Annals of Surgical Oncology

, 18:3330 | Cite as

Carbonic Anhydrase IX Overexpression is Associated with Diminished Prognosis in Esophageal Cancer and Correlates with Her-2 Expression

  • Peter Birner
  • Bettina Jesch
  • Julia Friedrich
  • Martin Riegler
  • Johannes Zacherl
  • Michael Hejna
  • Fritz Wrba
  • Andrea Schultheis
  • Sebastian F. Schoppmann
Gastrointestinal Oncology



Carbonic anhydrase IX (CAIX), a transmembrane glycoprotein, seems to play a key role in the adaption of tumor cells to hypoxia. This study was designed to investigate the clinical role of CAIX and its association with Her-2 in a large cohort of adeno- (AC) and squamous cell carcinomas (SCC) of the esophagus and their metastases.


Expression of CAIX and Her-2 was investigated immunohistochemically in formalin fixed, paraffin-embedded tissue from 330 esophageal cancers (182 ACS, 148 SCCs). Corresponding lymph node metastases in 137 cases, distant metastases in 34 cases, and local recurrences in 14 cases were analyzed for CAIX expression.


A total of 147 cases (44.5%) showed strong CAIX expression (AC: 46.7%; ACC: 41.9%). CAIX status of the primary tumor influenced CAIX expression in corresponding lymph node metastases (P < 0.001, linear regression). High CAIX-expression was an independent prognostic factor for shorter overall and disease-free survival (P ≤ 0.05, Cox regression). Twenty-nine ACs (15.9%) and 6 SCCs (4.1%) showed Her-2 overexpression. In AC, a significant positive correlation between the Her-2 status and CAIX expression was found (P = 0.009, chi-square test).


High CAIX expression is associated with shorter survival in esophageal cancer, and the hypoxic phenotype seems to be preserved at least during formation of lymph node metastases. Inhibition of CAIX might reduce the ability of tumor cells to establish disseminated disease. In Her-2 overexpressing ACs, blocking of this tyrosine kinase, e.g., by monoclonal antibodies, might induce this effect.


Squamous Cell Carcinoma Esophageal Cancer Correspond Lymph Node CAIX Expression Local Lymph Node Metastasis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Ku GY, Ilson DH. Esophagogastric cancer: targeted agents. Cancer Treat Rev. 2010;36:235–48.PubMedCrossRefGoogle Scholar
  2. 2.
    Blancher C, Harris AL. The molecular basis of the hypoxia response pathway: tumour hypoxia as a therapy target. Cancer Metastasis Rev. 1998;17:187–94.PubMedCrossRefGoogle Scholar
  3. 3.
    Alterio V, Hilvo M, Di Fiore A, et al. Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX. Proc Natl Acad Sci U S A. 2009;106:16233–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Opavsky R, Pastorekova S, Zelnik V, et al. Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships. Genomics. 1996;33:480–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov. 2008;7:168–81.PubMedCrossRefGoogle Scholar
  6. 6.
    Paul SA, Simons JW, Mabjeesh NJ. HIF at the crossroads between ischemia and carcinogenesis. J Cell Physiol. 2004;200:20–30.PubMedCrossRefGoogle Scholar
  7. 7.
    McKiernan JM, Buttyan R, Bander NH, et al. Expression of the tumor-associated gene MN: a potential biomarker for human renal cell carcinoma. Cancer Res. 1997;57:2362–5.PubMedGoogle Scholar
  8. 8.
    Vermylen P, Roufosse C, Burny A, et al. Carbonic anhydrase IX antigen differentiates between preneoplastic malignant lesions in non-small cell lung carcinoma. Eur Respir J. 1999;14:806–11.PubMedCrossRefGoogle Scholar
  9. 9.
    Liao SY, Brewer C, Zavada J, et al. Identification of the MN antigen as a diagnostic biomarker of cervical intraepithelial squamous and glandular neoplasia and cervical carcinomas. Am J Pathol. 1994;145:598–609.PubMedGoogle Scholar
  10. 10.
    Pastorek J, Pastorekova S, Callebaut I, et al. 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. 1994;9:2877–88.PubMedGoogle Scholar
  11. 11.
    Lurje G, Lenz HJ. EGFR signaling and drug discovery. Oncology. 2009;77:400–10.PubMedCrossRefGoogle Scholar
  12. 12.
    Dragowska WH, Warburton C, Yapp DT, et al. HER-2/neu overexpression increases the viable hypoxic cell population within solid tumors without causing changes in tumor vascularization. Mol Cancer Res. 2004;2:606–19.PubMedGoogle Scholar
  13. 13.
    Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 2001;21:3995–4004.PubMedCrossRefGoogle Scholar
  14. 14.
    Li YM, Zhou BP, Deng J, Pan Y, Hay N, Hung MC. A hypoxia-independent hypoxia-inducible factor-1 activation pathway induced by phosphatidylinositol-3 kinase/Akt in HER2 overexpressing cells. Cancer Res. 2005;65:3257–63.PubMedGoogle Scholar
  15. 15.
    Hardee ME, Dewhirst MW, Agarwal N, Sorg BS. Novel imaging provides new insights into mechanisms of oxygen transport in tumors. Curr Mol Med. 2009;9:435–41.PubMedCrossRefGoogle Scholar
  16. 16.
    Hardee ME, Eapen RJ, Rabbani ZN, Dreher MR, Marks J, Blackwell KL, Dewhirst MW. Her2/neu signaling blockade improves tumor oxygenation in a multifactorial fashion in Her2/neu+ tumors. Cancer Chemother Pharmacol. 2009;63:219–28.PubMedCrossRefGoogle Scholar
  17. 17.
    Tanaka N, Kato H, Inose T, et al. Expression of carbonic anhydrase 9, a potential intrinsic marker of hypoxia, is associated with poor prognosis in oesophageal squamous cell carcinoma. Br J Cancer. 2008;99:1468–75.PubMedCrossRefGoogle Scholar
  18. 18.
    Driessen A, Landuyt W, Pastorekova S, et al. Expression of carbonic anhydrase IX (CA IX), a hypoxia-related protein, rather than vascular-endothelial growth factor (VEGF), a pro-angiogenic factor, correlates with an extremely poor prognosis in esophageal and gastric adenocarcinomas. Ann Surg. 2006;243:334–40.PubMedCrossRefGoogle Scholar
  19. 19.
    Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52:797–805.PubMedCrossRefGoogle Scholar
  20. 20.
    Olive PL, Aquino-Parsons C, MacPhail SH, Liao SY, Raleigh JA, Lerman MI, Stanbridge EJ. Carbonic anhydrase 9 as an endogenous marker for hypoxic cells in cervical cancer. Cancer Res. 2001;61:8924–9.PubMedGoogle Scholar
  21. 21.
    Wykoff CC, Beasley NJ, Watson PH, et al. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 2000;60:7075–83.PubMedGoogle Scholar
  22. 22.
    Kato Y, Yashiro M, Noda S, et al. Expression of a hypoxia-associated protein, carbonic anhydrase-9, correlates with malignant phenotypes of gastric carcinoma. Digestion. 82:246–51.Google Scholar
  23. 23.
    Hutchison GJ, Valentine HR, Loncaster JA, et al. Hypoxia-inducible factor 1alpha expression as an intrinsic marker of hypoxia: correlation with tumor oxygen, pimonidazole measurements, and outcome in locally advanced carcinoma of the cervix. Clin Cancer Res. 2004;10:8405–12.PubMedCrossRefGoogle Scholar
  24. 24.
    Nordsmark M, Eriksen JG, Gebski V, Alsner J, Horsman MR, Overgaard J. Differential risk assessments from five hypoxia specific assays: The basis for biologically adapted individualized radiotherapy in advanced head and neck cancer patients. Radiother Oncol. 2007;83:389–97.PubMedCrossRefGoogle Scholar
  25. 25.
    Korkolopoulou P, Patsouris E, Konstantinidou AE, et al. Hypoxia-inducible factor 1alpha/vascular endothelial growth factor axis in astrocytomas. Associations with microvessel morphometry, proliferation and prognosis. Neuropathol Appl Neurobiol. 2004;30:267–78.Google Scholar
  26. 26.
    Winter SC, Shah KA, Han C, et al. The relation between hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression with anemia and outcome in surgically treated head and neck cancer. Cancer. 2006;107:757–66.PubMedCrossRefGoogle Scholar
  27. 27.
    Kappler M, Taubert H, Holzhausen HJ, et al. Immunohistochemical detection of HIF-1alpha and CAIX in advanced head-and-neck cancer. Prognostic role and correlation with tumor markers and tumor oxygenation parameters. Strahlenther Onkol. 2008;184:393–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Jewell UR, Kvietikova I, Scheid A, Bauer C, Wenger RH, Gassmann M. Induction of HIF-1alpha in response to hypoxia is instantaneous. FASEB J. 2001;15:1312–4.PubMedGoogle Scholar
  29. 29.
    Vordermark D, Brown JM. Endogenous markers of tumor hypoxia predictors of clinical radiation resistance? Strahlenther Onkol. 2003;179:801–11.PubMedCrossRefGoogle Scholar
  30. 30.
    Mayer A, Hockel M, Vaupel P. Endogenous hypoxia markers: case not proven! Adv Exp Med Biol. 2008;614:127–36.PubMedCrossRefGoogle Scholar
  31. 31.
    Giatromanolaki A, Koukourakis MI, Sivridis E, Pastorek J, Wykoff CC, Gatter KC, Harris AL. Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. Cancer Res. 2001;61:7992–8.PubMedGoogle Scholar
  32. 32.
    Bartosova M, Parkkila S, Pohlodek K, et al. Expression of carbonic anhydrase IX in breast is associated with malignant tissues and is related to overexpression of c-erbB2. J Pathol. 2002;197:314–21.PubMedCrossRefGoogle Scholar
  33. 33.
    Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, Kerbel RS. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol. 1997;151:1523–30.PubMedGoogle Scholar
  34. 34.
    Pastorekova S, Parkkila S, Parkkila AK, Opavsky R, Zelnik V, Saarnio J, Pastorek J. Carbonic anhydrase IX, MN/CA IX: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts. Gastroenterology. 1997;112:398–408.PubMedCrossRefGoogle Scholar
  35. 35.
    Rajaganeshan R, Prasad R, Guillou PJ, Scott N, Poston G, Jayne DG. Expression patterns of hypoxic markers at the invasive margin of colorectal cancers and liver metastases. Eur J Surg Oncol. 2009;35:1286–94.PubMedCrossRefGoogle Scholar
  36. 36.
    Hill R, Wu H. PTEN, stem cells, and cancer stem cells. J Biol Chem. 2009;284:11755–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Ebbesen P, Pettersen EO, Gorr TA, et al. Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies. J Enzyme Inhib Med Chem. 2009;24(Suppl 1):1–39.PubMedCrossRefGoogle Scholar
  38. 38.
    Cianchi F, Vinci MC, Supuran CT, et al. Selective inhibition of carbonic anhydrase IX decreases cell proliferation and induces ceramide-mediated apoptosis in human cancer cells. J Pharmacol Exp Ther. 2010;334:710–9.PubMedCrossRefGoogle Scholar
  39. 39.
    De Simone G, Supuran CT. Carbonic anhydrase IX: biochemical and crystallographic characterization of a novel antitumor target. Biochim Biophys Acta. 2010;1804:404–9.PubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2011

Authors and Affiliations

  • Peter Birner
    • 1
  • Bettina Jesch
    • 2
  • Julia Friedrich
    • 1
  • Martin Riegler
    • 2
  • Johannes Zacherl
    • 2
  • Michael Hejna
    • 3
  • Fritz Wrba
    • 1
  • Andrea Schultheis
    • 4
  • Sebastian F. Schoppmann
    • 2
    • 5
  1. 1.Institute of PathologyMedical University of ViennaViennaAustria
  2. 2.Department of SurgeryUniversity of ViennaViennaAustria
  3. 3.Department of OncologyMedical University of ViennaViennaAustria
  4. 4.Department of PathologyKaiserin-Elisabeth SpitalViennaAustria
  5. 5.Department of Surgery, Comprehensive Cancer Center ViennaUniversity of ViennaViennaAustria

Personalised recommendations