Skip to main content
SpringerLink
Log in

Influence of hypoxia-dependent factors on the progression of neuroblastoma

  • Original Article
  • Published:
Pediatric Surgery International Aims and scope Submit manuscript

Abstract

Purpose

Several oxygen-dependent factors, e.g., CAIX (carbonic anhydrase IX) or phosphoglycerate kinase 1 (PGK1) interacting with the CXCR4/SDF1 axis (chemokine receptor 4/stromal cell derived factor 1) have been shown to be involved in processes of tumour pathology including tumourigenicity, tumour cell dissemination and poor survival in several solid tumour entities. The aim of the current study was to evaluate the influence of the hypoxia-inducible factors CAIX and PGK1 on progression of neuroblastoma and to evaluate the clinical relevance of possible therapeutic approaches.

Methods

Expression of hypoxia-dependent factors PGK1 and CAIX was examined in neuroblastoma specimen, was correlated with clinical parameters, and was studied in neuroblastoma cells. The impact of these hypoxic factors was evaluated by proliferation assays under targeted therapy.

Results

Expression of hypoxia-dependent factors was found in 50 % of neuroblastoma specimen. In neuroblastoma cells, CAIX and PGK1 expression is up regulated under hypoxia and correlates with response to targeted anti-proliferative treatment. The negative impact on survival, although significant for both CAIX and PGk1, appears to be stronger for CAIX.

Conclusions

Our results show that the hypoxic factors in the tumour`s microenvironment further the progression of tumour disease. This strengthens the perspectives for additive novel therapeutic approaches targeting hypoxia-dependent factors in this childhood disease.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Jubb AM, Buffa FM, Harris AL (2010) Assessment of tumour hypoxia for prediction of response to therapy and cancer prognosis. J Cell Mol Med 14:18–29

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Kato Y, Yashiro M, Noda S, Kashiwagi S, Matsuoka J et al (2010) Expression of a hypoxia-associated protein, carbonic anhydrase-9, correlates with malignant phenotypes of gastric carcinoma. Digestion 82:246–251

    Article  CAS  PubMed  Google Scholar 

  3. Perez-Sayans M, Suarez-Penaranda JM, Pilar GD, Supuran CT, Pastorekova S et al (2012) Expression of CA-IX is associated with advanced stage tumors and poor survival in oral squamous cell carcinoma patients. J Oral Pathol Med 41:667–674

    Article  CAS  PubMed  Google Scholar 

  4. Chen J, Rocken C, Hoffmann J, Kruger S, Lendeckel U et al (2005) Expression of carbonic anhydrase 9 at the invasion front of gastric cancers. Gut 54:920–927

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Lou Y, McDonald PC, Oloumi A, Chia S, Ostlund C et al (2011) Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res 71:3364–3376

    Article  CAS  PubMed  Google Scholar 

  6. Fiaschi T, Giannoni E, Taddei ML, Cirri P, Marini A et al (2013) Carbonic anhydrase IX from cancer-associated fibroblasts drives epithelial-mesenchymal transition in prostate carcinoma cells. Cell Cycle 12:1791–1801

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Jung JH, Im S, Jung ES, Kang CS (2013) Clinicopathological implications of the expression of hypoxia-related proteins in gastric cancer. Int J Med Sci 10:1217–1223

    Article  PubMed Central  PubMed  Google Scholar 

  8. Lock FE, McDonald PC, Lou Y, Serrano I, Chafe SC et al (2013) Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche. Oncogene 32:5210–5219

    Article  CAS  PubMed  Google Scholar 

  9. Birner P, Jesch B, Friedrich J, Riegler M, Zacherl J et al (2011) Carbonic anhydrase IX overexpression is associated with diminished prognosis in esophageal cancer and correlates with Her-2 expression. Ann Surg Oncol 18:3330–3337

    Article  PubMed  Google Scholar 

  10. Tanaka N, Kato H, Inose T, Kimura H, Faried A et al (2008) Expression of carbonic anhydrase 9, a potential intrinsic marker of hypoxia, is associated with poor prognosis in oesophageal squamous cell carcinoma. Br J Cancer 99:1468–1475

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Ameis HM, Drenckhan A, von Loga K, Escherich G, Wenke K et al (2013) PGK1 as predictor of CXCR4 expression, bone marrow metastases and survival in neuroblastoma. PLoS ONE 8:e83701

    Article  PubMed Central  PubMed  Google Scholar 

  12. Chaudary N, Hill RP (2007) Hypoxia and metastasis. Clin Cancer Res 13:1947–1949

    Article  CAS  PubMed  Google Scholar 

  13. Chiche J, Ilc K, Laferriere J, Trottier E, Dayan F 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 

  14. Brahimi-Horn MC, Chiche J, Pouyssegur J (2007) Hypoxia and cancer. J Mol Med (Berl) 85:1301–1307

    Article  Google Scholar 

  15. Ameis HM, Drenckhan A, Freytag M, Izbicki JR, Supuran CT, et al. (2015) Carbonic anhydrase IX correlates with survival and is a potential therapeutic target for neuroblastoma. J Enzyme Inhib Med Chem 17:1–6

    Article  Google Scholar 

  16. Brown JM, Wilson WR (2004) Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4:437–447

    Article  CAS  PubMed  Google Scholar 

  17. Kimbro KS, Simons JW (2006) Hypoxia-inducible factor-1 in human breast and prostate cancer. Endocr Relat Cancer 13:739–749

    Article  CAS  PubMed  Google Scholar 

  18. Boyle RG, Travers S (2006) Hypoxia: targeting the tumour. Anticancer Agents Med Chem 6:281–286

    Article  CAS  PubMed  Google Scholar 

  19. Fyles A, Milosevic M, Pintilie M, Syed A, Levin W et al (2006) Long-term performance of interstial fluid pressure and hypoxia as prognostic factors in cervix cancer. Radiother Oncol 80:132–137

    Article  PubMed  Google Scholar 

  20. Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11:393–410

    Article  CAS  PubMed  Google Scholar 

  21. Gatenby RA, Gawlinski ET, Gmitro AF, Kaylor B, Gillies RJ (2006) Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res 66:5216–5223

    Article  CAS  PubMed  Google Scholar 

  22. Gillies RJ, Raghunand N, Karczmar GS, Bhujwalla ZM (2002) MRI of the tumor microenvironment. J Magn Reson Imaging 16:430–450

    Article  PubMed  Google Scholar 

  23. 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 

  24. 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  PubMed Central  CAS  PubMed  Google Scholar 

  25. Vaupel P (2004) The role of hypoxia-induced factors in tumor progression. Oncologist 9(Suppl 5):10–17

    Article  CAS  PubMed  Google Scholar 

  26. Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol (1985) 88: 1474–1480

  27. Semenza GL (2006) Regulation of physiological responses to continuous and intermittent hypoxia by hypoxia-inducible factor 1. Exp Physiol 91:803–806

    Article  CAS  PubMed  Google Scholar 

  28. Denko NC, Fontana LA, Hudson KM, Sutphin PD, Raychaudhuri S et al (2003) Investigating hypoxic tumor physiology through gene expression patterns. Oncogene 22:5907–5914

    Article  CAS  PubMed  Google Scholar 

  29. Lal A, Peters H, St Croix B, Haroon ZA, Dewhirst MW et al (2001) Transcriptional response to hypoxia in human tumors. J Natl Cancer Inst 93:1337–1343

    Article  CAS  PubMed  Google Scholar 

  30. Kim WY, Safran M, Buckley MR, Ebert BL, Glickman J et al (2006) Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo. EMBO J 25:4650–4662

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J et al (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  33. Stolze IP, Mole DR, Ratcliffe PJ (2006) Regulation of HIF: prolyl hydroxylases. Novartis Found Symp 272:15–25 (discussion 25–36)

    Article  CAS  PubMed  Google Scholar 

  34. Semenza GL (2000) Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol 35:71–103

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  36. Swietach P, Wigfield S, Cobden P, Supuran CT, Harris AL et al (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 

  37. 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 

  38. Ditte P, Dequiedt F, Svastova E, Hulikova A, Ohradanova-Repic A et al (2011) Phosphorylation of carbonic anhydrase IX controls its ability to mediate extracellular acidification in hypoxic tumors. Cancer Res 71:7558–7567

    Article  CAS  PubMed  Google Scholar 

  39. Potter C, Harris AL (2004) Hypoxia inducible carbonic anhydrase IX, marker of tumour hypoxia, survival pathway and therapy target. Cell Cycle 3:164–167

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Beate Roth and Brigit Appl for expert technical assistance.

Author information

Author notes

  1. Stephanie J. Gros

    Present address: Department of Pediatric Surgery, University Children’s Hospital of Basel, Spitalstrasse 33, 4031, Basel, Switzerland

Authors and Affiliations

  1. Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf/Altona Children’s Hospital, Hamburg, Germany

    Helen M. Ameis & Konrad Reinshagen

  2. Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

    Astrid Drenckhan, Morton Freytag, Jakob R. Izbicki & Stephanie J. Gros

  3. Department Neurofarba, Sezione di Scienze farmaceutiche, University of Florence, Florence, Italy

    Claudiu T. Supuran

  4. Department of Pediatric Surgery, University Children’s Hospital of Basel, Spitalstrasse 33, 4031, Basel, Switzerland

    Stefan Holland-Cunz

Authors
  1. Helen M. Ameis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Astrid Drenckhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Morton Freytag
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jakob R. Izbicki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claudiu T. Supuran
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Konrad Reinshagen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stefan Holland-Cunz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stephanie J. Gros
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephanie J. Gros.

Additional information

H. M. Ameis and A. Drenckhan contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ameis, H.M., Drenckhan, A., Freytag, M. et al. Influence of hypoxia-dependent factors on the progression of neuroblastoma. Pediatr Surg Int 32, 187–192 (2016). https://doi.org/10.1007/s00383-015-3831-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00383-015-3831-8

Keywords

Search

Navigation