carbonic anhydrase IX: biochemical and crystallographic characterization of a novel antitumor target. Biochim Biophys Acta 1804: 404–409.

    Article  CAS  PubMed  Google Scholar 

  • Dorai T, Sawczuk IS, Pastorek J, Wiernik PH, Dutcher JP . (2005). The role of carbonic anhydrase IX overexpression in kidney cancer. Eur J Cancer 41: 2935–2947.

    Article  CAS  PubMed  Google Scholar 

  • Fang JS, Gillies RD, Gatenby RA . (2008). Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression. Semin Cancer Biol 18: 330–337.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Franchi A, Silvestre P, Pouyssegur J . (1981). A genetic approach to the role of energy metabolism in the growth of tumor cells: tumorigenicity of fibroblast mutants deficient either in glycolysis or in respiration. Int J Cancer 27: 819–827.

    Article  CAS  PubMed  Google Scholar 

  • Gatenby RA, Gillies RJ . (2004). Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4: 891–899.

    Article  CAS  PubMed  Google Scholar 

  • Generali D, Fox SB, Berruti A, Brizzi MP, Campo L, Bonardi S et al. (2006). Role of carbonic anhydrase IX expression in prediction of the efficacy and outcome of primary epirubicin/tamoxifen therapy for breast cancer. Endocr Relat Cancer 13: 921–930.

    Article  CAS  PubMed  Google Scholar 

  • Giatromanolaki A, Koukourakis MI, Sivridis E, Pastorek J, Wykoff CC, Gatter KC et al. (2001). Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. Cancer Res 61: 7992–7998.

    CAS  PubMed  Google Scholar 

  • Gillies RJ, Martinez-Zaguilan R, Peterson EP, Perona R . (1992). Role of intracellular pH in mammalian cell proliferation. Cell Physiol Biochem 2: 159–179.

    Article  CAS  Google Scholar 

  • Gillies RJ, Martinez-Zaguilan R, Martinez GM, Serrano R, Perona R . (1990). Tumorigenic 3T3 cells maintain an alkaline intracellular pH under physiological conditions. Proc Natl Acad Sci USA 87: 7414–7418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gillies RJ, Raghunand N, Garcia-Martin ML, Gatenby RA . (2004). pH imaging. A review of pH measurement methods and applications in cancers. IEEE Eng Med Biol Mag 23: 57–64.

    Article  PubMed  Google Scholar 

  • Giusti I, D'Ascenzo S, Millimaggi D, Taraboletti G, Carta G, Franceschini N et al. (2008). Cathepsin B mediates the pH-dependent proinvasive activity of tumor-shed microvesicles. Neoplasia 10: 481–488.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gleadle JM, Ratcliffe PJ . (1998). Hypoxia and the regulation of gene expression. Mol Med Today 4: 122–129.

    Article  CAS  PubMed  Google Scholar 

  • Griffiths JR, McIntyre DJ, Howe FA, Stubbs M . (2001). Why are cancers acidic? A carrier-mediated diffusion model for H+ transport in the interstitial fluid. Novartis Found Symp 240: 46–62.

    CAS  PubMed  Google Scholar 

  • Griffiths JR, Stevens AN, Iles RA, Gordon RE, Shaw D . (1981). 31P-NMR investigation of solid tumours in the living rat. Biosci Rep 1: 319–325.

    Article  CAS  PubMed  Google Scholar 

  • Guler OO, De Simone G, Supuran CT . (2010). Drug design studies of the novel antitumor targets carbonic anhydrase IX and XII. Curr Med Chem 17: 1516–1526.

    Article  CAS  PubMed  Google Scholar 

  • Haapasalo J, Hilvo M, Nordfors K, Haapasalo H, Parkkila S, Hyrskyluoto A et al. (2008). Identification of an alternatively spliced isoform of carbonic anhydrase XII in diffusely infiltrating astrocytic gliomas. Neuro Oncol 10: 131–138.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Haapasalo JA, Nordfors KM, Hilvo M, Rantala IJ, Soini Y, Parkkila AK et al. (2006). Expression of carbonic anhydrase IX in astrocytic tumors predicts poor prognosis. Clin Cancer Res 12: 473–477.

    Article  CAS  PubMed  Google Scholar 

  • Halestrap AP, Meredith D . (2004). The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 447: 619–628.

    Article  CAS  PubMed  Google Scholar 

  • Harris AL . (2002). Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer 2: 38–47.

    Article  CAS  PubMed  Google Scholar 

  • Holm E, Hagmuller E, Staedt U, Schlickeiser G, Gunther HJ, Leweling H et al. (1995). Substrate balances across colonic carcinomas in humans. Cancer Res 55: 1373–1378.

    CAS  PubMed  Google Scholar 

  • Huang WC, Swietach P, Vaughan-Jones RD, Ansorge O, Glitsch MD . (2008). Extracellular acidification elicits spatially and temporally distinct Ca2+ signals. Curr Biol 18: 781–785.

    Article  CAS  PubMed  Google Scholar 

  • Hulikova A, Zatovicova M, Svastova E, Ditte P, Brasseur R, Kettmann R et al. (2009). Intact intracellular tail is critical for proper functioning of the tumor-associated, hypoxia-regulated carbonic anhydrase IX. FEBS Lett 583: 3563–3568.

    Article  CAS  PubMed  Google Scholar 

  • Innocenti A, Pastorekova S, Pastorek J, Scozzafava A, De Simone G, Supuran CT . (2009). The proteoglycan region of the tumor-associated carbonic anhydrase isoform IX acts as anintrinsic buffer optimizing CO2 hydration at acidic pH values characteristic of solid tumors. Bioorg Med Chem Lett 19: 5825–5828.

    Article  CAS  PubMed  Google Scholar 

  • Irving M, Maylie J, Sizto NL, Chandler WK . (1990). Intracellular diffusion in the presence of mobile buffers. Application to proton movement in muscle. Biophys J 57: 717–721.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ivanov S, Liao SY, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G et al. (2001). Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 158: 905–919.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kallinowski F, Schlenger KH, Runkel S, Kloes M, Stohrer M, Okunieff P et al. (1989). Blood flow, metabolism, cellular microenvironment, and growth rate of human tumor xenografts. Cancer Res 49: 3759–3764.

    CAS  PubMed  Google Scholar 

  • Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos K, Pastorek J, Wykoff CC et al. (2001). Hypoxia-regulated carbonic anhydrase-9 (CA9) relates to poor vascularization and resistance of squamous cell head and neck cancer to chemoradiotherapy. Clin Cancer Res 7: 3399–3403.

    CAS  PubMed  Google Scholar 

  • Kunz-Schughart LA, Doetsch J, Mueller-Klieser W, Groebe K . (2000). Proliferative activity and tumorigenic conversion: impact on cellular metabolism in 3-D culture. Am J Physiol Cell Physiol 278: C765–C780.

    Article  CAS  PubMed  Google Scholar 

  • L'Allemain G, Paris S, Pouyssegur J . (1985). Role of a Na+-dependent Cl-/HCO3- exchange in regulation of intracellular pH in fibroblasts. J Biol Chem 260: 4877–4883.

    Article  CAS  PubMed  Google Scholar 

  • Lagarde AE, Franchi AJ, Paris S, Pouyssegur JM . (1988). Effect of mutations affecting Na+: H+ antiport activity on tumorigenic potential of hamster lung fibroblasts. J Cell Biochem 36: 249–260.

    Article  CAS  PubMed  Google Scholar 

  • Lardner A . (2001). The effects of extracellular pH on immune function. J Leukoc Biol 69: 522–530.

    CAS  PubMed  Google Scholar 

  • Lee AH, Tannock IF . (1998). Heterogeneity of intracellular pH and of mechanisms that regulate intracellular pH in populations of cultured cells. Cancer Res 58: 1901–1908.

    CAS  PubMed  Google Scholar 

  • Leem CH, Lagadic-Gossmann D, Vaughan-Jones RD . (1999). Characterization of intracellular pH regulation in the guinea-pig ventricular myocyte. J Physiol 517 (Part 1): 159–180.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liao SY, Stanbridge EJ . (2000). Expression of MN/CA9 protein in Papanicolaou smears containing atypical glandular cells of undetermined significance is a diagnostic biomarker of cervical dysplasia and neoplasia. Cancer 88: 1108–1121.

    Article  CAS  PubMed  Google Scholar 

  • Lindner D, Raghavan D . (2009). Intra-tumoural extra-cellular pH: a useful parameter of response to chemotherapy in syngeneic tumour lines. Br J Cancer 100: 1287–1291.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Loncaster JA, Harris AL, Davidson SE, Logue JP, Hunter RD, Wycoff CC et al. (2001). 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.

    CAS  PubMed  Google Scholar 

  • Martinez-Zaguilan R, Lynch RM, Martinez GM, Gillies RJ . (1993). Vacuolar-type H(+)-ATPases are functionally expressed in plasma membranes of human tumor cells. Am J Physiol 265: C1015–C1029.

    Article  CAS  PubMed  Google Scholar 

  • Martinez-Zaguilan R, Raghunand N, Lynch RM, Bellamy W, Martinez GM, Rojas B et al. (1999). pH and drug resistance. I. Functional expression of plasmalemmal V-type H+-ATPase in drug-resistant human breast carcinoma cell lines. Biochem Pharmacol 57: 1037–1046.

    Article  CAS  PubMed  Google Scholar 

  • Martinez-Zaguilan R, Seftor EA, Seftor RE, Chu YW, Gillies RJ, Hendrix MJ . (1996). Acidic pH enhances the invasive behavior of human melanoma cells. Clin Exp Metastasis 14: 176–186.

    Article  CAS  PubMed  Google Scholar 

  • Matsuyama S, Llopis J, Deveraux QL, Tsien RY, Reed JC . (2000). Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis. Nat Cell Biol 2: 318–325.

    Article  CAS  PubMed  Google Scholar 

  • McLean LA, Roscoe J, Jorgensen NK, Gorin FA, Cala PM . (2000). Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes. Am J Physiol Cell Physiol 278: C676–C688.

    Article  CAS  PubMed  Google Scholar 

  • Morgan PE, Pastorekova S, Stuart-Tilley AK, Alper SL, Casey JR . (2007). Interactions of transmembrane carbonic anhydrase, CAIX, with bicarbonate transporters. Am J Physiol Cell Physiol 293: C738–C748.

    Article  CAS  PubMed  Google Scholar 

  • Nakhoul NL, Davis BA, Romero MF, Boron WF . (1998). Effect of expressing the water channel aquaporin-1 on the CO2 permeability of Xenopus oocytes. J Physiol 274: C543–C548.

    CAS  Google Scholar 

  • Newell K, Franchi A, Pouyssegur J, Tannock I . (1993). Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity. Proc Natl Acad Sci USA 90: 1127–1131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niederer SA, Swietach P, Wilson DA, Smith NP, Vaughan-Jones RD . (2008). Measuring and modeling chloride-hydroxyl exchange in the Guinea-pig ventricular myocyte. Biophys J 94: 2385–2403.

    Article  CAS  PubMed  Google Scholar 

  • Pan P, Leppilampi M, Pastorekova S, Pastorek J, Waheed A, Sly WS et al. (2006). Carbonic anhydrase gene expression in CA II-deficient (Car2-/-) and CA IX-deficient (Car9-/-) mice. J Physiol 571: 319–327.

    Article  CAS  PubMed  Google Scholar 

  • Pastorek J, Pastorekova S, Callebaut I, Mornon JP, Zelnik V, Opavsky R et al. (1994). Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment. Oncogene 9: 2877–2888.

    CAS  PubMed  Google Scholar 

  • Pastorekova S, Parkkila S, Parkkila AK, Opavsky R, Zelnik V, Saarnio J et al. (1997). Carbonic anhydrase IX, MN/CA IX: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts. Gastroenterology 112: 398–408.

    Article  CAS  PubMed  Google Scholar 

  • Pastorekova S, Pastorek J . (2004) Supuran C, Scozzafava A and Conway J (eds). Carbonic Anhydrase: its Inhibitors and Activators. CRC Press: Boca Raton, FL.

    Google Scholar 

  • Potter CP, Harris AL . (2003). Diagnostic, prognostic and therapeutic implications of carbonic anhydrases in cancer. Br J Cancer 89: 2–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pouyssegur J, Dayan F, Mazure NM . (2006). Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441: 437–443.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Pouyssegur J, Sardet C, Franchi A, L'Allemain G, Paris S . (1984). A specific mutation abolishing Na+/H+ antiport activity in hamster fibroblasts precludes growth at neutral and acidic pH. Proc Natl Acad Sci USA 81: 4833–4837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Romero MF, Fulton CM, Boron WF . (2004). The SLC4 family of HCO 3 – transporters. Pflugers Arch 447: 495–509.

    Article  CAS  PubMed  Google Scholar 

  • Saarnio J, Parkkila S, Parkkila AK, Haukipuro K, Pastorekova S, Pastorek J et al. (1998). Immunohistochemical study of colorectal tumors for expression of a novel transmembrane carbonic anhydrase, MN/CA IX, with potential value as a marker of cell proliferation. Am J Pathol 153: 279–285.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sardet C, Franchi A, Pouyssegur J . (1989). Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+/H+ antiporter. Cell 56: 271–280.

    Article  CAS  PubMed  Google Scholar 

  • Sauvant C, Nowak M, Wirth C, Schneider B, Riemann A, Gekle M et al. (2008). Acidosis induces multi-drug resistance in rat prostate cancer cells (AT1) in vitro and in vivo by increasing the activity of the p-glycoprotein via activation of p38. Int J Cancer 123: 2532–2542.

    Article  CAS  PubMed  Google Scholar 

  • Sennoune SR, Bakunts K, Martinez GM, Chua-Tuan JL, Kebir Y, Attaya MN et al. (2004). Vacuolar H+-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity. Am J Physiol Cell Physiol 286: C1443–C1452.

    Article  CAS  PubMed  Google Scholar 

  • Spitzer KW, Skolnick RL, Peercy BE, Keener JP, Vaughan-Jones RD . (2002). Facilitation of intracellular H(+) ion mobility by CO(2)/HCO(3)(-) in rabbit ventricular myocytes is regulated by carbonic anhydrase. J Physiol 541: 159–167.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sterling D, Reithmeier RA, Casey JR . (2001). A transport metabolon. Functional interaction of carbonic anhydrase II and chloride/bicarbonate exchangers. J Biol Chem 276: 47886–47894.

    Article  CAS  PubMed  Google Scholar 

  • Stewart AK, Kurschat CE, Vaughan-Jones RD, Alper SL . (2009). Putative re-entrant loop 1 of AE2 transmembrane domain has a major role in acute regulation of anion exchange by pH. J Biol Chem 284: 6126–6139.

    Article  CAS  Google Scholar 

  • Stock C, Mueller M, Kraehling H, Mally S, Noel J, Eder C et al. (2007). pH nanoenvironment at the surface of single melanoma cells. Cell Physiol Biochem 20: 679–686.

    Article  CAS  PubMed  Google Scholar 

  • Sun B, Leem CH, Vaughan-Jones RD . (1996). Novel chloride-dependent acid loader in the guinea-pig ventricular myocyte: part of a dual acid-loading mechanism. J Physiol 495 (Pt 1): 65–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Supuran CT . (2008). Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7: 168–181.

    Article  CAS  PubMed  Google Scholar 

  • Sutherland RM . (1988). Cell and environment interactions in tumor microregions: the multicell spheroid model. Science 240: 177–184.

    Article  CAS  PubMed  Google Scholar 

  • Svastova E, Zilka N, Zat'ovicova M, Gibadulinova A, Ciampor F, Pastorek J et al. (2003). Carbonic anhydrase IX reduces E-cadherin-mediated adhesion of MDCK cells via interaction with beta-catenin. Exp Cell Res 290: 332–345.

    Article  CAS  PubMed  Google Scholar 

  • Swietach P, Patiar S, Supuran CT, Harris AL, Vaughan-Jones RD . (2009). The role of carbonic anhydrase 9 in regulating extracellular and intracellular ph in three-dimensional tumor cell growths. J Biol Chem 284: 20299–20310.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Swietach P, Spitzer KW, Vaughan-Jones RD . (2007). pH-Dependence of extrinsic and intrinsic H(+)-ion mobility in the rat ventricular myocyte, investigated using flash photolysis of a caged-H(+) compound. Biophys J 92: 641–653.

    Article  CAS  PubMed  Google Scholar 

  • Swietach P, Wigfield S, Cobden P, Supuran CT, Harris AL, Vaughan-Jones RD . (2008). Tumor-associated carbonic anhydrase 9 spatially coordinates intracellular pH in three-dimensional multicellular growths. J Biol Chem 283: 20473–20483.

    Article  CAS  PubMed  Google Scholar 

  • Swietach P, Zaniboni M, Stewart AK, Rossini A, Spitzer KW, Vaughan-Jones RD . (2003). Modelling intracellular H+ ion diffusion. Prog Biophys Mol Biol 83: 69–100.

    Article  CAS  PubMed  Google Scholar 

  • Thomas RC . (1989). Cell growth factors. Bicarbonate and pHi response. Nature 337: 601.

    Article  CAS  PubMed  Google Scholar 

  • Thomlinson RH, Gray KH . (1955). The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9: 539–549.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Turner JR, Odze RD, Crum CP, Resnick MB . (1997). MN antigen expression in normal, preneoplastic, and neoplastic esophagus: a clinicopathological study of a new cancer-associated biomarker. Hum Pathol 28: 740–744.

    Article  CAS  PubMed  Google Scholar 

  • Turner KJ, Crew JP, Wykoff CC, Watson PH, Poulsom R, Pastorek J et al. (2002). The hypoxia-inducible genes VEGF and CA9 are differentially regulated in superficial vs invasive bladder cancer. Br J Cancer 86: 1276–1282.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vasseur M, Cauzac M, Alvarado F . (1989). Electroneutral, HCO3(-)-independent, pH gradient-dependent uphill transport of Cl- by ileal brush-border membrane vesicles. Possible role in the pathogenesis of chloridorrhea. Biochem J 263: 775–784.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vaughan-Jones RD, Peercy BE, Keener JP, Spitzer KW . (2002). Intrinsic H(+) ion mobility in the rabbit ventricular myocyte. J Physiol 541: 139–158.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vaughan-Jones RD, Wu ML . (1990). Extracellular H+ inactivation of Na(+)-H+ exchange in the sheep cardiac Purkinje fibre. J Physiol 428: 441–466.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vaupel P, Kallinowski F, Okunieff P . (1989). Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49: 6449–6465.

    CAS  PubMed  Google Scholar 

  • Wohlhueter RM, Plagemann PG . (1981). Hexose transport and phosphorylation by Novikoff rat hepatoma cells as function of extracellular pH. J Biol Chem 256: 869–875.

    Article  CAS  PubMed  Google Scholar 

  • Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A et al. (2000). Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60: 7075–7083.

    CAS  PubMed  Google Scholar 

  • Xu C, Lo A, Yammanuru A, Tallarico AS, Brady K, Murakami A et al. (2010). Unique biological properties of catalytic domain directed human anti-CAIX antibodies discovered through phage-display technology. PLoS One 5: e9625.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Zavada J, Zavadova Z, Pastorek J, Biesova Z, Jezek J, Velek J . (2000). Human tumour-associated cell adhesion protein MN/CA IX: identification of M75 epitope and of the region mediating cell adhesion. Br J Cancer 82: 1808–1813.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the Royal Society, Medical Research Council, British Heart Foundation, the Cancer Research UK and the European Union Framework 7 Metoxia.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P Swietach.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Swietach, P., Hulikova, A., Vaughan-Jones, R. et al. New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation. Oncogene 29, 6509–6521 (2010). https://doi.org/10.1038/onc.2010.455

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.455

Keywords

This article is cited by

Search

Quick links