Skip to main content
SpringerLink
Log in

Endogenous Hypoxia Markers: Case Not Proven!

  • Conference paper
Oxygen Transport to Tissue XXIX

Part of the book series: Advances In Experimental Medicine And Biology ((AEMB,volume 614))

Abstract

The pivotal role of hypoxia within the pathophysiological framework of solid malignant tumors is now considered to be indisputable. The fact that hypoxia can cause resistance to various cancer therapies and promote malignant progression is reflected in its adverse impact on prognosis which is repeatedly shown for various tumor entities. Knowledge in this area is based on direct assessment of the oxygenation status using O2-sensitive microsensors. However, weaknesses of this standard method are its invasiveness and limitation to accessible tumor entities. Hypoxia-inducible factor (HIF)-1α, the master transcriptional regulator of the hypoxic response, as well as certain downstream genes, e.g., glucose transporter (GLUT)-1 and carbonic anhydrase (CA) IX, have been considered to be suitable as surrogate biomarkers of hypoxia due to their tight regulation by O2 levels under certain, well-defined in vitro conditions. The fact that statistical correlations between the expression of these proteins and direct pO2 measurements in the clinic have been sporadically reported seemed to support their role as “endogenous hypoxia markers”. Remaining disparities were mainly attributed to the influence of tumor heterogeneity. In a series of studies, we have addressed this question by examining the expression of HIF-1α, GLUT-1 and CA IX in tissue microareas where direct O2 measurements had previously been carried out, so that the influence of tumor heterogeneity could be reduced to a minimum. Using this methodology, no correlation between the expression of “endogenous hypoxia markers” and direct pO2 measurements could be found. In conclusion, while there may be a stringent association between these markers and the oxygenation status under standardized in vitro conditions, this is not transferable to the clinical assessment of oxygenation status in patients. The term “endogenous hypoxia markers” should therefore be avoided, at least in the clinical oncology setting.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. P. Vaupel, O. Thews, M. Höckel, Treatment resistance of solid tumors: role of hypoxia and anemia, Med. Oncol. 18(4), 243–259 (2001).

    Article  PubMed  CAS  Google Scholar 

  2. M. Höckel, K. Schlenger, B. Aral, M. Mitze, U. Schäffer, P. Vaupel, Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix, Cancer Res. 56(19), 4509–4515 (1996).

    PubMed  Google Scholar 

  3. M. Höckel, P. Vaupel, Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects, J. Natl. Cancer Inst. 93(4), 266–276 (2001).

    Article  PubMed  Google Scholar 

  4. B. Krishnamachary, S. Berg-Dixon, B. Kelly, F. Agani, D. Feldser, G. Ferreira, N. Iyer, J. LaRusch, B. Pak, P. Taghavi, G. L. Semenza, Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1, Cancer Res. 63(5), 1138–1143 (2003).

    PubMed  CAS  Google Scholar 

  5. S. Pennacchietti, P. Michieli, M. Galluzzo, M. Mazzone, S. Giordano, P. M. Comoglio, Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene, Cancer Cell 3(4), 347–361 (2003).

    Article  PubMed  Google Scholar 

  6. R. A. Cairns, T. Kalliomaki, R. P. Hill, Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors, Cancer Res. 61(24), 8903–8908 (2001).

    PubMed  CAS  Google Scholar 

  7. E. K. Rofstad, H. Rasmussen, K. Galappathi, B. Mathiesen, K. Nilsen, B. A. Graff, Hypoxia promotes lymph node metastasis in human melanoma xenografts by up-regulating the urokinase-type plasminogen activator receptor, Cancer Res. 62(6), 1847–1853 (2002).

    PubMed  CAS  Google Scholar 

  8. L. H. Gray, A. D. Conger, M. Ebert, S. Hornsey, O. C. A. Scott, The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy, Br. J. Radiol. 26, 638–648 (1953).

    Article  PubMed  CAS  Google Scholar 

  9. A. Kondo, R. Safaei, M. Mishima, H. Niedner, X. Lin, S. B. Howell, Hypoxia-induced enrichment and mutagenesis of cells that have lost DNA mismatch repair, Cancer Res. 61(20), 7603–7607 (2001).

    PubMed  CAS  Google Scholar 

  10. K. M. Comerford, T. J. Wallace, J. Karhausen, N. A. Louis, M. C. Montalto, S. P. Colgan, Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene, Cancer Res. 62(12), 3387–3394 (2002).

    PubMed  CAS  Google Scholar 

  11. A. I. Minchinton, I. F. Tannock, Drug penetration in solid tumours, Nat. Rev. Cancer 6(8), 583–592 (2006).

    Article  PubMed  CAS  Google Scholar 

  12. M. Höckel, C. Knoop, K. Schlenger, B. Vorndran, E. Baussmann, M. Mitze, P. G. Knapstein, P. Vaupel, Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix, Radiother. Oncol. 26(1), 45–50 (1993).

    Article  PubMed  Google Scholar 

  13. D. M. Brizel, G. S. Sibley, L. R. Prosnitz, R. L. Scher, M. W. Dewhirst, Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck, Int. J. Radiat. Oncol. Biol. Phys. 38(2), 285–289 (1997).

    Article  PubMed  CAS  Google Scholar 

  14. A. W. Fyles, M. Milosevic, R. Wong, M. C. Kavanagh, M. Pintilie, A. Sun, W. Chapman, W. Levin, L. Manchul, T. J. Keane, R. P. Hill, Oxygenation predicts radiation response and survival in patients with cervix cancer, Radiother. Oncol. 48(2), 149–156 (1998).

    Article  PubMed  CAS  Google Scholar 

  15. K. Sundfor, H. Lyng, E. K. Rofstad, Tumour hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix, Br. J. Cancer 78(6), 822–827 (1998).

    PubMed  CAS  Google Scholar 

  16. M. Höckel, K. Schlenger, S. Höckel, P. Vaupel, Hypoxic cervical cancers with low apoptotic index are highly aggressive, Cancer Res. 59(18), 4525–4528 (1999).

    PubMed  Google Scholar 

  17. M. Nordsmark, J. Alsner, J. Keller, O. S. Nielsen, O. M. Jensen, M. R. Horsman, J. Overgaard, Hypoxia in human soft tissue sarcomas: adverse impact on survival and no association with p53 mutations, Br. J. Cancer 84(8), 1070–1075 (2001).

    Article  PubMed  CAS  Google Scholar 

  18. M. Nordsmark, J. Overgaard, Tumor hypoxia is independent of hemoglobin and prognostic for loco-regional tumor control after primary radiotherapy in advanced head and neck cancer, Acta Oncol. 43(4), 396–403 (2004).

    Article  PubMed  Google Scholar 

  19. M. Nordsmark, S. M. Bentzen, V. Rudat, D. Brizel, E. Lartigau, P. Stadler, A. Becker, M. Adam, M. Molls, J. Dunst, D. J. Terris, J. Overgaard, Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study, Radiother. Oncol. 77(1), 18–24 (2005).

    Article  PubMed  Google Scholar 

  20. G. L. Wang, G. L. Semenza, Purification and characterization of hypoxia-inducible factor 1, J. Biol. Chem. 270(3), 1230–1237 (1995).

    Article  PubMed  CAS  Google Scholar 

  21. M. Ivan, K. Kondo, H. Yang, W. Kim, J. Valiando, M. Ohh, A. Salic, J. M. Asara, W. S. Lane, W. G. Kaelin, Jr., HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing, Science 292(5516), 464–468 (2001).

    Article  PubMed  CAS  Google Scholar 

  22. P. Jaakkola, D. R. Mole, Y. M. Tian, M. I. Wilson, J. Gielbert, S. J. Gaskell, A. Kriegsheim, H. F. Hebestreit, M. Mukherji, C. J. Schofield, P. H. Maxwell, C. W. Pugh, P. J. Ratcliffe, Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation, Science 292(5516), 468–472 (2001).

    Article  PubMed  CAS  Google Scholar 

  23. P. H. Maxwell, M. S. Wiesener, G. W. Chang, S. C. Clifford, E. C. Vaux, M. E. Cockman, C. C. Wykoff, C. W. Pugh, E. R. Maher, P. J. Ratcliffe, The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis, Nature 399(6733), 271–275 (1999).

    Article  PubMed  CAS  Google Scholar 

  24. G. L. Semenza, Targeting HIF-1 for cancer therapy, Nat. Rev. Cancer 3(10), 721–732 (2003).

    Article  PubMed  CAS  Google Scholar 

  25. U. R. Jewell, I. Kvietikova, A. Scheid, C. Bauer, R. H. Wenger, M. Gassmann, Induction of HIF-1α in response to hypoxia is instantaneous, FASEB J. 15(7), 1312–1314 (2001).

    PubMed  CAS  Google Scholar 

  26. B. H. Jiang, G. L. Semenza, C. Bauer, H. H. Marti, Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension, Am. J. Physiol. 271(4 Pt 1), C1172–1180 (1996).

    PubMed  CAS  Google Scholar 

  27. G. Gruber, R. H. Greiner, R. Hlushchuk, D. M. Aebersold, H. J. Altermatt, G. Berclaz, V. Djonov, Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter?, Breast Cancer Res. 6(3), R191–198 (2004).

    Article  PubMed  CAS  Google Scholar 

  28. H. K. Haugland, V. Vukovic, M. Pintilie, A. W. Fyles, M. Milosevic, R. P. Hill, D. W. Hedley, Expression of hypoxia-inducible factor-1α in cervical carcinomas: correlation with tumor oxygenation, Int. J. Radiat. Oncol. Biol. Phys. 53(4), 854–861 (2002).

    Article  PubMed  CAS  Google Scholar 

  29. G. J. Hutchison, H. R. Valentine, J. A. Loncaster, S. E. Davidson, R. D. Hunter, S. A. Roberts, A. L. Harris, I. J. Stratford, P. M. Price, C. M. West, Hypoxia-inducible factor 1α 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. 10(24), 8405–8412 (2004).

    Article  PubMed  CAS  Google Scholar 

  30. A. Mayer, A. Wree, M. Höckel, C. Leo, H. Pilch, P. Vaupel, Lack of correlation between expression of HIF-1α protein and oxygenation status in identical tissue areas of squamous cell carcinomas of the uterine cervix, Cancer Res. 64(16), 5876–5881 (2004).

    Article  PubMed  CAS  Google Scholar 

  31. H. Zhong, A. M. De Marzo, E. Laughner, M. Lim, D. A. Hilton, D. Zagzag, P. Buechler, W. B. Isaacs, G. L. Semenza, J. W. Simons, Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases, Cancer Res. 59(22), 5830–5835 (1999).

    PubMed  CAS  Google Scholar 

  32. D. M. Aebersold, P. Burri, K. T. Beer, J. Laissue, V. Djonov, R. H. Greiner, G. L. Semenza, Expression of hypoxia-inducible factor-1α: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer, Cancer Res. 61(7), 2911–2916 (2001).

    PubMed  CAS  Google Scholar 

  33. K. Mekhail, L. Gunaratnam, M. E. Bonicalzi, S. Lee, HIF activation by pH-dependent nucleolar sequestration of VHL, Nat. Cell Biol. 6(7), 642–647 (2004).

    Article  PubMed  CAS  Google Scholar 

  34. H. Lu, R. A. Forbes, A. Verma, Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis, J. Biol. Chem. 277(26), 23111–23115 (2002).

    Article  PubMed  CAS  Google Scholar 

  35. S. B. Catrina, K. Okamoto, T. Pereira, K. Brismar, L. Poellinger, Hyperglycemia regulates hypoxia-inducible factor-1α protein stability and function, Diabetes 53(12), 3226–3232 (2004).

    Article  PubMed  CAS  Google Scholar 

  36. S. J. Kwon, Y. J. Lee, Effect of low glutamine/glucose on hypoxia-induced elevation of hypoxia-inducible factor-1α in human pancreatic cancer MiaPaCa-2 and human prostatic cancer DU-145 cells, Clin. Cancer Res. 11(13), 4694–4700 (2005).

    Article  PubMed  CAS  Google Scholar 

  37. G. Höpfl, O. Ogunshola, M. Gassmann, HIFs and tumors – causes and consequences, Am. J. Physiol. Regul. Integr. Comp. Physiol. 286(4), R608–623 (2004).

    Google Scholar 

  38. A. Mayer, M. Höckel, P. Vaupel, Endogenous hypoxia markers in locally advanced cancers of the uterine cervix: reality or wishful thinking? Strahlenther. Onkol. 182(9), 501–510 (2006).

    Article  PubMed  Google Scholar 

  39. D. Feldser, F. Agani, N. V. Iyer, B. Pak, G. Ferreira, G. L. Semenza, Reciprocal positive regulation of hypoxia-inducible factor 1α and insulin-like growth factor 2, Cancer Res. 59(16), 3915–3918 (1999).

    PubMed  CAS  Google Scholar 

  40. S. J. Mandriota, K. J. Turner, D. R. Davies, P. G. Murray, N. V. Morgan, H. M. Sowter, C. C. Wykoff, E. R. Maher, A. L. Harris, P. J. Ratcliffe, P. H. Maxwell, HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron, Cancer Cell. 1(5), 459–468 (2002).

    Article  PubMed  CAS  Google Scholar 

  41. X. S. Fu, E. Choi, G. J. Bubley, S. P. Balk, Identification of hypoxia-inducible factor-1α (HIF-1α) polymorphism as a mutation in prostate cancer that prevents normoxia-induced degradation, Prostate 63(3), 215–221 (2005).

    Article  PubMed  CAS  Google Scholar 

  42. O. R. Saramaki, K. J. Savinainen, N. N. Nupponen, O. Bratt, T. Visakorpi, Amplification of hypoxia-inducible factor 1α gene in prostate cancer, Cancer Genet. Cytogenet. 128(1), 31–34 (2001).

    Article  PubMed  CAS  Google Scholar 

  43. R. Ravi, B. Mookerjee, Z. M. Bhujwalla, C. H. Sutter, D. Artemov, Q. Zeng, L. E. Dillehay, A. Madan, G. L. Semenza, A. Bedi, Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α, Genes Dev. 14(1), 34–44 (2000).

    PubMed  CAS  Google Scholar 

  44. A. King, M. A. Selak, E. Gottlieb, Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer, Oncogene 25(34), 4675–4682 (2006).

    Article  PubMed  CAS  Google Scholar 

  45. P. Koivunen, M. Hirsila, V. Gunzler, K. I. Kivirikko, J. Myllyharju, Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases, J. Biol. Chem. 279(11), 9899–9904 (2004).

    Article  PubMed  CAS  Google Scholar 

  46. A. Lal, H. Peters, B. St Croix, Z. A. Haroon, M. W. Dewhirst, R. L. Strausberg, J. H. Kaanders, A. J. van der Kogel, G. J. Riggins, Transcriptional response to hypoxia in human tumors, J. Natl. Cancer Inst. 93(17), 1337–1343 (2001).

    Article  PubMed  CAS  Google Scholar 

  47. D. Vordermark, A. Kaffer, S. Riedl, A. Katzer, M. Flentje, Characterization of carbonic anhydrase IX (CA IX) as an endogenous marker of chronic hypoxia in live human tumor cells, Int. J. Radiat. Oncol. Biol. Phys. 61(4), 1197–1207 (2005).

    Article  PubMed  CAS  Google Scholar 

  48. J. A. Loncaster, A. L. Harris, S. E. Davidson, J. P. Logue, R. D. Hunter, C. C. Wycoff, J. Pastorek, P. J. Ratcliffe, I. J. Stratford, C. M. West, 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(17), 6394–6399 (2001).

    PubMed  CAS  Google Scholar 

  49. Q. T. Le, E. Chen, A. Salim, H. Cao, C. S. Kong, R. Whyte, J. Donington, W. Cannon, H. Wakelee, R. Tibshirani, J. D. Mitchell, D. Richardson, K. J. O'Byrne, A. C. Koong, A. J. Giaccia, An evaluation of tumor oxygenation and gene expression in patients with early stage non-small cell lung cancers, Clin. Cancer Res. 12(5), 1507–1514 (2006).

    Article  PubMed  CAS  Google Scholar 

  50. D. Hedley, M. Pintilie, J. Woo, A. Morrison, D. Birle, A. Fyles, M. Milosevic, R. Hill, Carbonic anhydrase IX expression, hypoxia, and prognosis in patients with uterine cervical carcinomas, Clin. Cancer Res. 9(15), 5666–5674 (2003).

    PubMed  CAS  Google Scholar 

  51. B. Jankovic, C. Aquino-Parsons, J. A. Raleigh, E. J. Stanbridge, R. E. Durand, J. P. Banath, S. H. Macphail, P. L. Olive, Comparison between pimonidazole binding, oxygen electrode measurements, and expression of endogenous hypoxia markers in cancer of the uterine cervix, Cytometry B Clin. Cytom. 70(2), 45–55 (2006).

    PubMed  CAS  Google Scholar 

  52. A. Mayer, M. Höckel, P. Vaupel, 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(20), 7220–7225 (2005).

    Article  PubMed  CAS  Google Scholar 

  53. B. S. Sorensen, J. Hao, J. Overgaard, H. Vorum, B. Honore, J. Alsner, M. R. Horsman, Influence of oxygen concentration and pH on expression of hypoxia induced genes, Radiother. Oncol. 76(2), 187–193 (2005).

    Article  PubMed  CAS  Google Scholar 

  54. M. Rafajova, M. Zatovicova, R. Kettmann, J. Pastorek, S. Pastorekova, 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(4), 995–1004 (2004).

    PubMed  CAS  Google Scholar 

  55. J. Pastorek, S. Pastorekova, I. Callebaut, J. P. Mornon, V. Zelnik, R. Opavsky, M. Zat'ovicova, S. Liao, D. Portetelle, E. J. Stanbridge, 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(10), 2877–2888 (1994).

    PubMed  CAS  Google Scholar 

  56. P. J. Hoskin, A. Sibtain, F. M. Daley, G. D. Wilson, 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(7), 1290–1297 (2003).

    Article  PubMed  CAS  Google Scholar 

  57. R. Airley, J. Loncaster, S. Davidson, M. Bromley, S. Roberts, A. Patterson, R. Hunter, I. Stratford, C. West, Glucose transporter Glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix, Clin. Cancer Res. 7(4), 928–934 (2001).

    PubMed  CAS  Google Scholar 

  58. A. Mayer, M. Höckel, A. Wree, P. Vaupel, Microregional expression of glucose transporter-1 and oxygenation status: lack of correlation in locally advanced cervical cancers, Clin. Cancer Res. 11(7), 2768–2773 (2005).

    Article  PubMed  CAS  Google Scholar 

  59. K. I. Sakata, M. Someya, H. Nagakura, K. Nakata, A. Oouchi, M. Hareyama, M. Satoh, A clinical study of hypoxia using endogenous hypoxic markers and polarographic oxygen electrodes, Strahlenther. Onkol. 182(9), 511–517 (2006).

    Article  PubMed  Google Scholar 

  60. I. Stein, M. Neeman, D. Shweiki, A. Itin, E. Keshet, Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes, Mol. Cell Biol. 15(10), 5363–5368 (1995).

    PubMed  CAS  Google Scholar 

  61. R. J. Boado, W. M. Pardridge, Glucose deprivation and hypoxia increase the expression of the GLUT1 glucose transporter via a specific mRNA cis-acting regulatory element, J. Neurochem. 80(3), 552–554 (2002).

    Article  PubMed  CAS  Google Scholar 

  62. E. Wertheimer, S. Sasson, E. Cerasi, Y. Ben-Neriah, The ubiquitous glucose transporter GLUT-1 belongs to the glucose-regulated protein family of stress-inducible proteins, Proc. Natl. Acad. Sci. U. S. A. 88(6), 2525–2529 (1991).

    Article  PubMed  CAS  Google Scholar 

  63. S. Walenta, M. Wetterling, M. Lehrke, G. Schwickert, K. Sundfor, E. K. Rofstad, W. Mueller-Klieser, High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers, Cancer Res. 60(4), 916–921 (2000).

    PubMed  CAS  Google Scholar 

  64. P. Vaupel, F. Kallinowski, P. Okunieff, Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review, Cancer Res. 49(23), 6449–6465 (1989).

    PubMed  CAS  Google Scholar 

  65. R. C. Osthus, H. Shim, S. Kim, Q. Li, R. Reddy, M. Mukherjee, Y. Xu, D. Wonsey, L. A. Lee, C. V. Dang, Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc, J. Biol. Chem. 275(29), 21797–21800 (2000).

    Article  PubMed  CAS  Google Scholar 

  66. K. Barnes, J. C. Ingram, O. H. Porras, L. F. Barros, E. R. Hudson, L. G. Fryer, F. Foufelle, D. Carling, D. G. Hardie, S. A. Baldwin, Activation of GLUT1 by metabolic and osmotic stress: potential involvement of AMP-activated protein kinase (AMPK), J. Cell. Sci. 115(Pt 11), 2433–2442 (2002).

    PubMed  CAS  Google Scholar 

  67. D. Y. Hwang, F. Ismail-Beigi, Stimulation of GLUT-1 glucose transporter expression in response to hyperosmolarity, Am. J. Physiol. Cell Physiol. 281(4), C1365–1372 (2001).

    Google Scholar 

  68. L. C. Moeller, A. M. Dumitrescu, S. Refetoff, Cytosolic action of thyroid hormone leads to induction of HIF-1α and glycolytic genes, Mol. Endocrinol. 90(2), 936–943 (2005).

    CAS  Google Scholar 

  69. C. M. West, R. A. Cooper, J. A. Loncaster, D. P. Wilks, M. Bromley, Tumor vascularity: a histological measure of angiogenesis and hypoxia, Cancer Res. 61(7), 2907–2910 (2001).

    PubMed  CAS  Google Scholar 

  70. S. Lukacova, J. Overgaard, J. Alsner, M. R. Horsman, Strain and tumour specific variations in the effect of hypoxia on osteopontin levels in experimental models, Radiother. Oncol. 80(2), 165–171 (2006).

    Article  PubMed  CAS  Google Scholar 

  71. P. Kabuubi, J. A. Loncaster, S. E. Davidson, R. D. Hunter, C. Kobylecki, I. J. Stratford, C. M. West, No relationship between thymidine phosphorylase (TP, PD-ECGF) expression and hypoxia in carcinoma of the cervix, Br. J. Cancer 94(1), 115–120 (2006).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Physiology and Pathophysiology, University of Mainz, 55099 Mainz, Germany

    Arnulf Mayer & Peter Vaupel

  2. Department of Gynecology and Obstetrics, University of Leipzig, 04103 Leipzig, Germany

    Michael Höckel

Authors
  1. Arnulf Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Höckel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Vaupel
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Chemical Engineering, University of Louisville, Louisville, KY 40292, USA

    Kyung A. Kang

  2. Durham Unit Regional Medical Physics Department, University Hospital of North Durham, Durham, UK

    David K. Harrison

  3. Synthesizer Inc, Ellicott City, MD, USA

    Duane F. Bruley

  4. UMBC, Baltimore, MD, USA

    Duane F. Bruley

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer Science+Business Media, LLC

About this paper

Cite this paper

Mayer, A., Höckel, M., Vaupel, P. (2008). Endogenous Hypoxia Markers: Case Not Proven!. In: Kang, K.A., Harrison, D.K., Bruley, D.F. (eds) Oxygen Transport to Tissue XXIX. Advances In Experimental Medicine And Biology, vol 614. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-74911-2_15

Download citation

Publish with us

Policies and ethics

Search

Navigation