Carbonic Anhydrase IX as an Imaging and Therapeutic Target for Tumors and Metastases

  • Narges K. Tafreshi
  • Mark C. Lloyd
  • Marilyn M. Bui
  • Robert J. Gillies
  • David L. Morse
Part of the Subcellular Biochemistry book series (SCBI, volume 75)


Carbonic anhydrase IX (CAIX) which is a zinc containing metalloprotein, efficiently catalyzes the reversible hydration of carbon dioxide. It is constitutively up-regulated in several cancer types and has an important role in tumor progression, acidification and metastasis. High expression of CAIX generally correlates with poor prognosis and is related to a decrease in the disease-free interval following successful therapy. Therefore, it is considered as a prognostic indicator in oncology.

In this review, we describe CAIX regulation and its role in tumor hypoxia, acidification and metastasis. In addition, the molecular imaging of CAIX and its potential for use in cancer detection, diagnosis, staging, and for use in following therapy response is discussed. Both antibodies and small molecular weight compounds have been used for targeted imaging of CAIX expression. The use of CAIX expression as an attractive and promising candidate marker for systemic anticancer therapy is also discussed.


Carbonic anhydrase IX Carbonic anhydrase XII Tumor hypoxia Imaging HIF-1 Acid-mediated invasion Cancer Antibody Small molecular probes Fluorescent sulfonamide 


  1. 1.
    Supuran CT (2008) Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7:168–181PubMedGoogle Scholar
  2. 2.
    Supuran CT (2010) Carbonic anhydrase inhibitors. Bioorg Med Chem Lett 20:3467–3474PubMedGoogle Scholar
  3. 3.
    Okamoto N, Fujikawa-Adachi K, Nishimori I, Taniuchi K, Onishi S (2001) cDNA sequence of human carbonic anhydrase-related protein, CA-RP X: mRNA expressions of CA-RP X and XI in human brain. Biochim Biophys Acta 1518:311–316PubMedGoogle Scholar
  4. 4.
    Picaud SS, Muniz JR, Kramm A, Pilka ES, Kochan G, Oppermann U, Yue WW (2009) Crystal structure of human carbonic anhydrase-related protein VIII reveals the basis for catalytic silencing. Proteins 76:507–511PubMedGoogle Scholar
  5. 5.
    Saczewski F, Innocenti A, Brzozowski Z, Slawinski J, Pomarnacka E, Kornicka A, Scozzafava A, Supuran CT (2006) Carbonic anhydrase inhibitors. Selective inhibition of human tumor-associated isozymes IX and XII and cytosolic isozymes I and II with some substituted-2-mercapto-benzenesulfonamides. J Enzyme Inhib Med Chem 21:563–568PubMedGoogle Scholar
  6. 6.
    Saczewski F, Slawinski J, Kornicka A, Brzozowski Z, Pomarnacka E, Innocenti A, Scozzafava A, Supuran CT (2006) Carbonic anhydrase inhibitors. Inhibition of the cytosolic human isozymes I and II, and the transmembrane, tumor-associated isozymes IX and XII with substituted aromatic sulfonamides activatable in hypoxic tumors. Bioorg Med Chem Lett 16:4846–4851PubMedGoogle Scholar
  7. 7.
    Imtaiyaz Hassan M, Shajee B, Waheed A, Ahmad F, Sly WS (2012) Structure, function and applications of carbonic anhydrase isozymes. Bioorg Med Chem 21:1570–1582PubMedGoogle Scholar
  8. 8.
    Supuran CT, Scozzafava A, Casini A (2003) Carbonic anhydrase inhibitors. Med Res Rev 23:146–189PubMedGoogle Scholar
  9. 9.
    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 283:20473–20483PubMedGoogle Scholar
  10. 10.
    Pastorek J, Pastorekova S, Callebaut I, Mornon JP, Zelnik V, Opavsky R, Zat’ovicova M, Liao S, Portetelle D, Stanbridge EJ (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 9:2877–2888PubMedGoogle Scholar
  11. 11.
    Opavsky R, Pastorekova S, Zelnik V, Gibadulinova A, Stanbridge EJ, Zavada J, Kettmann R, Pastorek J (1996) Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships. Genomics 33:480–487PubMedGoogle Scholar
  12. 12.
    Pastorekova S, Zavadova Z, Kostal M, Babusikova O, Zavada J (1992) A novel quasi-viral agent, MaTu, is a two-component system. Virology 187:620–626PubMedGoogle Scholar
  13. 13.
    Zavada J, Zavadova Z, Pastorekova S, Ciampor F, Pastorek J, Zelnik V (1993) Expression of MaTu-MN protein in human tumor cultures and in clinical specimens. Int J Cancer 54:268–274PubMedGoogle Scholar
  14. 14.
    Oosterwijk E, Ruiter DJ, Hoedemaeker PJ, Pauwels EK, Jonas U, Zwartendijk J, Warnaar SO (1986) Monoclonal antibody G 250 recognizes a determinant present in renal-cell carcinoma and absent from normal kidney. Int J Cancer 38:489–494PubMedGoogle Scholar
  15. 15.
    Grabmaier K, Vissers JL, De Weijert MC, Oosterwijk-Wakka JC, Van Bokhoven A, Brakenhoff RH, Noessner E, Mulders PA, Merkx G, Figdor CG, Adema GJ, Oosterwijk E (2000) Molecular cloning and immunogenicity of renal cell carcinoma-associated antigen G250. Int J Cancer 85:865–870PubMedGoogle Scholar
  16. 16.
    Hilvo M, Baranauskiene L, Salzano AM, Scaloni A, Matulis D, Innocenti A, Scozzafava A, Monti SM, Di Fiore A, De Simone G, Lindfors M, Janis J, Valjakka J, Pastorekova S, Pastorek J, Kulomaa MS, Nordlund HR, Supuran CT, Parkkila S (2008) Biochemical characterization of CA IX, one of the most active carbonic anhydrase isozymes. J Biol Chem 283:27799–27809PubMedGoogle Scholar
  17. 17.
    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 82:1808–1813PubMedGoogle Scholar
  18. 18.
    De Simone G, Supuran CT (2010) Carbonic anhydrase IX: biochemical and crystallographic characterization of a novel antitumor target. Biochim Biophys Acta 1804:404–409PubMedGoogle Scholar
  19. 19.
    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 19:5825–5828PubMedGoogle Scholar
  20. 20.
    Svastova E, Zilka N, Zat'ovicova M, Gibadulinova A, Ciampor F, Pastorek J, Pastorekova S (2003) Carbonic anhydrase IX reduces E-cadherin-mediated adhesion of MDCK cells via interaction with beta-catenin. Exp Cell Res 290:332–345PubMedGoogle Scholar
  21. 21.
    Zavadova Z, Zavada J (2005) Carbonic anhydrase IX (CA IX) mediates tumor cell interactions with microenvironment. Oncol Rep 13:977–982PubMedGoogle Scholar
  22. 22.
    Dorai T, Sawczuk IS, Pastorek J, Wiernik PH, Dutcher JP (2005) The role of carbonic anhydrase IX overexpression in kidney cancer. Eur J Cancer 41:2935–2947PubMedGoogle Scholar
  23. 23.
    Alterio V, Hilvo M, Di Fiore A, Supuran CT, Pan P, Parkkila S, Scaloni A, Pastorek J, Pastorekova S, Pedone C, Scozzafava A, Monti SM, De Simone G (2009) Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX. Proc Natl Acad Sci U S A 106:16233–16238PubMedGoogle Scholar
  24. 24.
    Whittington DA, Waheed A, Ulmasov B, Shah GN, Grubb JH, Sly WS, Christianson DW (2001) Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells. Proc Natl Acad Sci U S A 98:9545–9550PubMedGoogle Scholar
  25. 25.
    Li Y, Wang H, Tu C, Shiverick KT, Silverman DN, Frost SC (2011) Role of hypoxia and EGF on expression, activity, localization and phosphorylation of carbonic anhydrase IX in MDA-MB-231 breast cancer cells. Biochim Biophys Acta 1813:159–167PubMedGoogle Scholar
  26. 26.
    Ivanov S, Liao SY, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G, Merrill MJ, Proescholdt MA, Oldfield EH, Lee J, Zavada J, Waheed A, Sly W, Lerman MI, Stanbridge EJ (2001) Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 158:905–919PubMedGoogle Scholar
  27. 27.
    Pastorekova S, Parkkila S, Parkkila AK, Opavsky R, Zelnik V, Saarnio J, Pastorek J (1997) Carbonic anhydrase IX, MN/CA IX: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts. Gastroenterology 112:398–408PubMedGoogle Scholar
  28. 28.
    McDonald PC, Winum JY, Supuran CT, Dedhar S (2012) Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget 3:84–97PubMedGoogle Scholar
  29. 29.
    Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60:7075–7083PubMedGoogle Scholar
  30. 30.
    Kaluz S, Kaluzova M, Liao SY, Lerman M, Stanbridge EJ (2009) Transcriptional control of the tumor- and hypoxia-marker carbonic anhydrase 9: a one transcription factor (HIF-1) show? Biochim Biophys Acta 1795:162–172PubMedGoogle Scholar
  31. 31.
    Barathova M, Takacova M, Holotnakova T, Gibadulinova A, Ohradanova A, Zatovicova M, Hulikova A, Kopacek J, Parkkila S, Supuran CT, Pastorekova S, Pastorek J (2008) Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype. Br J Cancer 98:129–136PubMedGoogle Scholar
  32. 32.
    Zatovicova M, Sedlakova O, Svastova E, Ohradanova A, Ciampor F, Arribas J, Pastorek J, Pastorekova S (2005) Ectodomain shedding of the hypoxia-induced carbonic anhydrase IX is a metalloprotease-dependent process regulated by TACE/ADAM17. Br J Cancer 93:1267–1276PubMedGoogle Scholar
  33. 33.
    Salceda S, Caro J (1997) Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 272:22642–22647PubMedGoogle Scholar
  34. 34.
    Metzen E, Berchner-Pfannschmidt U, Stengel P, Marxsen JH, Stolze I, Klinger M, Huang WQ, Wotzlaw C, Hellwig-Burgel T, Jelkmann W, Acker H, Fandrey J (2003) Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing. J Cell Sci 116:1319–1326PubMedGoogle Scholar
  35. 35.
    Semenza GL (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15:551–578PubMedGoogle Scholar
  36. 36.
    Kallio PJ, Pongratz I, Gradin K, McGuire J, Poellinger L (1997) Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proc Natl Acad Sci U S A 94:5667–5672PubMedGoogle Scholar
  37. 37.
    Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275PubMedGoogle Scholar
  38. 38.
    Ke Q, Costa M (2006) Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 70:1469–1480PubMedGoogle Scholar
  39. 39.
    Semenza GL (2012) Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci 33:207–214PubMedGoogle Scholar
  40. 40.
    Lu H, Forbes RA, Verma A (2002) Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 277:23111–23115PubMedGoogle Scholar
  41. 41.
    Kaluzova M, Kaluz S, Lerman MI, Stanbridge EJ (2004) DNA damage is a prerequisite for p53-mediated proteasomal degradation of HIF-1alpha in hypoxic cells and downregulation of the hypoxia marker carbonic anhydrase IX. Mol Cell Biol 24:5757–5766PubMedGoogle Scholar
  42. 42.
    Kondo K, Kaelin WG Jr (2001) The von Hippel-Lindau tumor suppressor gene. Exp Cell Res 264:117–125PubMedGoogle Scholar
  43. 43.
    Ivanov SV, Kuzmin I, Wei MH, Pack S, Geil L, Johnson BE, Stanbridge EJ, Lerman MI (1998) Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes. Proc Natl Acad Sci U S A 95:12596–12601PubMedGoogle Scholar
  44. 44.
    Grabmaier K, A de Weijert MC, Verhaegh GW, Schalken JA, Oosterwijk E (2004) Strict regulation of CAIX(G250/MN) by HIF-1alpha in clear cell renal cell carcinoma. Oncogene 23:5624–5631PubMedGoogle Scholar
  45. 45.
    Das B, Tsuchida R, Malkin D, Koren G, Baruchel S, Yeger H (2008) Hypoxia enhances tumor stemness by increasing the invasive and tumorigenic side population fraction. Stem Cells 26:1818–1830PubMedGoogle Scholar
  46. 46.
    Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A (2010) Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 7:150–161PubMedGoogle Scholar
  47. 47.
    Xing F, Okuda H, Watabe M, Kobayashi A, Pai SK, Liu W, Pandey PR, Fukuda K, Hirota S, Sugai T, Wakabayshi G, Koeda K, Kashiwaba M, Suzuki K, Chiba T, Endo M, Mo YY, Watabe K (2011) Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells. Oncogene 30:4075–4086PubMedGoogle Scholar
  48. 48.
    Lock FE, McDonald PC, Lou Y, Serrano I, Chafe SC, Ostlund C, Aparicio S, Winum JY, Supuran CT, Dedhar S (2012) Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche. Oncogene 1–10Google Scholar
  49. 49.
    Horree N, van Diest PJ, Sie-Go DM, Heintz AP (2007) The invasive front in endometrial carcinoma: higher proliferation and associated derailment of cell cycle regulators. Hum Pathol 38:1232–1238PubMedGoogle Scholar
  50. 50.
    Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T (2005) Opinion: migrating cancer stem cells – an integrated concept of malignant tumour progression. Nat Rev Cancer 5:744–749PubMedGoogle Scholar
  51. 51.
    Gut MO, Parkkila S, Vernerova Z, Rohde E, Zavada J, Hocker M, Pastorek J, Karttunen T, Gibadulinova A, Zavadova Z, Knobeloch KP, Wiedenmann B, Svoboda J, Horak I, Pastorekova S (2002) Gastric hyperplasia in mice with targeted disruption of the carbonic anhydrase gene Car9. Gastroenterology 123:1889–1903PubMedGoogle Scholar
  52. 52.
    Leppilampi M, Karttunen TJ, Kivela J, Gut MO, Pastorekova S, Pastorek J, Parkkila S (2005) Gastric pit cell hyperplasia and glandular atrophy in carbonic anhydrase IX knockout mice: studies on two strains C57/BL6 and BALB/C. Transgenic Res 14:655–663PubMedGoogle Scholar
  53. 53.
    Pan P, Leppilampi M, Pastorekova S, Pastorek J, Waheed A, Sly WS, Parkkila S (2006) Carbonic anhydrase gene expression in CA II-deficient (Car2−/−) and CA IX-deficient (Car9−/−) mice. J Physiol 571:319–327PubMedGoogle Scholar
  54. 54.
    Chiche J, Ilc K, Laferriere J, Trottier E, Dayan F, Mazure NM, Brahimi-Horn MC, Pouyssegur J (2009) Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res 69:358–368PubMedGoogle Scholar
  55. 55.
    Chiche J, Ilc K, Brahimi-Horn MC, Pouyssegur J (2010) Membrane-bound carbonic anhydrases are key pH regulators controlling tumor growth and cell migration. Adv Enzyme Regul 50:20–33PubMedGoogle Scholar
  56. 56.
    Harris AL (2002) Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47PubMedGoogle Scholar
  57. 57.
    Wouters A, Pauwels B, Lardon F, Vermorken JB (2007) Review: implications of in vitro research on the effect of radiotherapy and chemotherapy under hypoxic conditions. Oncologist 12:690–712PubMedGoogle Scholar
  58. 58.
    Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP (2002) Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62:3387–3394PubMedGoogle Scholar
  59. 59.
    Rohwer N, Cramer T (2011) Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updat 14:191–201PubMedGoogle Scholar
  60. 60.
    Hockel M, Schlenger K, Mitze M, Schaffer U, Vaupel P (1996) Hypoxia and radiation response in human tumors. Semin Radiat Oncol 6:3–9PubMedGoogle Scholar
  61. 61.
    Evans SM, Koch CJ (2003) Prognostic significance of tumor oxygenation in humans. Cancer Lett 195:1–16PubMedGoogle Scholar
  62. 62.
    Sun JD, Liu Q, Wang J, Ahluwalia D, Ferraro D, Wang Y, Duan JX, Ammons WS, Curd JG, Matteucci MD, Hart CP (2012) Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancer. Clin Cancer Res 18:758–770PubMedGoogle Scholar
  63. 63.
    Gatenby RA, Kessler HB, Rosenblum JS, Coia LR, Moldofsky PJ, Hartz WH, Broder GJ (1988) Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys 14:831–838PubMedGoogle Scholar
  64. 64.
    Mees G, Dierckx R, Vangestel C, Van de Wiele C (2009) Molecular imaging of hypoxia with radiolabelled agents. Eur J Nucl Med Mol Imaging 36:1674–1686PubMedGoogle Scholar
  65. 65.
    Nozue M, Lee I, Yuan F, Teicher BA, Brizel DM, Dewhirst MW, Milross CG, Milas L, Song CW, Thomas CD, Guichard M, Evans SM, Koch CJ, Lord EM, Jain RK, Suit HD (1997) Interlaboratory variation in oxygen tension measurement by Eppendorf “Histograph” and comparison with hypoxic marker. J Surg Oncol 66:30–38PubMedGoogle Scholar
  66. 66.
    Jenkins WT, Evans SM, Koch CJ (2000) Hypoxia and necrosis in rat 9L glioma and Morris 7777 hepatoma tumors: comparative measurements using EF5 binding and the Eppendorf needle electrode. Int J Radiat Oncol Biol Phys 46:1005–1017PubMedGoogle Scholar
  67. 67.
    Cook GJ (2003) Oncological molecular imaging: nuclear medicine techniques. Br J Radiol 76:S152–S158PubMedGoogle Scholar
  68. 68.
    Hoskin PJ, Sibtain A, Daley FM, Wilson GD (2003) GLUT1 and CAIX as intrinsic markers of hypoxia in bladder cancer: relationship with vascularity and proliferation as predictors of outcome of ARCON. Br J Cancer 89:1290–1297PubMedGoogle Scholar
  69. 69.
    Jankovic B, Aquino-Parsons C, Raleigh JA, Stanbridge EJ, Durand RE, Banath JP, MacPhail SH, Olive PL (2006) Comparison between pimonidazole binding, oxygen electrode measurements, and expression of endogenous hypoxia markers in cancer of the uterine cervix. Cytometry B Clin Cytom 70:45–55PubMedGoogle Scholar
  70. 70.
    Li XF, Carlin S, Urano M, Russell J, Ling CC, O'Donoghue JA (2007) Visualization of hypoxia in microscopic tumors by immunofluorescent microscopy. Cancer Res 67:7646–7653PubMedGoogle Scholar
  71. 71.
    Olive PL, Aquino-Parsons C, MacPhail SH, Liao SY, Raleigh JA, Lerman MI, Stanbridge EJ (2001) Carbonic anhydrase 9 as an endogenous marker for hypoxic cells in cervical cancer. Cancer Res 61:8924–8929PubMedGoogle Scholar
  72. 72.
    Sobhanifar S, Aquino-Parsons C, Stanbridge EJ, Olive P (2005) Reduced expression of hypoxia-inducible factor-1alpha in perinecrotic regions of solid tumors. Cancer Res 65:7259–7266PubMedGoogle Scholar
  73. 73.
    Carlin S, Khan N, Ku T, Longo VA, Larson SM, Smith-Jones PM (2010) Molecular targeting of carbonic anhydrase IX in mice with hypoxic HT29 colorectal tumor xenografts. PLoS One 5:e10857PubMedGoogle Scholar
  74. 74.
    Beasley NJ, Wykoff CC, Watson PH, Leek R, Turley H, Gatter K, Pastorek J, Cox GJ, Ratcliffe P, Harris 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 61:5262–5267PubMedGoogle Scholar
  75. 75.
    Mayer A, Hockel M, Vaupel P (2005) Carbonic anhydrase IX expression and tumor oxygenation status do not correlate at the microregional level in locally advanced cancers of the uterine cervix. Clin Cancer Res 11:7220–7225PubMedGoogle Scholar
  76. 76.
    Rafajova M, Zatovicova M, Kettmann R, Pastorek J, Pastorekova S (2004) Induction by hypoxia combined with low glucose or low bicarbonate and high posttranslational stability upon reoxygenation contribute to carbonic anhydrase IX expression in cancer cells. Int J Oncol 24:995–1004PubMedGoogle Scholar
  77. 77.
    Chiche J, Brahimi-Horn MC, Pouyssegur J (2010) Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J Cell Mol Med 14:771–794PubMedGoogle Scholar
  78. 78.
    Brown JM, Wilson WR (2004) Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4:437–447PubMedGoogle Scholar
  79. 79.
    Dewhirst MW, Cao Y, Moeller B (2008) Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 8:425–437PubMedGoogle Scholar
  80. 80.
    Koritzinsky M, Magagnin MG, van den Beucken T, Seigneuric R, Savelkouls K, Dostie J, Pyronnet S, Kaufman RJ, Weppler SA, Voncken JW, Lambin P, Koumenis C, Sonenberg N, Wouters BG (2006) Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. EMBO J 25:1114–1125PubMedGoogle Scholar
  81. 81.
    Brahimi-Horn MC, Chiche J, Pouyssegur J (2007) Hypoxia and cancer. J Mol Med (Berl) 85:1301–1307Google Scholar
  82. 82.
    Brahimi-Horn MC, Chiche J, Pouyssegur J (2007) Hypoxia signalling controls metabolic demand. Curr Opin Cell Biol 19:223–229PubMedGoogle Scholar
  83. 83.
    Brahimi-Horn MC, Pouyssegur J (2007) Oxygen, a source of life and stress. FEBS Lett 581:3582–3591PubMedGoogle Scholar
  84. 84.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70PubMedGoogle Scholar
  85. 85.
    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 164:282–294PubMedGoogle Scholar
  86. 86.
    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 U S A 81:4833–4837PubMedGoogle Scholar
  87. 87.
    Roos A, Boron WF (1981) Intracellular pH. Physiol Rev 61:296–434PubMedGoogle Scholar
  88. 88.
    Neri D, Supuran CT (2011) Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov 10:767–777PubMedGoogle Scholar
  89. 89.
    Parks SK, Chiche J, Pouyssegur J (2011) pH control mechanisms of tumor survival and growth. J Cell Physiol 226:299–308PubMedGoogle Scholar
  90. 90.
    Cardone RA, Casavola V, Reshkin SJ (2005) The role of disturbed pH dynamics and the Na+/H + exchanger in metastasis. Nat Rev Cancer 5:786–795PubMedGoogle Scholar
  91. 91.
    Counillon L, Pouyssegur J (2000) The expanding family of eucaryotic Na(+)/H(+) exchangers. J Biol Chem 275:1–4PubMedGoogle Scholar
  92. 92.
    Ullah MS, Davies AJ, Halestrap AP (2006) The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem 281:9030–9037PubMedGoogle Scholar
  93. 93.
    Karumanchi SA, Jiang L, Knebelmann B, Stuart-Tilley AK, Alper SL, Sukhatme VP (2001) VHL tumor suppressor regulates Cl−/HCO3− exchange and Na+/H + exchange activities in renal carcinoma cells. Physiol Genomics 5:119–128PubMedGoogle Scholar
  94. 94.
    Svastova E, Hulikova A, Rafajova M, Zat'ovicova M, Gibadulinova A, Casini A, Cecchi A, Scozzafava A, Supuran CT, Pastorek J, Pastorekova S (2004) Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett 577:439–445PubMedGoogle Scholar
  95. 95.
    Raghunand N, Gatenby RA, Gillies RJ (2003) Microenvironmental and cellular consequences of altered blood flow in tumours. Br J Radiol 76:S11–S22PubMedGoogle Scholar
  96. 96.
    Li Y, Tu C, Wang H, Silverman DN, Frost SC (2011) Catalysis and pH control by membrane-associated carbonic anhydrase IX in MDA-MB-231 breast cancer cells. J Biol Chem 286:15789–15796PubMedGoogle Scholar
  97. 97.
    Swietach P, Vaughan-Jones RD, Harris AL (2007) Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Rev 26:299–310PubMedGoogle Scholar
  98. 98.
    Pastorekova S, Ratcliffe PJ, Pastorek J (2008) Molecular mechanisms of carbonic anhydrase IX-mediated pH regulation under hypoxia. BJU Int 101(Suppl 4):8–15PubMedGoogle Scholar
  99. 99.
    Wojtkowiak JW, Verduzco D, Schramm KJ, Gillies RJ (2011) Drug resistance and cellular adaptation to tumor acidic pH microenvironment. Mol Pharm 8:2032–2038PubMedGoogle Scholar
  100. 100.
    De Milito A, Canese R, Marino ML, Borghi M, Iero M, Villa A, Venturi G, Lozupone F, Iessi E, Logozzi M, Della Mina P, Santinami M, Rodolfo M, Podo F, Rivoltini L, Fais S (2010) pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int J Cancer 127:207–219PubMedGoogle Scholar
  101. 101.
    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 284:20299–20310PubMedGoogle Scholar
  102. 102.
    Swietach P, Hulikova A, Vaughan-Jones RD, Harris AL (2010) New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation. Oncogene 29:6509–6521PubMedGoogle Scholar
  103. 103.
    Raghunand N, He X, van Sluis R, Mahoney B, Baggett B, Taylor CW, Paine-Murrieta G, Roe D, Bhujwalla ZM, Gillies RJ (1999) Enhancement of chemotherapy by manipulation of tumour pH. Br J Cancer 80:1005–1011PubMedGoogle Scholar
  104. 104.
    Robey IF, Baggett BK, Kirkpatrick ND, Roe DJ, Dosescu J, Sloane BF, Hashim AI, Morse DL, Raghunand N, Gatenby RA, Gillies RJ (2009) Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Res 69:2260–2268PubMedGoogle Scholar
  105. 105.
    Ibrahim-Hashim A, Cornnell HH, Abrahams D, Lloyd M, Bui M, Gillies RJ, Gatenby RA (2012) Systemic buffers inhibit carcinogenesis in TRAMP mice. J Urol 188:624–631PubMedGoogle Scholar
  106. 106.
    Silva AS, Yunes JA, Gillies RJ, Gatenby RA (2009) The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion. Cancer Res 69:2677–2684PubMedGoogle Scholar
  107. 107.
    Gullotti E, Yeo Y (2009) Extracellularly activated nanocarriers: a new paradigm of tumor targeted drug delivery. Mol Pharm 6:1041–1051PubMedGoogle Scholar
  108. 108.
    Rios-Doria J, Carie A, Costich T, Burke B, Skaff H, Panicucci R, Sill K (2012) A versatile polymer micelle drug delivery system for encapsulation and in vivo stabilization of hydrophobic anticancer drugs. J Drug Deliv 2012:951741PubMedGoogle Scholar
  109. 109.
    Swinson DE, Jones JL, Richardson D, Wykoff C, Turley H, Pastorek J, Taub N, Harris AL, O'Byrne KJ (2003) Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer. J Clin Oncol 21:473–482PubMedGoogle Scholar
  110. 110.
    Kim SJ, Rabbani ZN, Dewhirst MW, Vujaskovic Z, Vollmer RT, Schreiber EG, Oosterwijk E, Kelley MJ (2005) Expression of HIF-1alpha, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer. Lung Cancer 49:325–335PubMedGoogle Scholar
  111. 111.
    Ilie M, Mazure NM, Hofman V, Ammadi RE, Ortholan C, Bonnetaud C, Havet K, Venissac N, Mograbi B, Mouroux J, Pouyssegur J, Hofman P (2010) 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 102:1627–1635PubMedGoogle Scholar
  112. 112.
    Saarnio J, Parkkila S, Parkkila AK, Haukipuro K, Pastorekova S, Pastorek J, Kairaluoma MI, Karttunen TJ (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 153:279–285PubMedGoogle Scholar
  113. 113.
    Korkeila E, Talvinen K, Jaakkola PM, Minn H, Syrjanen K, Sundstrom J, Pyrhonen S (2009) Expression of carbonic anhydrase IX suggests poor outcome in rectal cancer. Br J Cancer 100:874–880PubMedGoogle Scholar
  114. 114.
    Niemela AM, Hynninen P, Mecklin JP, Kuopio T, Kokko A, Aaltonen L, Parkkila AK, Pastorekova S, Pastorek J, Waheed A, Sly WS, Orntoft TF, Kruhoffer M, Haapasalo H, Parkkila S, Kivela AJ (2007) Carbonic anhydrase IX is highly expressed in hereditary nonpolyposis colorectal cancer. Cancer Epidemiol Biomarkers Prev 16:1760–1766PubMedGoogle Scholar
  115. 115.
    Chen J, Rocken C, Hoffmann J, Kruger S, Lendeckel U, Rocco A, Pastorekova S, Malfertheiner P, Ebert MP (2005) Expression of carbonic anhydrase 9 at the invasion front of gastric cancers. Gut 54:920–927PubMedGoogle Scholar
  116. 116.
    Juhasz M, Chen J, Lendeckel U, Kellner U, Kasper HU, Tulassay Z, Pastorekova S, Malfertheiner P, Ebert MP (2003) Expression of carbonic anhydrase IX in human pancreatic cancer. Aliment Pharmacol Ther 18:837–846PubMedGoogle Scholar
  117. 117.
    Chia SK, Wykoff CC, Watson PH, Han C, Leek RD, Pastorek J, Gatter KC, Ratcliffe P, Harris AL (2001) Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol 19:3660–3668PubMedGoogle Scholar
  118. 118.
    Trastour C, Benizri E, Ettore F, Ramaioli A, Chamorey E, Pouyssegur J, Berra E (2007) HIF-1alpha and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome. Int J Cancer 120:1451–1458PubMedGoogle Scholar
  119. 119.
    Tan EY, Yan M, Campo L, Han C, Takano E, Turley H, Candiloro I, Pezzella F, Gatter KC, Millar EK, O'Toole SA, McNeil CM, Crea P, Segara D, Sutherland RL, Harris AL, Fox SB (2009) The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy. Br J Cancer 100:405–411PubMedGoogle Scholar
  120. 120.
    Hussain SA, Ganesan R, Reynolds G, Gross L, Stevens A, Pastorek J, Murray PG, Perunovic B, Anwar MS, Billingham L, James ND, Spooner D, Poole CJ, Rea DW, Palmer DH (2007) Hypoxia-regulated carbonic anhydrase IX expression is associated with poor survival in patients with invasive breast cancer. Br J Cancer 96:104–109PubMedGoogle Scholar
  121. 121.
    Neumeister VM, Sullivan CA, Lindner R, Lezon-Geyda K, Li J, Zavada J, Martel M, Glazer PM, Tuck DP, Rimm DL, Harris L (2012) Hypoxia-induced protein CAIX is associated with somatic loss of BRCA1 protein and pathway activity in triple negative breast cancer. Breast Cancer Res Treat 136:67–75PubMedGoogle Scholar
  122. 122.
    Loncaster JA, Harris AL, Davidson SE, Logue JP, Hunter RD, Wycoff CC, Pastorek J, Ratcliffe PJ, Stratford IJ, West CM (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 61:6394–6399PubMedGoogle Scholar
  123. 123.
    Kim JY, Shin HJ, Kim TH, Cho KH, Shin KH, Kim BK, Roh JW, Lee S, Park SY, Hwang YJ, Han IO (2006) Tumor-associated carbonic anhydrases are linked to metastases in primary cervical cancer. J Cancer Res Clin Oncol 132:302–308PubMedGoogle Scholar
  124. 124.
    Lee S, Shin HJ, Han IO, Hong EK, Park SY, Roh JW, Shin KH, Kim TH, Kim JY (2007) Tumor carbonic anhydrase 9 expression is associated with the presence of lymph node metastases in uterine cervical cancer. Cancer Sci 98:329–333PubMedGoogle Scholar
  125. 125.
    Woelber L, Kress K, Kersten JF, Choschzick M, Kilic E, Herwig U, Lindner C, Schwarz J, Jaenicke F, Mahner S, Milde-Langosch K, Mueller V, Ihnen M (2011) Carbonic anhydrase IX in tumor tissue and sera of patients with primary cervical cancer. BMC Cancer 11:12PubMedGoogle Scholar
  126. 126.
    Klatte T, Seligson DB, Rao JY, Yu H, de Martino M, Kawaoka K, Wong SG, Belldegrun AS, Pantuck AJ (2009) Carbonic anhydrase IX in bladder cancer: a diagnostic, prognostic, and therapeutic molecular marker. Cancer 115:1448–1458PubMedGoogle Scholar
  127. 127.
    Choschzick M, Oosterwijk E, Muller V, Woelber L, Simon R, Moch H, Tennstedt P (2011) Overexpression of carbonic anhydrase IX (CAIX) is an independent unfavorable prognostic marker in endometrioid ovarian cancer. Virchows Arch 459:193–200PubMedGoogle Scholar
  128. 128.
    Nordfors K, Haapasalo J, Korja M, Niemela A, Laine J, Parkkila AK, Pastorekova S, Pastorek J, Waheed A, Sly WS, Parkkila S, Haapasalo H (2010) The tumour-associated carbonic anhydrases CA II, CA IX and CA XII in a group of medulloblastomas and supratentorial primitive neuroectodermal tumours: an association of CA IX with poor prognosis. BMC Cancer 10:148PubMedGoogle Scholar
  129. 129.
    Proescholdt MA, Merrill MJ, Stoerr EM, Lohmeier A, Pohl F, Brawanski A (2012) Function of carbonic anhydrase IX in glioblastoma multiforme. Neuro Oncol 14:1357–1366PubMedGoogle Scholar
  130. 130.
    Hoogsteen IJ, Marres HA, Wijffels KI, Rijken PF, Peters JP, van den Hoogen FJ, Oosterwijk E, van der Kogel AJ, Kaanders JH (2005) Colocalization of carbonic anhydrase 9 expression and cell proliferation in human head and neck squamous cell carcinoma. Clin Cancer Res 11:97–106PubMedGoogle Scholar
  131. 131.
    De Schutter H, Landuyt W, Verbeken E, Goethals L, Hermans R, Nuyts S (2005) The prognostic value of the hypoxia markers CA IX and GLUT 1 and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy +/− chemotherapy. BMC Cancer 5:42PubMedGoogle Scholar
  132. 132.
    Koukourakis MI, Bentzen SM, Giatromanolaki A, Wilson GD, Daley FM, Saunders MI, Dische S, Sivridis E, Harris AL (2006) Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck cancer patients recruited in the CHART randomized trial. J Clin Oncol 24:727–735PubMedGoogle Scholar
  133. 133.
    Haapasalo JA, Nordfors KM, Hilvo M, Rantala IJ, Soini Y, Parkkila AK, Pastorekova S, Pastorek J, Parkkila SM, Haapasalo HK (2006) Expression of carbonic anhydrase IX in astrocytic tumors predicts poor prognosis. Clin Cancer Res 12:473–477PubMedGoogle Scholar
  134. 134.
    Eckert AW, Kappler M, Schubert J, Taubert H (2012) Correlation of expression of hypoxia-related proteins with prognosis in oral squamous cell carcinoma patients. Oral Maxillofac Surg 16:189–196PubMedGoogle Scholar
  135. 135.
    Eckert AW, Lautner MH, Schutze A, Bolte K, Bache M, Kappler M, Schubert J, Taubert H, Bilkenroth U (2010) Co-expression of Hif1alpha and CAIX is associated with poor prognosis in oral squamous cell carcinoma patients. J Oral Pathol Med 39:313–317PubMedGoogle Scholar
  136. 136.
    Choi SW, Kim JY, Park JY, Cha IH, Kim J, Lee S (2008) Expression of carbonic anhydrase IX is associated with postoperative recurrence and poor prognosis in surgically treated oral squamous cell carcinoma. Hum Pathol 39:1317–1322PubMedGoogle Scholar
  137. 137.
    Pouyssegur J, Dayan F, Mazure NM (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441:437–443PubMedGoogle Scholar
  138. 138.
    Liao SY, Aurelio ON, Jan K, Zavada J, Stanbridge EJ (1997) Identification of the MN/CA9 protein as a reliable diagnostic biomarker of clear cell carcinoma of the kidney. Cancer Res 57:2827–2831PubMedGoogle Scholar
  139. 139.
    Muriel Lopez C, Esteban E, Berros JP, Pardo P, Astudillo A, Izquierdo M, Crespo G, Sanmamed M, Fonseca PJ, Martinez-Camblor P (2012) Prognostic factors in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 10:262–270PubMedGoogle Scholar
  140. 140.
    Jiang YD, Ren F, Zheng SB (2012) Value of MN/CAIX in the diagnosis of renal cell carcinoma. Nan Fang Yi Ke Da Xue Xue Bao 32:412–414PubMedGoogle Scholar
  141. 141.
    Lou Y, McDonald PC, Oloumi A, Chia S, Ostlund C, Ahmadi A, Kyle A, Auf dem Keller U, Leung S, Huntsman D, Clarke B, Sutherland BW, Waterhouse D, Bally M, Roskelley C, Overall CM, Minchinton A, Pacchiano F, Carta F, Scozzafava A, Touisni N, Winum JY, Supuran CT, Dedhar S (2011) Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res 71:3364–3376PubMedGoogle Scholar
  142. 142.
    Choueiri TK, Regan MM, Rosenberg JE, Oh WK, Clement J, Amato AM, McDermott D, Cho DC, Atkins MB, Signoretti S (2010) Carbonic anhydrase IX and pathological features as predictors of outcome in patients with metastatic clear-cell renal cell carcinoma receiving vascular endothelial growth factor-targeted therapy. BJU Int 106:772–778PubMedGoogle Scholar
  143. 143.
    Zhou GX, Ireland J, Rayman P, Finke J, Zhou M (2010) Quantification of carbonic anhydrase IX expression in serum and tissue of renal cell carcinoma patients using enzyme-linked immunosorbent assay: prognostic and diagnostic potentials. Urology 75:257–261PubMedGoogle Scholar
  144. 144.
    Eriksen JG, Overgaard J (2007) Lack of prognostic and predictive value of CA IX in radiotherapy of squamous cell carcinoma of the head and neck with known modifiable hypoxia: an evaluation of the DAHANCA 5 study. Radiother Oncol 83:383–388PubMedGoogle Scholar
  145. 145.
    Liao ND, Lee WY (2012) Detection of carbonic anhydrase IX protein in the diagnosis of malignant pleural effusion by enzyme-linked immunosorbent assay and immunocytochemistry. Cancer Cytopathol 120:269–275PubMedGoogle Scholar
  146. 146.
    Garcia S, Dales JP, Charafe-Jauffret E, Carpentier-Meunier S, Andrac-Meyer L, Jacquemier J, Andonian C, Lavaut MN, Allasia C, Bonnier P, Charpin C (2007) Poor prognosis in breast carcinomas correlates with increased expression of targetable CD146 and c-Met and with proteomic basal-like phenotype. Hum Pathol 38:830–841PubMedGoogle Scholar
  147. 147.
    Liao SY, Darcy KM, Randall LM, Tian C, Monk BJ, Burger RA, Fruehauf JP, Peters WA, Stock RJ, Stanbridge EJ (2010) Prognostic relevance of carbonic anhydrase-IX in high-risk, early-stage cervical cancer: a Gynecologic Oncology Group study. Gynecol Oncol 116:452–458PubMedGoogle Scholar
  148. 148.
    Brockton NT, Klimowicz AC, Bose P, Petrillo SK, Konno M, Rudmik L, Dean M, Nakoneshny SC, Matthews TW, Chandarana S, Lau HY, Magliocco AM, Dort JC (2012) High stromal carbonic anhydrase IX expression is associated with nodal metastasis and decreased survival in patients with surgically-treated oral cavity squamous cell carcinoma. Oral Oncol 48:615–622PubMedGoogle Scholar
  149. 149.
    Atkins M, Regan M, McDermott D, Mier J, Stanbridge E, Youmans A, Febbo P, Upton M, Lechpammer M, Signoretti S (2005) Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 11:3714–3721PubMedGoogle Scholar
  150. 150.
    Generali D, Berruti A, Brizzi MP, Campo L, Bonardi S, Wigfield S, Bersiga A, Allevi G, Milani M, Aguggini S, Gandolfi V, Dogliotti L, Bottini A, Harris AL, Fox SB (2006) Hypoxia-inducible factor-1alpha expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer. Clin Cancer Res 12:4562–4568PubMedGoogle Scholar
  151. 151.
    Goonewardene TI, Sowter HM, Harris AL (2002) Hypoxia-induced pathways in breast cancer. Microsc Res Tech 59:41–48PubMedGoogle Scholar
  152. 152.
    Tafreshi NK, Bui MM, Bishop K, Lloyd MC, Enkemann SA, Lopez AS, Abrahams D, Carter BW, Vagner J, Grobmyer SR, Gillies RJ, Morse DL (2012) Noninvasive detection of breast cancer lymph node metastasis using carbonic anhydrases IX and XII targeted imaging probes. Clin Cancer Res 18:207–219PubMedGoogle Scholar
  153. 153.
    Zavada J, Zavadova Z, Zat'ovicova M, Hyrsl L, Kawaciuk I (2003) Soluble form of carbonic anhydrase IX (CA IX) in the serum and urine of renal carcinoma patients. Br J Cancer 89:1067–1071PubMedGoogle Scholar
  154. 154.
    Li G, Feng G, Gentil-Perret A, Genin C, Tostain J (2008) Serum carbonic anhydrase 9 level is associated with postoperative recurrence of conventional renal cell cancer. J Urol 180:510–513PubMedGoogle Scholar
  155. 155.
    Murakami Y, Kanda K, Tsuji M, Kanayama H, Kagawa S (1999) MN/CA9 gene expression as a potential biomarker in renal cell carcinoma. BJU Int 83:743–747PubMedGoogle Scholar
  156. 156.
    Hyrsl L, Zavada J, Zavadova Z, Kawaciuk I, Vesely S, Skapa P (2009) Soluble form of carbonic anhydrase IX (CAIX) in transitional cell carcinoma of urinary tract. Neoplasma 56:298–302PubMedGoogle Scholar
  157. 157.
    Kock L, Mahner S, Choschzick M, Eulenburg C, Milde-Langosch K, Schwarz J, Jaenicke F, Muller V, Woelber L (2011) Serum carbonic anhydrase IX and its prognostic relevance in vulvar cancer. Int J Gynecol Cancer 21:141–148PubMedGoogle Scholar
  158. 158.
    Muller V, Riethdorf S, Rack B, Janni W, Fasching PA, Solomayer E, Aktas B, Kasimir-Bauer S, Zeitz J, Pantel K, Fehm T (2011) Prospective evaluation of serum tissue inhibitor of metalloproteinase 1 and carbonic anhydrase IX in correlation to circulating tumor cells in patients with metastatic breast cancer. Breast Cancer Res 13:R71PubMedGoogle Scholar
  159. 159.
    Woelber L, Mueller V, Eulenburg C, Schwarz J, Carney W, Jaenicke F, Milde-Langosch K, Mahner S (2010) Serum carbonic anhydrase IX during first-line therapy of ovarian cancer. Gynecol Oncol 117:183–188PubMedGoogle Scholar
  160. 160.
    Bertout JA, Patel SA, Simon MC (2008) The impact of O2 availability on human cancer. Nat Rev Cancer 8:967–975PubMedGoogle Scholar
  161. 161.
    Scheurer SB, Rybak JN, Rosli C, Neri D, Elia G (2004) Modulation of gene expression by hypoxia in human umbilical cord vein endothelial cells: a transcriptomic and proteomic study. Proteomics 4:1737–1760PubMedGoogle Scholar
  162. 162.
    Steffens MG, Boerman OC, Oosterwijk-Wakka JC, Oosterhof GO, Witjes JA, Koenders EB, Oyen WJ, Buijs WC, Debruyne FM, Corstens FH, Oosterwijk E (1997) Targeting of renal cell carcinoma with iodine-131-labeled chimeric monoclonal antibody G250. J Clin Oncol 15:1529–1537PubMedGoogle Scholar
  163. 163.
    Stillebroer AB, Oosterwijk E, Oyen WJ, Mulders PF, Boerman OC (2007) Radiolabeled antibodies in renal cell carcinoma. Cancer Imaging 7:179–188PubMedGoogle Scholar
  164. 164.
    Divgi CR, Pandit-Taskar N, Jungbluth AA, Reuter VE, Gonen M, Ruan S, Pierre C, Nagel A, Pryma DA, Humm J, Larson SM, Old LJ, Russo P (2007) Preoperative characterisation of clear-cell renal carcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses: a phase I trial. Lancet Oncol 8:304–310PubMedGoogle Scholar
  165. 165.
    Reichert JM (2011) Next generation and biosimilar monoclonal antibodies: essential considerations towards regulatory acceptance in Europe. February 3–4, 2011, Freiburg, Germany. MAbs 3:223–240PubMedGoogle Scholar
  166. 166.
    Li Y, Wang H, Oosterwijk E, Selman Y, Mira JC, Medrano T, Shiverick KT, Frost SC (2009) Antibody-specific detection of CAIX in breast and prostate cancers. Biochem Biophys Res Commun 386:488–492PubMedGoogle Scholar
  167. 167.
    Chrastina A, Zavada J, Parkkila S, Kaluz S, Kaluzova M, Rajcani J, Pastorek J, Pastorekova S (2003) Biodistribution and pharmacokinetics of 125I-labeled monoclonal antibody M75 specific for carbonic anhydrase IX, an intrinsic marker of hypoxia, in nude mice xenografted with human colorectal carcinoma. Int J Cancer 105:873–881PubMedGoogle Scholar
  168. 168.
    Chrastina A, Pastorekova S, Pastorek J (2003) Immunotargeting of human cervical carcinoma xenograft expressing CA IX tumor-associated antigen by 125I-labeled M75 monoclonal antibody. Neoplasma 50:13–21PubMedGoogle Scholar
  169. 169.
    Ahlskog JK, Schliemann C, Marlind J, Qureshi U, Ammar A, Pedley RB, Neri D (2009) Human monoclonal antibodies targeting carbonic anhydrase IX for the molecular imaging of hypoxic regions in solid tumours. Br J Cancer 101:645–657PubMedGoogle Scholar
  170. 170.
    Vullo D, Franchi M, Gallori E, Pastorek J, Scozzafava A, Pastorekova S, Supuran CT (2003) Carbonic anhydrase inhibitors. inhibition of cytosolic isozymes I and II and transmembrane, cancer-associated isozyme IX with anions. J Enzyme Inhib Med Chem 18:403–406PubMedGoogle Scholar
  171. 171.
    Innocenti A, Vullo D, Scozzafava A, Supuran CT (2008) Carbonic anhydrase inhibitors: interactions of phenols with the 12 catalytically active mammalian isoforms (CA I-XIV). Bioorg Med Chem Lett 18:1583–1587PubMedGoogle Scholar
  172. 172.
    Maresca A, Temperini C, Vu H, Pham NB, Poulsen SA, Scozzafava A, Quinn RJ, Supuran CT (2009) Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors. J Am Chem Soc 131:3057–3062PubMedGoogle Scholar
  173. 173.
    Pastorekova S, Casini A, Scozzafava A, Vullo D, Pastorek J, Supuran CT (2004) Carbonic anhydrase inhibitors: the first selective, membrane-impermeant inhibitors targeting the tumor-associated isozyme IX. Bioorg Med Chem Lett 14:869–873PubMedGoogle Scholar
  174. 174.
    Casey JR, Morgan PE, Vullo D, Scozzafava A, Mastrolorenzo A, Supuran CT (2004) Carbonic anhydrase inhibitors. Design of selective, membrane-impermeant inhibitors targeting the human tumor-associated isozyme IX. J Med Chem 47:2337–2347PubMedGoogle Scholar
  175. 175.
    Winum JY, Pastorekova S, Jakubickova L, Montero JL, Scozzafava A, Pastorek J, Vullo D, Innocenti A, Supuran CT (2005) Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with bis-sulfamates. Bioorg Med Chem Lett 15:579–584PubMedGoogle Scholar
  176. 176.
    Pacchiano F, Carta F, McDonald PC, Lou Y, Vullo D, Scozzafava A, Dedhar S, Supuran CT (2011) Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J Med Chem 54:1896–1902PubMedGoogle Scholar
  177. 177.
    Dubois L, Lieuwes NG, Maresca A, Thiry A, Supuran CT, Scozzafava A, Wouters BG, Lambin P (2009) Imaging of CA IX with fluorescent labelled sulfonamides distinguishes hypoxic and (re)-oxygenated cells in a xenograft tumour model. Radiother Oncol 92:423–428PubMedGoogle Scholar
  178. 178.
    Cecchi A, Hulikova A, Pastorek J, Pastorekova S, Scozzafava A, Winum JY, Montero JL, Supuran CT (2005) Carbonic anhydrase inhibitors. Design of fluorescent sulfonamides as probes of tumor-associated carbonic anhydrase IX that inhibit isozyme IX-mediated acidification of hypoxic tumors. J Med Chem 48:4834–4841PubMedGoogle Scholar
  179. 179.
    Dubois L, Douma K, Supuran CT, Chiu RK, van Zandvoort MA, Pastorekova S, Scozzafava A, Wouters BG, Lambin P (2007) Imaging the hypoxia surrogate marker CA IX requires expression and catalytic activity for binding fluorescent sulfonamide inhibitors. Radiother Oncol 83:367–373PubMedGoogle Scholar
  180. 180.
    Thiry A, Supuran CT, Masereel B, Dogne JM (2008) Recent developments of carbonic anhydrase inhibitors as potential anticancer drugs. J Med Chem 51:3051–3056PubMedGoogle Scholar
  181. 181.
    Winum JY, Rami M, Scozzafava A, Montero JL, Supuran C (2008) Carbonic anhydrase IX: a new druggable target for the design of antitumor agents. Med Res Rev 28:445–463PubMedGoogle Scholar
  182. 182.
    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 19:4851–4856PubMedGoogle Scholar
  183. 183.
    Helmlinger G, Sckell A, Dellian M, Forbes NS, Jain RK (2002) Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism. Clin Cancer Res 8:1284–1291PubMedGoogle Scholar
  184. 184.
    Groves K, Bao B, Zhang J, Handy E, Kennedy P, Cuneo G, Supuran CT, Yared W, Peterson JD, Rajopadhye M (2012) Synthesis and evaluation of near-infrared fluorescent sulfonamide derivatives for imaging of hypoxia-induced carbonic anhydrase IX expression in tumors. Bioorg Med Chem Lett 22:653–657PubMedGoogle Scholar
  185. 185.
    Akurathi V, Dubois L, Lieuwes NG, Chitneni SK, Cleynhens BJ, Vullo D, Supuran CT, Verbruggen AM, Lambin P, Bormans GM (2010) Synthesis and biological evaluation of a 99mTc-labelled sulfonamide conjugate for in vivo visualization of carbonic anhydrase IX expression in tumor hypoxia. Nucl Med Biol 37:557–564PubMedGoogle Scholar
  186. 186.
    Surfus JE, Hank JA, Oosterwijk E, Welt S, Lindstrom MJ, Albertini MR, Schiller JH, Sondel PM (1996) Anti-renal-cell carcinoma chimeric antibody G250 facilitates antibody-dependent cellular cytotoxicity with in vitro and in vivo interleukin-2-activated effectors. J Immunother Emphasis Tumor Immunol 19:184–191PubMedGoogle Scholar
  187. 187.
    Siebels M, Rohrmann K, Oberneder R, Stahler M, Haseke N, Beck J, Hofmann R, Kindler M, Kloepfer P, Stief C (2011) A clinical phase I/II trial with the monoclonal antibody cG250 (RENCAREX(R)) and interferon-alpha-2a in metastatic renal cell carcinoma patients. World J Urol 29:121–126PubMedGoogle Scholar
  188. 188.
    Davis ID, Wiseman GA, Lee FT, Gansen DN, Hopkins W, Papenfuss AT, Liu Z, Moynihan TJ, Croghan GA, Adjei AA, Hoffman EW, Ingle JN, Old LJ, Scott AM (2007) A phase I multiple dose, dose escalation study of cG250 monoclonal antibody in patients with advanced renal cell carcinoma. Cancer Immun 7:13PubMedGoogle Scholar
  189. 189.
    Zatovicova M, Jelenska L, Hulikova A, Csaderova L, Ditte Z, Ditte P, Goliasova T, Pastorek J, Pastorekova S (2010) Carbonic anhydrase IX as an anticancer therapy target: preclinical evaluation of internalizing monoclonal antibody directed to catalytic domain. Curr Pharm Des 16:3255–3263PubMedGoogle Scholar
  190. 190.
    Murri-Plesko MT, Hulikova A, Oosterwijk E, Scott AM, Zortea A, Harris AL, Ritter G, Old L, Bauer S, Swietach P, Renner C (2011) Antibody inhibiting enzymatic activity of tumour-associated carbonic anhydrase isoform IX. Eur J Pharmacol 657:173–183PubMedGoogle Scholar
  191. 191.
    Brouwers AH, van Eerd JE, Frielink C, Oosterwijk E, Oyen WJ, Corstens FH, Boerman OC (2004) Optimization of radioimmunotherapy of renal cell carcinoma: labeling of monoclonal antibody cG250 with 131I, 90Y, 177Lu, or 186Re. J Nucl Med 45:327–337PubMedGoogle Scholar
  192. 192.
    Stillebroer AB, Zegers CM, Boerman OC, Oosterwijk E, Mulders PF, O'Donoghue JA, Visser EP, Oyen WJ (2012) Dosimetric analysis of 177Lu-cG250 radioimmunotherapy in renal cell carcinoma patients: correlation with myelotoxicity and pretherapeutic absorbed dose predictions based on 111In-cG250 imaging. J Nucl Med 53:82–89PubMedGoogle Scholar
  193. 193.
    Petrul HM, Schatz CA, Kopitz CC, Adnane L, McCabe TJ, Trail P, Ha S, Chang YS, Voznesensky A, Ranges G, Tamburini PP (2012) Therapeutic mechanism and efficacy of the antibody-drug conjugate BAY 79–4620 targeting human carbonic anhydrase 9. Mol Cancer Ther 11:340–349PubMedGoogle Scholar
  194. 194.
    Lamers CH, Sleijfer S, Vulto AG, Kruit WH, Kliffen M, Debets R, Gratama JW, Stoter G, Oosterwijk E (2006) Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol 24:e20–e22PubMedGoogle Scholar
  195. 195.
    Dittrich C, Zandvliet AS, Gneist M, Huitema AD, King AA, Wanders J (2007) A phase I and pharmacokinetic study of indisulam in combination with carboplatin. Br J Cancer 96:559–566PubMedGoogle Scholar
  196. 196.
    Buller F, Steiner M, Frey K, Mircsof D, Scheuermann J, Kalisch M, Buhlmann P, Supuran CT, Neri D (2011) Selection of carbonic anhydrase IX Inhibitors from one million DNA-encoded compounds. ACS Chem Biol 6:336–344PubMedGoogle Scholar
  197. 197.
    Stiti M, Cecchi A, Rami M, Abdaoui M, Barragan-Montero V, Scozzafava A, Guari Y, Winum JY, Supuran CT (2008) Carbonic anhydrase inhibitor coated gold nanoparticles selectively inhibit the tumor-associated isoform IX over the cytosolic isozymes I and II. J Am Chem Soc 130:16130–16131PubMedGoogle Scholar
  198. 198.
    Tureci O, Sahin U, Vollmar E, Siemer S, Gottert E, Seitz G, Parkkila AK, Shah GN, Grubb JH, Pfreundschuh M, Sly WS (1998) Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is overexpressed in some renal cell cancers. Proc Natl Acad Sci U S A 95:7608–7613PubMedGoogle Scholar
  199. 199.
    Kivela A, Parkkila S, Saarnio J, Karttunen TJ, Kivela J, Parkkila AK, Waheed A, Sly WS, Grubb JH, Shah G, Tureci O, Rajaniemi H (2000) Expression of a novel transmembrane carbonic anhydrase isozyme XII in normal human gut and colorectal tumors. Am J Pathol 156:577–584PubMedGoogle Scholar
  200. 200.
    Parkkila S, Parkkila AK, Saarnio J, Kivela J, Karttunen TJ, Kaunisto K, Waheed A, Sly WS, Tureci O, Virtanen I, Rajaniemi H (2000) Expression of the membrane-associated carbonic anhydrase isozyme XII in the human kidney and renal tumors. J Histochem Cytochem 48:1601–1608PubMedGoogle Scholar
  201. 201.
    Kivela AJ, Parkkila S, Saarnio J, Karttunen TJ, Kivela J, Parkkila AK, Pastorekova S, Pastorek J, Waheed A, Sly WS, Rajaniemi H (2000) Expression of transmembrane carbonic anhydrase isoenzymes IX and XII in normal human pancreas and pancreatic tumours. Histochem Cell Biol 114:197–204PubMedGoogle Scholar
  202. 202.
    Kivela AJ, Parkkila S, Saarnio J, Karttunen TJ, Kivela J, Parkkila AK, Bartosova M, Mucha V, Novak M, Waheed A, Sly WS, Rajaniemi H, Pastorekova S, Pastorek J (2005) Expression of von Hippel-Lindau tumor suppressor and tumor-associated carbonic anhydrases IX and XII in normal and neoplastic colorectal mucosa. World J Gastroenterol 11:2616–2625PubMedGoogle Scholar
  203. 203.
    Brennan DJ, Jirstrom K, Kronblad A, Millikan RC, Landberg G, Duffy MJ, Ryden L, Gallagher WM, O'Brien SL (2006) CA IX is an independent prognostic marker in premenopausal breast cancer patients with one to three positive lymph nodes and a putative marker of radiation resistance. Clin Cancer Res 12:6421–6431PubMedGoogle Scholar
  204. 204.
    Span PN, Bussink J, Manders P, Beex LV, Sweep CG (2003) Carbonic anhydrase-9 expression levels and prognosis in human breast cancer: association with treatment outcome. Br J Cancer 89:271–276PubMedGoogle Scholar
  205. 205.
    Watson PH, Chia SK, Wykoff CC, Han C, Leek RD, Sly WS, Gatter KC, Ratcliffe P, Harris AL (2003) Carbonic anhydrase XII is a marker of good prognosis in invasive breast carcinoma. Br J Cancer 88:1065–1070PubMedGoogle Scholar
  206. 206.
    Marr A, Markert A, Altmann A, Askoxylakis V, Haberkorn U (2011) Biotechnology techniques for the development of new tumor specific peptides. Methods 55:215–222PubMedGoogle Scholar
  207. 207.
    Askoxylakis V, Garcia-Boy R, Rana S, Kramer S, Hebling U, Mier W, Altmann A, Markert A, Debus J, Haberkorn U (2010) A new peptide ligand for targeting human carbonic anhydrase IX, identified through the phage display technology. PLoS One 5:e15962PubMedGoogle Scholar
  208. 208.
    Rana S, Nissen F, Marr A, Markert A, Altmann A, Mier W, Debus J, Haberkorn U, Askoxylakis V (2012) Optimization of a novel peptide ligand targeting human carbonic anhydrase IX. PLoS One 7:e38279PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Narges K. Tafreshi
    • 1
  • Mark C. Lloyd
    • 2
  • Marilyn M. Bui
    • 3
  • Robert J. Gillies
    • 1
  • David L. Morse
    • 1
  1. 1.Department of Cancer Imaging and MetabolismH. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  2. 2.Analytical Microscopy Core FacilityH. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  3. 3.Analytical Microscopy Core Facility and Department of Anatomic PathologyH. Lee Moffitt Cancer Center and Research InstituteTampaUSA

Personalised recommendations