Molecular Oncology
Volume 2, Issue 1 , Pages 41-53 , June 2008

Molecular aspects of tumour hypoxia

  • Saskia E. Rademakers

      Affiliations

    • Department of Radiation Oncology, 874 Radboud University Nijmegen Medical Centre, P.O. Box 9101, Nijmegen 6500 HB, The Netherlands
  • ,
  • Paul N. Span

      Affiliations

    • Department of Chemical Endocrinology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, Nijmegen 6500 HB, The Netherlands
  • ,
  • Johannes H.A.M. Kaanders

      Affiliations

    • Department of Radiation Oncology, 874 Radboud University Nijmegen Medical Centre, P.O. Box 9101, Nijmegen 6500 HB, The Netherlands
  • ,
  • Fred C.G.J. Sweep

      Affiliations

    • Department of Chemical Endocrinology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, Nijmegen 6500 HB, The Netherlands
  • ,
  • Albert J. van der Kogel

      Affiliations

    • Department of Radiation Oncology, 874 Radboud University Nijmegen Medical Centre, P.O. Box 9101, Nijmegen 6500 HB, The Netherlands
  • ,
  • Johan Bussink

      Affiliations

    • Department of Radiation Oncology, 874 Radboud University Nijmegen Medical Centre, P.O. Box 9101, Nijmegen 6500 HB, The Netherlands
    • Corresponding Author InformationCorresponding author. Tel.: +31 24 3614515. fax: +31 24 3610792.

Received 12 March 2008 ,Revised 14 March 2008 ,Accepted 17 March 2008.

References 

  1. Airley R, Loncaster J, Davidson S, Bromley M, Roberts S, Patterson A, et al. Glucose transporter glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix. Clin. Cancer Res. 2001;7:928–934
  2. Airley RE, Loncaster J, Raleigh JA, Harris AL, Davidson SE, Hunter RD, et al. GLUT-1 and CAIX as intrinsic markers of hypoxia in carcinoma of the cervix: relationship to pimonidazole binding. Int. J. Cancer. 2003;104:85–91
  3. Baer S, Casaubon L, Schwartz MR, Marcogliese A, Younes M. Glut3 expression in biopsy specimens of laryngeal carcinoma is associated with poor survival. The Laryngoscope. 2002;112:393–396
  4. Bajou K, Masson V, Gerard RD, Schmitt PM, Albert V, Praus M, et al The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. J. Cell Biol. 2001;152:777–784
  5. Beasley NJ, Leek R, Alam M, Turley H, Cox GJ, Gatter K, et al. Hypoxia-inducible factors HIF-1alpha and HIF-2alpha in head and neck cancer: relationship to tumor biology and treatment outcome in surgically resected patients. Cancer Res. 2002;62:2493–2497
  6. Bennewith KL, Durand RE. Quantifying transient hypoxia in human tumor xenografts by flow cytometry. Cancer Res. 2004;64:6183–6189
  7. Bennewith KL, Raleigh JA, Durand RE. Orally administered pimonidazole to label hypoxic tumor cells. Cancer Res. 2002;62:6827–6830
  8. Blais J, Bell JC. Novel therapeutic target: the PERKs of inhibiting the integrated stress response. Cell Cycle. 2006;5:2874–2877
  9. Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Bean JM, Prosnitz LR, et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 1996;56:941–943
  10. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int. J. Radiat. Oncol. Biol. Phys. 1997;38:285–289
  11. Brown LF, Papadopoulos-Sergiou A, Berse B, Manseau EJ, Tognazzi K, Perruzzi CA, et al. Osteopontin expression and distribution in human carcinomas. Am. J. Pathol. 1994;145:610–623
  12. Bussink J, Kaanders JH, van-der-Kogel AJ. Tumor hypoxia at the micro-regional level: clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers. Radiother. Oncol. 2003;67:3–15
  13. Bussink J, van der Kogel AJ, Kaanders JH. Acivation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol. 2008;9:288–296
  14. Chambers AF, Wilson SM, Kerkvliet N, O'Malley FP, Harris JF, Casson AG. Osteopontin expression in lung cancer. Lung Cancer (Amsterdam, Netherlands). 1996;15:311–323
  15. Coppola D, Szabo M, Boulware D, Muraca P, Alsarraj M, Chambers AF, et al. Correlation of osteopontin protein expression and pathological stage across a wide variety of tumor histologies. Clin. Cancer Res. 2004;10:184–190
  16. Dass K, Ahmad A, Azmi A, Sarkar S, Sarkar F. Evolving role of uPA/uPAR system in human cancers. Cancer Treat. Rev. 2007;
  17. Davis ID, Wiseman GA, Lee FT, Gansen DN, Hopkins W, Papenfuss AT, et al A phase I multiple dose, dose escalation study of cG250 monoclonal antibody in patients with advanced renal cell carcinoma. Cancer Immun. 2007;7:13
  18. Dehdashti F, Mintun MA, Lewis JS, Bradley J, Govindan R, Laforest R, et al. In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM. Eur. J. Nucl. Med. Mol. Imaging. 2003;30:844–850
  19. Dewhirst MW. Concepts of oxygen transport at the microcirculatory level. Semin. Radiat. Oncol. 1998;8:143–150
  20. Dische S. Hyperbaric oxygen: the Medical Research Council trials and their clinical significance. Br. J. Radiol. 1978;51:888–894
  21. Evans SM, Du KL, Chalian AA, Mick R, Zhang PJ, Hahn SM, et al. Patterns and levels of hypoxia in head and neck squamous cell carcinomas and their relationship to patient outcome. Int. J. Radiat. Oncol. Biol. Phys. 2007;69:1024–1031
  22. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat. Med. 2003;9:669–676
  23. Fillies T, Werkmeister R, van-Diest PJ, Brandt B, Joos U, Buerger H. HIF1-alpha overexpression indicates a good prognosis in early stage squamous cell carcinomas of the oral floor. BMC Cancer. 2005;5:84
  24. Fink T, Kazlauskas A, Poellinger L, Ebbesen P, Zachar V. Identification of a tightly regulated hypoxia-response element in the promoter of human plasminogen activator inhibitor-1. Blood. 2002;99:2077–2083
  25. Fong TA, Shawver LK, Sun L, Tang C, App H, Powell TJ, et al SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res. 1999;59:99–106
  26. Gatenby RA, Kessler HB, Rosenblum JS, Coia LR, Moldofsky PJ, Hartz WH, et al. Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 1988;14:831–838
  27. Grabmaier K, A-de-Weijert MC, Verhaegh GW, Schalken JA, Oosterwijk E. Strict regulation of CAIX(G250/MN) by HIF-1alpha in clear cell renal cell carcinoma. Oncogene. 2004;23:5624–5631
  28. Grau C, Overgaard J. Effect of etoposide, carmustine, vincristine, 5-fluorouracil, or methotrexate on radiobiologically oxic and hypoxic cells in a C3H mouse mammary carcinoma in situ. Cancer Chemother. Pharm. 1992;30:277–280
  29. Gray L, Conger AD, Ebert M, Hornsey S, Scott OCA. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br. J. Radiol. 1953;28:638–648
  30. Hanrahan EO, Heymach JV. Vascular endothelial growth factor receptor tyrosine kinase inhibitors vandetanib (ZD6474) and AZD2171 in lung cancer. Clin. Cancer Res. 2007;13:4617–4622
  31. Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J. Clin. Oncol. 2007;25:5287–5312Official Journal of the American Society of Clinical Oncology
  32. Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 1996;56:4509–4515
  33. Hockel M, Schlenger K, Hockel S, Vaupel P. Hypoxic cervical cancers with low apoptotic index are highly aggressive. Cancer Res. 1999;59:4525–4528
  34. Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J. Natl. Cancer Inst. 2001;93:266–276
  35. Hoogsteen IJ, Marres HAM, Wijffels KIEM, Rijken PFJW, Peters JPW, van den Hoogen FJ, et al. Colocalization of carbonic anhydrase 9 expression and cell proliferation in human head and neck squamous cell carcinoma. Clin. Cancer Res. 2005;11:97–106
  36. Horsman MR, Siemann DW. Pathophysiologic effects of vascular-targeting agents and the implications for combination with conventional therapies. Cancer Res. 2006;66:11,520–11,539
  37. Hu M, Polyak K. Microenvironmental regulation of cancer development. Curr. Opin. Genet. Dev. 2008;
  38. Ivanov S, Liao SY, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G, et al Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am. J. Pathol. 2001;158:905–919
  39. Jonathan RA, Wijffels KI, Peeters W, de Wilde PC, Marres HA, Merkx MA, et al. The prognostic value of endogenous hypoxia-related markers for head and neck squamous cell carcinomas treated with ARCON. Radiother. Oncol. 2006;79:288–297
  40. Kaanders JH, Bussink J, van der Kogel AJ. ARCON: a novel biology-based approach in radiotherapy. Lancet Oncol. 2002;3:728–737
  41. Kaanders JH, Pop LA, Marres HA, Bruaset I, van den Hoogen FJ, Merkx MA, et al. ARCON: experience in 215 patients with advanced head-and-neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 2002;52:769–778
  42. Kaanders JH, Wijffels KI, Marres HA, Ljungkvist AS, Pop LA, van den Hoogen FJ, et al. Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res. 2002;62:7066–7074
  43. Kim SJ, Shin HJ, Jung KY, Baek SK, Shin BK, Choi J, et al Prognostic value of carbonic anhydrase IX and Ki-67 expression in squamous cell carcinoma of the tongue. Jpn. J. Clin. Oncol. 2007;37:812–819
  44. Konerding MA, Miodonski AJ, Lametschwandtner A. Microvascular corrosion casting in the study of tumor vascularity: a review. Scanning Microsc. 1995;9:1233–1244
  45. Koukourakis MI, Bentzen SM, Giatromanolaki A, Wilson GD, Daley FM, Saunders MI, et al. 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. 2006;24:727–735
  46. Koumenis C, Wouters BG. “Translating” tumor hypoxia: unfolded protein response (UPR)-dependent and UPR-independent pathways. Mol. Cancer Res. 2006;4:423–436
  47. Kwaan HC, Wang J, Svoboda K, Declerck PJ. Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis. Br. J. Cancer. 2000;82:1702–1708
  48. Le QT, Kong C, Lavori PW, O'Byrne K, Erler JT, Huang X, et al Expression and prognostic significance of a panel of tissue hypoxia markers in head-and-neck squamous cell carcinomas. Int. J. Radiat. Oncol. Biol. Phys. 2007;69:167–175
  49. Le QT, Sutphin PD, Raychaudhuri S, Yu SC, Terris DJ, Lin HS, et al. Identification of osteopontin as a prognostic plasma marker for head and neck squamous cell carcinomas. Clin. Cancer Res. 2003;9:59–67
  50. Lee AS. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res. 2007;67:3496–3499
  51. Lee J, Siemann DW, Koch CJ, Lord EM. Direct relationship between radiobiological hypoxia in tumors and monoclonal antibody detection of EF5 cellular adducts. Int. J. Cancer. 1996;67:372–378
  52. Look MP, van-Putten WL, Duffy MJ, Harbeck N, Christensen IJ, Thomssen C, et al Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J. Natl. Cancer Inst. 2002;94:116–128
  53. Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J. Cell Physiol. 2005;202:654–662
  54. Matthews NE, Adams MA, Maxwell LR, Gofton TE, Graham CH. Nitric oxide-mediated regulation of chemosensitivity in cancer cells. J. Natl. Cancer Inst. 2001;93:1879–1885
  55. Mayer A, Hockel M, Vaupel P. 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. 2005;11:7220–7225
  56. Mayer A, Hockel M, Wree A, Vaupel P. Microregional expression of glucose transporter-1 and oxygenation status: lack of correlation in locally advanced cervical cancers. Clin. Cancer Res. 2005;11:2768–2773
  57. Mayer A, Wree A, Hockel M, Leo C, Pilch H, Vaupel P. Lack of correlation between expression of HIF-1alpha protein and oxygenation status in identical tissue areas of squamous cell carcinomas of the uterine cervix. Cancer Res. 2004;64:5876–5881
  58. Mizukami Y, Kohgo Y, Chung DC. Hypoxia inducible factor-1 independent pathways in tumor angiogenesis. Clin. Cancer Res. 2007;13:5670–5674
  59. Moon EJ, Brizel DM, Chi JT, Dewhirst MW. The potential role of intrinsic hypoxia markers as prognostic variables in cancer. Antioxid. Redox. Signal. 2007;9:1237–1294
  60. Morgan PE, Pastorekova S, Stuart-Tilley AK, Alper SL, Casey JR. Interactions of transmembrane carbonic anhydrase, CAIX, with bicarbonate transporters. Am. J. Physiol. Cell Physiol. 2007;293:738–748
  61. Mottram JC. A factor of importance in the radiosensitivity of tumours. Br. J. Radiol. 1936;IX:606–614
  62. Nordsmark M, Alsner J, Keller J, Nielsen OS, Jensen OM, Horsman MR, et al. Hypoxia in human soft tissue sarcomas: adverse impact on survival and no association with p53 mutations. Br. J. Cancer. 2001;84:1070–1075
  63. Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, et al Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother. Oncol. 2005;77:18–24
  64. Nordsmark M, Loncaster J, Aquino-Parsons C, Chou SC, Gebski V, West C, et al The prognostic value of pimonidazole and tumour pO2 in human cervix carcinomas after radiation therapy: a prospective international multi-center study. Radiother. Oncol. 2006;80:123–131
  65. Nozue M, Lee I, Yuan F, Teicher BA, Brizel DM, Dewhirst MW, et al Interlaboratory variation in oxygen tension measurement by Eppendorf “Histograph” and comparison with hypoxic marker. J. Surg. Oncol. 1997;66:30–38
  66. Oliver RJ, Woodwards RT, Sloan P, Thakker NS, Stratford IJ, Airley RE. Prognostic value of facilitative glucose transporter Glut-1 in oral squamous cell carcinomas treated by surgical resection; results of EORTC Translational Research Fund studies. Eur. J. Cancer. 2004;40:503–507
  67. Overgaard J, Eriksen JG, Nordsmark M, Alsner J, Horsman MR. Plasma osteopontin, hypoxia, and response to the hypoxia sensitiser nimorazole in radiotherapy of head and neck cancer: results from the DAHANCA 5 randomised double-blind placebo-controlled trial. Lancet Oncol. 2005;6:757–764
  68. Overgaard J, Hansen HS, Overgaard M, Bastholt L, Berthelsen A, Specht L, et al. A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85. Radiother. Oncol. 1998;46:135–146
  69. von Pawel J, von-Roemeling R, Gatzemeier U, Boyer M, Elisson LO, Clark P, et al Tirapazamine plus cisplatin versus cisplatin in advanced non-small-cell lung cancer: a report of the international CATAPULT I study group. Cisplatin and tirapazamine in subjects with advanced previously untreated non-small-cell lung tumors. J. Clin. Oncol. 2000;18:1351–1359
  70. Padhani AR, Krohn KA, Lewis JS, Alber M. Imaging oxygenation of human tumours. Eur. Radiol. 2007;17:861–872
  71. Palit V, Phillips RM, Puri R, Shah T, Bibby MC. Expression of HIF-1alpha and Glut-1 in human bladder cancer. Oncol. Rep. 2005;14:909–913
  72. Patterson DM, Rustin GJ. Vascular damaging agents. Clin. Oncol. 2007;19:443–456
  73. Petersen I. Antiangiogenesis, anti-VEGF(R) and outlook. Recent Results Cancer Res. 2007;176:189–199
  74. Pore N, Liu S, Shu HK, Li B, Haas-Kogan D, Stokoe D, et al Sp1 is involved in Akt-mediated induction of VEGF expression through an HIF-1-independent mechanism. Mol. Biol. Cell. 2004;15:4841–4853
  75. Potter CP, Harris AL. Diagnostic, prognostic and therapeutic implications of carbonic anhydrases in cancer. Br. J. Cancer. 2003;89:2–7
  76. Rajendran JG, Schwartz DL, O'Sullivan J, Peterson LM, Ng P, Scharnhorst J, et al. Tumor hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck cancer. Clin. Cancer Res. 2006;12:5435–5441
  77. Raleigh JA, Chou SC, Arteel GE, Horsman MR. Comparisons among pimonidazole binding, oxygen electrode measurements, and radiation response in C3H mouse tumors. Radiat. Res. 1999;151:580–589
  78. Ramankulov A, Lein M, Kristiansen G, Meyer HA, Loening SA, Jung K. Elevated plasma osteopontin as marker for distant metastases and poor survival in patients with renal cell carcinoma. J. Cancer Res. Clin. 2007;133:643–652
  79. Rangaswami H, Bulbule A, Kundu GC. Osteopontin: role in cell signaling and cancer progression. Trends Cell Biol. 2006;16:79–87
  80. Rijpkema M, Kaanders JH, Joosten FB, van der Kogel AJ, Heerschap A. Effects of breathing a hyperoxic hypercapnic gas mixture on blood oxygenation and vascularity of head-and-neck tumors as measured by magnetic resonance imaging. Int. J. Radiat. Oncol. Biol. Phys. 2002;53:1185–1191
  81. Rischin D, Peters L, Fisher R, Macann A, Denham J, Poulsen M, et al Tirapazamine, cisplatin, and radiation versus fluorouracil, cisplatin, and radiation in patients with locally advanced head and neck cancer: a randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). J. Clin. Oncol. 2005;23:79–87
  82. Rittling SR, Chambers AF. Role of osteopontin in tumour progression. Br. J. Cancer. 2004;90:1877–1881
  83. Rogers S, Macheda ML, Docherty SE, Carty MD, Henderson MA, Soeller WC, et al. Identification of a novel glucose transporter-like protein-GLUT-12. Am. J. Physiol. Endocrinol. Metab. 2002;282:E733–E738
  84. Rudland PS, Platt-Higgins A, El-Tanani M, De-Silva-Rudland S, Barraclough R, Winstanley JH, et al. Prognostic significance of the metastasis-associated protein osteopontin in human breast cancer. Cancer Res. 2002;62:3417–3427
  85. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. New Engl. J. Med. 2006;355:2542–2550
  86. Schilling D, Bayer C, Geurts-Moespot A, Sweep FC, Pruschy M, Mengele K, et al. Induction of plasminogen activator inhibitor type-1 (PAI-1) by hypoxia and irradiation in human head and neck carcinoma cell lines. BMC Cancer. 2007;7:143
  87. Schuuring J, Bussink J, Bernsen HJ, Peeters W, van-Der-Kogel AJ. Irradiation combined with SU5416: microvascular changes and growth delay in a human xenograft glioblastoma tumor line. Int. J. Radiat. Oncol. Biol. Phys. 2005;61:529–534
  88. Semenza GL. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit. Rev. Biochem. Mol. Biol. 2000;35:71–103
  89. Semenza GL. Evaluation of HIF-1 inhibitors as anticancer agents. Drug Discov. Today. 2007;12:853–859
  90. Span PN, Bussink J, Manders P, Beex LV, Sweep CG. Carbonic anhydrase-9 expression levels and prognosis in human breast cancer: association with treatment outcome. Br. J. Cancer. 2003;89:271–276
  91. Stillebroer AB, Oosterwijk E, Oyen WJ, Mulders PF, Boerman OC. Radiolabeled antibodies in renal cell carcinoma. Cancer Imaging. 2007;7:179–188The official publication of the International Cancer Imaging Society
  92. Talbot DC, von Pawel J, Cattell E, Yule SM, Johnston C, Zandvliet AS, et al A randomized phase II pharmacokinetic and pharmacodynamic study of indisulam as second-line therapy in patients with advanced non-small cell lung cancer. Clin. Cancer Res. 2007;13:1816–1822
  93. Tredan O, Galmarini CM, Patel K, Tannock IF. Drug resistance and the solid tumor microenvironment. J. Natl. Cancer Inst. 2007;99:1441–1454
  94. Troost EG, Bussink J, Kaanders JH, van-Eerd J, Peters JP, Rijken PF, et al. Comparison of different methods of CAIX quantification in relation to hypoxia in three human head and neck tumor lines. Radiother. Oncol. 2005;76:194–199
  95. Vaupel P, Thews O, Hoeckel M. Treatment resistance of solid tumors: role of hypoxia and anemia. Med. Oncol. 2001;18:243–259
  96. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop–helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA. 1995;92:5510–5514
  97. Williamson SK, Crowley JJ, Lara PN, McCoy J, Lau DH, Tucker RW, et al. Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003. J. Clin. Oncol. 2005;23:9097–9104
  98. Wilson RE, Keng PC, Sutherland RM. Drug resistance in Chinese hamster ovary cells during recovery from severe hypoxia. J. Natl. Cancer Inst. 1989;81:1235–1240
  99. Wouters BG, Brown JM. Cells at intermediate oxygen levels can be more important than the “hypoxic fraction” in determining tumor response to fractionated radiotherapy. Radiat. Res. 1997;147:541–550
  100. Wykoff CC, Beasley NJP, Watson PH, Turner KJ, Pastorek J, Sibtain A, et al Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 2000;60:7075–7083
  101. Zhang H, Ye QH, Ren N, Zhao L, Wang YF, Wu X, et al The prognostic significance of preoperative plasma levels of osteopontin in patients with hepatocellular carcinoma. J. Cancer Res. Clin. 2006;132:709–717
  102. Zhong H, De-Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999;59:5830–5835

PII: S1574-7891(08)00039-2

doi: 10.1016/j.molonc.2008.03.006

Molecular Oncology
Volume 2, Issue 1 , Pages 41-53 , June 2008