Journal of Neuro-Oncology

, Volume 92, Issue 3, pp 317–335

Brain tumor hypoxia: tumorigenesis, angiogenesis, imaging, pseudoprogression, and as a therapeutic target

Topic Review

Abstract

Hypoxia is implicated in many aspects of tumor development, angiogenesis, and growth in many different tumors. Brain tumors, particularly the highly aggressive glioblastoma multiforme (GBM) with its necrotic tissues, are likely affected similarly by hypoxia, although this involvement has not been closely studied. Invasion, apoptosis, chemoresistance, resistance to antiangiogenic therapy, and radiation resistance may all have hypoxic mechanisms. The extent of the influence of hypoxia in these processes makes it an attractive therapeutic target for GBM. Because of their relationship to glioma and meningioma growth and angiogenesis, hypoxia-regulated molecules, including hypoxia inducible factor-1, carbonic anhydrase IX, glucose transporter 1, and vascular endothelial growth factor, may be suitable subjects for therapies. Furthermore, other novel hypoxia-regulated molecules that may play a role in GBM may provide further options. Emerging imaging techniques may allow for improved determination of hypoxia in human brain tumors to better focus therapeutic treatments; however, tumor pseudoprogression, which may be prompted by hypoxia, poses further challenges. An understanding of the role of hypoxia in tumor development and growth is important for physicians involved in the care of patients with brain tumors.

Keywords

Hypoxia inducible factor Glioblastoma Meningioma Carbonic anhydrase IX Glucose transporter 1 Vascular endothelial growth factor Pseudoprogression Hypoxia imaging 

References

  1. 1.
    Sundfor K, Lyng H, Rofstad EK (1998) Tumour hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix. Br J Cancer 78:822–827PubMedGoogle Scholar
  2. 2.
    Hockel M, Schlenger K, Hockel S, Aral B, Schaffer U, Vaupel P (1998) Tumor hypoxia in pelvic recurrences of cervical cancer. Int J Cancer 79:365–369. doi:10.1002/(SICI)1097-0215(19980821)79:4<365::AID-IJC10>3.0.CO;2-4 PubMedCrossRefGoogle Scholar
  3. 3.
    Sanna K, Rofstad EK (1994) Hypoxia-induced resistance to doxorubicin and methotrexate in human melanoma cell lines in vitro. Int J Cancer 58:258–262. doi:10.1002/ijc.2910580219 PubMedCrossRefGoogle Scholar
  4. 4.
    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
  5. 5.
    Rice GC, Hoy C, Schimke RT (1986) Transient hypoxia enhances the frequency of dihydrofolate reductase gene amplification in Chinese hamster ovary cells. Proc Natl Acad Sci USA 83:5978–5982. doi:10.1073/pnas.83.16.5978 PubMedCrossRefGoogle Scholar
  6. 6.
    Wilson RE, Keng PC, Sutherland RM (1989) Drug resistance in Chinese hamster ovary cells during recovery from severe hypoxia. J Natl Cancer Inst 81:1235–1240. doi:10.1093/jnci/81.16.1235 PubMedCrossRefGoogle Scholar
  7. 7.
    Cuvier C, Jang A, Hill RP (1997) Exposure to hypoxia, glucose starvation and acidosis: effect on invasive capacity of murine tumor cells and correlation with cathepsin (L+B) secretion. Clin Exp Metastasis 15:19–25. doi:10.1023/A:1018428105463 PubMedCrossRefGoogle Scholar
  8. 8.
    Graham CH, Forsdike J, Fitzgerald CJ, Macdonald-Goodfellow S (1999) Hypoxia-mediated stimulation of carcinoma cell invasiveness via upregulation of urokinase receptor expression. Int J Cancer 80:617–623. doi:10.1002/(SICI)1097-0215(19990209)80:4<617::AID-IJC22>3.0.CO;2-C PubMedCrossRefGoogle Scholar
  9. 9.
    Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K, Rofstad EK, Mueller-Klieser W (2000) High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res 60:916–921PubMedGoogle Scholar
  10. 10.
    Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P (1996) Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56:4509–4515PubMedGoogle Scholar
  11. 11.
    Sakata K, Kwok TT, Murphy BJ, Laderoute KR, Gordon GR, Sutherland RM (1991) Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance. Br J Cancer 64:809–814PubMedGoogle Scholar
  12. 12.
    Seimiya H, Tanji M, Oh-hara T, Tomida A, Naasani I, Tsuruo T (1999) Hypoxia up-regulates telomerase activity via mitogen-activated protein kinase signaling in human solid tumor cells. Biochem Biophys Res Commun 260:365–370. doi:10.1006/bbrc.1999.0910 PubMedCrossRefGoogle Scholar
  13. 13.
    Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379:88–91. doi:10.1038/379088a0 PubMedCrossRefGoogle Scholar
  14. 14.
    Eckerich C, Zapf S, Fillbrandt R, Loges S, Westphal M, Lamszus K (2007) Hypoxia can induce c-Met expression in glioma cells and enhance SF/HGF-induced cell migration. Int J Cancer 121:276–283. doi:10.1002/ijc.22679 PubMedCrossRefGoogle Scholar
  15. 15.
    Jogi A, Ora I, Nilsson H, Lindeheim A, Makino Y, Poellinger L, Axelson H, Pahlman S (2002) Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. Proc Natl Acad Sci USA 99:7021–7026. doi:10.1073/pnas.102660199 PubMedCrossRefGoogle Scholar
  16. 16.
    Raza SM, Lang FF, Aggarwal BB, Fuller GN, Wildrick DM, Sawaya R (2002) Necrosis and glioblastoma: a friend or a foe? A review and a hypothesis. Neurosurgery 51:2–12, discussion 12–13PubMedCrossRefGoogle Scholar
  17. 17.
    Russo CA, Weber TK, Volpe CM, Stoler DL, Petrelli NJ, Rodriguez-Bigas M, Burhans WC, Anderson GR (1995) An anoxia inducible endonuclease and enhanced DNA breakage as contributors to genomic instability in cancer. Cancer Res 55:1122–1128PubMedGoogle Scholar
  18. 18.
    Stoler DL, Anderson GR, Russo CA, Spina AM, Beerman TA (1992) Anoxia-inducible endonuclease activity as a potential basis of the genomic instability of cancer cells. Cancer Res 52:4372–4378PubMedGoogle Scholar
  19. 19.
    Sutherland RM (1998) Tumor hypoxia and gene expression—implications for malignant progression and therapy. Acta Oncol 37:567–574. doi:10.1080/028418698430278 PubMedCrossRefGoogle Scholar
  20. 20.
    Kaur B, Khwaja FW, Severson EA, Matheny SL, Brat DJ, Van Meir EG (2005) Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro-oncology 7:134–153. doi:10.1215/S1152851704001115 PubMedCrossRefGoogle Scholar
  21. 21.
    Brat DJ, Mapstone TB (2003) Malignant glioma physiology: cellular response to hypoxia and its role in tumor progression. Ann Intern Med 138:659–668PubMedGoogle Scholar
  22. 22.
    Jensen RL (2006) Hypoxia in the tumorigenesis of gliomas and as a potential target for therapeutic measures. Neurosurg Focus 20(4):E24. doi:10.3171/foc.2006.20.4.16 PubMedCrossRefGoogle Scholar
  23. 23.
    Gilhuis HJ, Bernse HJ, Jeuken JW, Wesselin P, Sprenger SH, Kerstens HM, Wiegant J, Boerman RH (2001) The relationship between genetic aberrations as detected by comparative genomic hybridization and vascularization in glioblastoma xenografts. J Neurooncol 51:121–127. doi:10.1023/A:1010675831154 PubMedCrossRefGoogle Scholar
  24. 24.
    Burton TR, Henson ES, Baijal P, Eisenstat DD, Gibson SB (2006) The pro-cell death Bcl-2 family member, BNIP3, is localized to the nucleus of human glial cells: Implications for glioblastoma multiforme tumor cell survival under hypoxia. Int J Cancer 118:1660–1669. doi:10.1002/ijc.21547 PubMedCrossRefGoogle Scholar
  25. 25.
    Fischer U, Radermacher J, Mayer J, Mehraein Y, Meese E (2008) Tumor hypoxia: Impact on gene amplification in glioblastoma. Int J Oncol 33:509–515PubMedGoogle Scholar
  26. 26.
    Rak J, Filmus J, Finkenzeller G, Grugel S, Marme D, Kerbel RS (1995) Oncogenes as inducers of tumor angiogenesis. Cancer Metastasis Rev 14:263–277. doi:10.1007/BF00690598 PubMedCrossRefGoogle Scholar
  27. 27.
    Giaccia AJ (1996) Hypoxic stress proteins: survival of the fittest. Semin Radiat Oncol 6:46–58. doi:10.1016/S1053-4296(96)80035-X PubMedCrossRefGoogle Scholar
  28. 28.
    Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364. doi:10.1016/S0092-8674(00)80108-7 PubMedCrossRefGoogle Scholar
  29. 29.
    Kerbel RS, Viloria-Petit A, Okada F, Rak J (1998) Establishing a link between oncogenes and tumor angiogenesis. Mol Med 4:286–295PubMedGoogle Scholar
  30. 30.
    Louis DN, Gusella JF (1995) A tiger behind many doors: multiple genetic pathways to malignant glioma. Trends Genet 11:412–415. doi:10.1016/S0168-9525(00)89125-8 PubMedCrossRefGoogle Scholar
  31. 31.
    Blazek ER, Foutch JL, Maki G (2007) Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133-cells, and the CD133+ sector is enlarged by hypoxia. Int J Radiat Oncol Biol Phys 67:1–5. doi:10.1016/j.ijrobp.2006.09.037 PubMedGoogle Scholar
  32. 32.
    Rodriguez-Jimenez FJ, Moreno-Manzano V, Lucas-Dominguez R, Sanchez-Puelles JM (2008) Hypoxia causes downregulation of mismatch repair system and genomic instability in stem cells. Stem Cells 26:2052–2062. doi:10.1634/stemcells.2007-1016 PubMedCrossRefGoogle Scholar
  33. 33.
    Li JL, Sainson RC, Shi W, Leek R, Harrington LS, Preusser M, Biswas S, Turley H, Heikamp E, Hainfellner JA, Harris AL (2007) Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res 67:11244–11253. doi:10.1158/0008-5472.CAN-07-0969 PubMedCrossRefGoogle Scholar
  34. 34.
    Raza SM, Fuller GN, Rhee CH, Huang S, Hess K, Zhang W, Sawaya R (2004) Identification of necrosis-associated genes in glioblastoma by cDNA microarray analysis. Clin Cancer Res 10:212–221. doi:10.1158/1078-0432.CCR-0155-3 PubMedCrossRefGoogle Scholar
  35. 35.
    Blasberg RG, Kobayashi T, Horowitz M, Rice JM, Groothuis D, Molnar P, Fenstermacher JD (1983) Regional blood flow in ethylnitrosourea-induced brain tumors. Ann Neurol 14:189–201. doi:10.1002/ana.410140206 PubMedCrossRefGoogle Scholar
  36. 36.
    Groothuis DR, Pasternak JF, Fischer JM, Blasberg RG, Bigner DD, Vick NA (1983) Regional measurements of blood flow in experimental RG-2 rat gliomas. Cancer Res 43:3362–3367PubMedGoogle Scholar
  37. 37.
    Hossman KA, Bloink M (1981) Blood flow and regulation of blood flow in experimental peritumoral edema. Stroke 12:211–217PubMedGoogle Scholar
  38. 38.
    Jain RK (1988) Determinants of tumor blood flow: a review. Cancer Res 48:2641–2658PubMedGoogle Scholar
  39. 39.
    Vajkoczy P, Menger MD (2004) Vascular microenvironment in gliomas. Cancer Treat Res 117:249–262PubMedGoogle Scholar
  40. 40.
    Groshar D, McEwan AJ, Parliament MB, Urtasun RC, Golberg LE, Hoskinson M, Mercer JR, Mannan RH, Wiebe LI, Chapman JD (1993) Imaging tumor hypoxia and tumor perfusion. J Nucl Med 34:885–888PubMedGoogle Scholar
  41. 41.
    Parliament MB, Franko AJ, Allalunis-Turner MJ, Mielke BW, Santos CL, Wolokoff BG, Mercer JR (1997) Anomalous patterns of nitroimidazole binding adjacent to necrosis in human glioma xenografts: possible role of decreased oxygen consumption. Br J Cancer 75:311–318PubMedGoogle Scholar
  42. 42.
    Rampling R, Cruickshank G, Lewis AD, Fitzsimmons SA, Workman P (1994) Direct measurement of pO2 distribution and bioreductive enzymes in human malignant brain tumors. Int J Radiat Oncol Biol Phys 29:427–431PubMedGoogle Scholar
  43. 43.
    Valk PE, Mathis CA, Prados MD, Gilbert JC, Budinger TF (1992) Hypoxia in human gliomas: demonstration by PET with fluorine-18-fluoromisonidazole. J Nucl Med 33:2133–2137PubMedGoogle Scholar
  44. 44.
    Rong Y, Post DE, Pieper RO, Durden DL, Van Meir EG, Brat DJ (2005) PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. Cancer Res 65:1406–1413. doi:10.1158/0008-5472.CAN-04-3376 PubMedCrossRefGoogle Scholar
  45. 45.
    Rong Y, Hu F, Huang R, Mackman N, Horowitz JM, Jensen RL, Durden DL, Van Meir EG, Brat DJ (2006) Early growth response gene-1 regulates hypoxia-induced expression of tissue factor in glioblastoma multiforme through hypoxia-inducible factor-1-independent mechanisms. Cancer Res 66:7067–7074. doi:10.1158/0008-5472.CAN-06-0346 PubMedCrossRefGoogle Scholar
  46. 46.
    Hammoud MA, Sawaya R, Shi W, Thall PF, Leeds NE (1996) Prognostic significance of preoperative MRI scans in glioblastoma multiforme. J Neurooncol 27:65–73. doi:10.1007/BF00146086 PubMedCrossRefGoogle Scholar
  47. 47.
    Knisely JP, Rockwell S (2002) Importance of hypoxia in the biology and treatment of brain tumors. Neuroimaging Clin N Am 12:525–536. doi:10.1016/S1052-5149(02)00032-1 PubMedCrossRefGoogle Scholar
  48. 48.
    Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, Lang FF, McCutcheon IE, Hassenbusch SJ, Holland E, Hess K, Michael C, Miller D, Sawaya R (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95:190–198PubMedGoogle Scholar
  49. 49.
    Flynn JR, Wang L, Gillespie DL, Stoddard GJ, Reid JK, Owens J, Ellsworth GB, Salzman KL, Kinney AY, Jensen RL (2008) Hypoxia-regulated protein expression, patient characteristics, and preoperative imaging as predictors of survival in adults with glioblastoma multiforme. Cancer 113:1032–1042. doi:10.1002/cncr.23678 PubMedCrossRefGoogle Scholar
  50. 50.
    Rong Y, Durden DL, Van Meir EG, Brat DJ (2006) ‘Pseudopalisading’ necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 65:529–539. doi:10.1097/00005072-200606000-00001 PubMedCrossRefGoogle Scholar
  51. 51.
    Brat DJ, Castellano-Sanchez AA, Hunter SB, Pecot M, Cohen C, Hammond EH, Devi SN, Kaur B, Van Meir EG (2004) Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population. Cancer Res 64:920–927. doi:10.1158/0008-5472.CAN-03-2073 PubMedCrossRefGoogle Scholar
  52. 52.
    Zagzag D, Esencay M, Mendez O, Yee H, Smirnova I, Huang Y, Chiriboga L, Lukyanov E, Liu M, Newcomb EW (2008) Hypoxia- and vascular endothelial growth factor-induced stromal cell-derived factor-1alpha/CXCR4 expression in glioblastomas: one plausible explanation of Scherer’s structures. Am J Pathol 173:545–560. doi:10.2353/ajpath.2008.071197 PubMedCrossRefGoogle Scholar
  53. 53.
    Elstner A, Holtkamp N, von Deimling A (2007) Involvement of Hif-1 in desferrioxamine-induced invasion of glioblastoma cells. Clin Exp Metastasis 24:57–66. doi:10.1007/s10585-007-9057-y PubMedCrossRefGoogle Scholar
  54. 54.
    Zagzag D, Lukyanov Y, Lan L, Ali MA, Esencay M, Mendez O, Yee H, Voura EB, Newcomb EW (2006) Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest 86:1221–1232. doi:10.1038/labinvest.3700482 PubMedCrossRefGoogle Scholar
  55. 55.
    Mirimanoff RO (2006) The evolution of chemoradiation for glioblastoma: a modern success story. Curr Oncol Rep 8:50–53. doi:10.1007/s11912-006-0009-5 PubMedCrossRefGoogle Scholar
  56. 56.
    Stupp R, Weber DC (2005) The role of radio- and chemotherapy in glioblastoma. Onkologie 28:315–317. doi:10.1159/000085575 PubMedCrossRefGoogle Scholar
  57. 57.
    Sarkaria JN, Kitange GJ, James CD, Plummer R, Calvert H, Weller M, Wick W (2008) Mechanisms of chemoresistance to alkylating agents in malignant glioma. Clin Cancer Res 14:2900–2908. doi:10.1158/1078-0432.CCR-07-1719 PubMedCrossRefGoogle Scholar
  58. 58.
    Chen Z, Htay A, Santos WD, Gillies GT, Fillmore HL, Sholley MM, Broaddus WC (2008) In vitro angiogenesis by human umbilical vein endothelial cells (HUVEC) induced by three-dimensional co-culture with glioblastoma cells. J Neurooncol 92(2):121–128. doi:10.1007/s11060-008-9742-y Google Scholar
  59. 59.
    Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Leung E, Maclennan S, Baraldi PG, Borea PA (2007) Hypoxia inhibits paclitaxel-induced apoptosis through adenosine-mediated phosphorylation of bad in glioblastoma cells. Mol Pharmacol 72:162–172. doi:10.1124/mol.106.031849 PubMedCrossRefGoogle Scholar
  60. 60.
    Newcomb EW, Lukyanov Y, Smirnova I, Schnee T, Zagzag D (2008) Noscapine induces apoptosis in human glioma cells by an apoptosis-inducing factor-dependent pathway. Anticancer Drugs 19:553–563. doi:10.1097/CAD.0b013e3282ffd68d PubMedCrossRefGoogle Scholar
  61. 61.
    Ezhilarasan R, Mohanam I, Govindarajan K, Mohanam S (2007) Glioma cells suppress hypoxia-induced endothelial cell apoptosis and promote the angiogenic process. Int J Oncol 30:701–707PubMedGoogle Scholar
  62. 62.
    Sathornsumetee S, Cao Y, Marcello JE, Herndon JE II, McLendon RE, Desjardins A, Friedman HS, Dewhirst MW, Vredenburgh JJ, Rich JN (2008) Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J Clin Oncol 26:271–278. doi:10.1200/JCO.2007.13.3652 PubMedCrossRefGoogle Scholar
  63. 63.
    Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603. doi:10.1038/nrc2442 PubMedCrossRefGoogle Scholar
  64. 64.
    Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864. doi:10.1038/nm1075 PubMedCrossRefGoogle Scholar
  65. 65.
    De Falco E, Porcelli D, Torella AR, Straino S, Iachininoto MG, Orlandi A, Truffa S, Biglioli P, Napolitano M, Capogrossi MC, Pesce M (2004) SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. Blood 104:3472–3482. doi:10.1182/blood-2003-12-4423 PubMedCrossRefGoogle Scholar
  66. 66.
    Petit I, Jin D, Rafii S (2007) The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol 28:299–307. doi:10.1016/j.it.2007.05.007 PubMedCrossRefGoogle Scholar
  67. 67.
    Aghi M, Cohen KS, Klein RJ, Scadden DT, Chiocca EA (2006) Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. Cancer Res 66:9054–9064. doi:10.1158/0008-5472.CAN-05-3759 PubMedCrossRefGoogle Scholar
  68. 68.
    Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, Song H, Vandenberg S, Johnson RS, Werb Z, Bergers G (2008) HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13:206–220. doi:10.1016/j.ccr.2008.01.034 PubMedCrossRefGoogle Scholar
  69. 69.
    Tabatabai G, Frank B, Mohle R, Weller M, Wick W (2006) Irradiation and hypoxia promote homing of haematopoietic progenitor cells towards gliomas by TGFbeta-dependent HIF-1alpha-mediated induction of CXCL12. Brain 129:2426–2435. doi:10.1093/brain/awl173 PubMedCrossRefGoogle Scholar
  70. 70.
    Leibel SA, Scott CB, Loeffler JS (1994) Contemporary approaches to the treatment of malignant gliomas with radiation therapy. Semin Oncol 21:198–219PubMedGoogle Scholar
  71. 71.
    Stieber VW, Mehta MP (2007) Advances in radiation therapy for brain tumors. Neurol Clin 25:1005–1033, ixPubMedCrossRefGoogle Scholar
  72. 72.
    Bloom HJ (1982) Intracranial tumors: response and resistance to therapeutic endeavors, 1970–1980. Int J Radiat Oncol Biol Phys 8:1083–1113PubMedGoogle Scholar
  73. 73.
    Eyler CE, Rich JN (2008) Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol 26:2839–2845. doi:10.1200/JCO.2007.15.1829 PubMedCrossRefGoogle Scholar
  74. 74.
    Spence AM, Muzi M, Swanson KR, O’Sullivan F, Rockhill JK, Rajendran JG, Adamsen TC, Link JM, Swanson PE, Yagle KJ, Rostomily RC, Silbergeld DL, Krohn KA (2008) Regional hypoxia in glioblastoma multiforme quantified with [18F]fluoromisonidazole positron emission tomography before radiotherapy: correlation with time to progression and survival. Clin Cancer Res 14:2623–2630. doi:10.1158/1078-0432.CCR-07-4995 PubMedCrossRefGoogle Scholar
  75. 75.
    Chen JK, Hu LJ, Wang J, Lamborn KR, Kong EL, Deen DF (2005) Hypoxia-induced BAX overexpression and radiation killing of hypoxic glioblastoma cells. Radiat Res 163:644–653. doi:10.1667/RR3377 PubMedCrossRefGoogle Scholar
  76. 76.
    Jiang BH, Rue E, Wang GL, Roe R, Semenza GL (1996) Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem 271:17771–17778. doi:10.1074/jbc.271.30.17771 PubMedCrossRefGoogle Scholar
  77. 77.
    Cho S, Choi YJ, Kim JM, Jeong ST, Kim JH, Kim SH, Ryu SE (2001) Binding and regulation of HIF-1 by a subunit of the proteasome complex, PSMA7. FEBS Lett 498:62–66. doi:10.1016/S0014-5793(01)02499-1 PubMedCrossRefGoogle Scholar
  78. 78.
    Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, Maxwell PH (2000) Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 275:25733–25741. doi:10.1074/jbc.M002740200 PubMedCrossRefGoogle Scholar
  79. 79.
    Iwai K, Yamanaka K, Kamura T, Minato N, Conaway RC, Conaway JW, Klausner RD, Pause A (1999) Identification of the von Hippel-Lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc Natl Acad Sci USA 96:12436–12441. doi:10.1073/pnas.96.22.12436 PubMedCrossRefGoogle Scholar
  80. 80.
    Sutter CH, Laughner E, Semenza GL (2000) Hypoxia-inducible factor 1alpha protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations. Proc Natl Acad Sci USA 97:4748–4753. doi:10.1073/pnas.080072497 PubMedCrossRefGoogle Scholar
  81. 81.
    Hewitson KS, McNeill LA, Riordan MV, Tian YM, Bullock AN, Welford RW, Elkins JM, Oldham NJ, Bhattacharya S, Gleadle JM, Ratcliffe PJ, Pugh CW, Schofield CJ (2002) Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J Biol Chem 277:26351–26355. doi:10.1074/jbc.C200273200 PubMedCrossRefGoogle Scholar
  82. 82.
    Mahon PC, Hirota K, Semenza GL (2001) FIH-1: a novel protein that interacts with HIF-1 and VHL to mediate repression of HIF-1alpha transcriptional activity. Genes Dev 15:2675–2686. doi:10.1101/gad.924501 PubMedCrossRefGoogle Scholar
  83. 83.
    Brahimi-Horn C, Berra E, Pouyssegur J (2001) Hypoxia: the tumor’s gateway to progression along the angiogenic pathway. Trends Cell Biol 11:S32–S36. doi:10.1016/S0962-8924(01)02126-2 PubMedCrossRefGoogle Scholar
  84. 84.
    Lal A, Peters H, St. Croix B, Haroon ZA, Dewhirst MW, Strausberg RL, Kaanders JH, van der Kogel AJ, Riggins GJ (2001) Transcriptional response to hypoxia in human tumors. J Natl Cancer Inst 93:1337–1343. doi:10.1093/jnci/93.17.1337 PubMedCrossRefGoogle Scholar
  85. 85.
    Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468. doi:10.1126/science.1059817 PubMedCrossRefGoogle Scholar
  86. 86.
    Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIFalpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472. doi:10.1126/science.1059796 PubMedCrossRefGoogle Scholar
  87. 87.
    Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK (2002) FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 16:1466–1471. doi:10.1101/gad.991402 PubMedCrossRefGoogle Scholar
  88. 88.
    Semenza G (2002) Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol 64:993–998. doi:10.1016/S0006-2952(02)01168-1 PubMedCrossRefGoogle Scholar
  89. 89.
    Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514. doi:10.1073/pnas.92.12.5510 PubMedCrossRefGoogle Scholar
  90. 90.
    Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9:677–684. doi:10.1038/nm0603-677 PubMedCrossRefGoogle Scholar
  91. 91.
    Wykoff CC, Pugh CW, Maxwell PH, Harris AL, Ratcliffe PJ (2000) Identification of novel hypoxia dependent and independent target genes of the von Hippel-Lindau (VHL) tumour suppressor by mRNA differential expression profiling. Oncogene 19:6297–6305. doi:10.1038/sj.onc.1204012 PubMedCrossRefGoogle Scholar
  92. 92.
    Brat DJ, Kaur B, Van Meir EG (2003) Genetic modulation of hypoxia induced gene expression and angiogenesis: relevance to brain tumors. Front Biosci 8:d100–d116. doi:10.2741/942 PubMedCrossRefGoogle Scholar
  93. 93.
    Kietzmann T, Krones-Herzig A, Jungermann K (2002) Signaling cross-talk between hypoxia and glucose via hypoxia-inducible factor 1 and glucose response elements. Biochem Pharmacol 64:903–911. doi:10.1016/S0006-2952(02)01160-7 PubMedCrossRefGoogle Scholar
  94. 94.
    Semenza GL (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15:551–578. doi:10.1146/annurev.cellbio.15.1.551 PubMedCrossRefGoogle Scholar
  95. 95.
    Krieg M, Haas R, Brauch H, Acker T, Flamme I, Plate KH (2000) Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene 19:5435–5443. doi:10.1038/sj.onc.1203938 PubMedCrossRefGoogle Scholar
  96. 96.
    Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG (2000) Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2:423–427. doi:10.1038/35017054 PubMedCrossRefGoogle Scholar
  97. 97.
    Richard DE, Berra E, Pouyssegur J (1999) Angiogenesis: how a tumor adapts to hypoxia. Biochem Biophys Res Commun 266:718–722. doi:10.1006/bbrc.1999.1889 PubMedCrossRefGoogle Scholar
  98. 98.
    Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW (1999) Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59:5830–5835PubMedGoogle Scholar
  99. 99.
    Friedrich CA (2001) Genotype–phenotype correlation in von Hippel-Lindau syndrome. Hum Mol Genet 10:763–767. doi:10.1093/hmg/10.7.763 PubMedCrossRefGoogle Scholar
  100. 100.
    Kaelin WG Jr (2002) Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2:673–682. doi:10.1038/nrc885 PubMedCrossRefGoogle Scholar
  101. 101.
    Kaelin WG, Iliopoulos O, Lonergan KM, Ohh M (1998) Functions of the von Hippel-Lindau tumour suppressor protein. J Intern Med 243:535–539. doi:10.1046/j.1365-2796.1998.00335.x PubMedCrossRefGoogle Scholar
  102. 102.
    Kaelin WG Jr, Maher ER (1998) The VHL tumour-suppressor gene paradigm. Trends Genet 14:423–426. doi:10.1016/S0168-9525(98)01558-3 PubMedCrossRefGoogle Scholar
  103. 103.
    Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L et al (1993) Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317–1320. doi:10.1126/science.8493574 PubMedCrossRefGoogle Scholar
  104. 104.
    Chen F, Kishida T, Duh FM, Renbaum P, Orcutt ML, Schmidt L, Zbar B (1995) Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene. Cancer Res 55:4804–4807PubMedGoogle Scholar
  105. 105.
    Friedrich CA (1999) Von Hippel-Lindau syndrome. A pleomorphic condition. Cancer 86:2478–2482. doi:10.1002/(SICI)1097-0142(19991201)86:11+<2478::AID-CNCR4>3.0.CO;2-5 PubMedCrossRefGoogle Scholar
  106. 106.
    Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG Jr (2002) Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 1:237–246. doi:10.1016/S1535-6108(02)00043-0 PubMedCrossRefGoogle Scholar
  107. 107.
    Gnarra JR, Zhou S, Merrill MJ, Wagner JR, Krumm A, Papavassiliou E, Oldfield EH, Klausner RD, Linehan WM (1996) Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci USA 93:10589–10594. doi:10.1073/pnas.93.20.10589 PubMedCrossRefGoogle Scholar
  108. 108.
    Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA (1996) Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci USA 93:10595–10599. doi:10.1073/pnas.93.20.10595 PubMedCrossRefGoogle Scholar
  109. 109.
    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 399:271–275. doi:10.1038/20459 PubMedCrossRefGoogle Scholar
  110. 110.
    Siemeister G, Weindel K, Mohrs K, Barleon B, Martiny-Baron G, Marme D (1996) Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res 56:2299–2301PubMedGoogle Scholar
  111. 111.
    Stratman NC, Carter DB, Sethy VH (1997) Ibuprofen: effect on inducible nitric oxide synthase. Brain Res Mol Brain Res 50:107–112. doi:10.1016/S0169-328X(97)00168-X PubMedCrossRefGoogle Scholar
  112. 112.
    Kanno H, Shuin T, Kondo K, Yamamoto I, Ito S, Shinonaga M, Yoshida M, Yao M (1997) Somatic mutations of the von Hippel-Lindau tumor suppressor gene and loss of heterozygosity on chromosome 3p in human glial tumors. Cancer Res 57:1035–1038PubMedGoogle Scholar
  113. 113.
    Chun YS, Choi E, Kim TY, Kim MS, Park JW (2002) A dominant-negative isoform lacking exons 11 and 12 of the human hypoxia-inducible factor-1alpha gene. Biochem J 362:71–79. doi:10.1042/0264-6021:3620071 PubMedCrossRefGoogle Scholar
  114. 114.
    Mazure NM, Chen EY, Laderoute KR, Giaccia AJ (1997) Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood 90:3322–3331PubMedGoogle Scholar
  115. 115.
    Richard DE, Berra E, Pouyssegur J (2000) Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells. J Biol Chem 275:26765–26771PubMedGoogle Scholar
  116. 116.
    Tacchini L, Dansi P, Matteucci E, Desiderio MA (2001) Hepatocyte growth factor signalling stimulates hypoxia inducible factor-1 (HIF-1) activity in HepG2 hepatoma cells. Carcinogenesis 22:1363–1371. doi:10.1093/carcin/22.9.1363 PubMedCrossRefGoogle Scholar
  117. 117.
    Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B (1998) Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. EMBO J 17:5085–5094. doi:10.1093/emboj/17.17.5085 PubMedCrossRefGoogle Scholar
  118. 118.
    Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB, Stokoe D, Giaccia AJ (2000) Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 14:391–396PubMedGoogle Scholar
  119. 119.
    Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL (1999) Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res 59:3915–3918PubMedGoogle Scholar
  120. 120.
    Jiang BH, Semenza GL, Bauer C, Marti HH (1996) Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol 271:C1172–C1180PubMedGoogle Scholar
  121. 121.
    Beasley NJ, Leek R, Alam M, Turley H, Cox GJ, Gatter K, Millard P, Fuggle S, Harris AL (2002) 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 62:2493–2497PubMedGoogle Scholar
  122. 122.
    Volm M, Koomagi R (2000) Hypoxia-inducible factor (HIF-1) and its relationship to apoptosis and proliferation in lung cancer. Anticancer Res 20:1527–1533PubMedGoogle Scholar
  123. 123.
    Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, Abeloff MD, Simons JW, van Diest PJ, van der Wall E (2001) Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst 93:309–314. doi:10.1093/jnci/93.4.309 PubMedCrossRefGoogle Scholar
  124. 124.
    Leek RD, Talks KL, Pezzella F, Turley H, Campo L, Brown NS, Bicknell R, Taylor M, Gatter KC, Harris AL (2002) Relation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in Human breast cancer. Cancer Res 62:1326–1329PubMedGoogle Scholar
  125. 125.
    Jones A, Fujiyama C, Blanche C, Moore JW, Fuggle S, Cranston D, Bicknell R, Harris AL (2001) Relation of vascular endothelial growth factor production to expression and regulation of hypoxia-inducible factor-1 alpha and hypoxia-inducible factor-2 alpha in human bladder tumors and cell lines. Clin Cancer Res 7:1263–1272PubMedGoogle Scholar
  126. 126.
    Akakura N, Kobayashi M, Horiuchi I, Suzuki A, Wang J, Chen J, Niizeki H, Kawamura K, Hosokawa M, Asaka M (2001) Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res 61:6548–6554PubMedGoogle Scholar
  127. 127.
    Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH, Semenza GL (2001) Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 61:2911–2916PubMedGoogle Scholar
  128. 128.
    Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G (2000) Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 60:4693–4696PubMedGoogle Scholar
  129. 129.
    Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der Wall E (2003) Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 97:1573–1581. doi:10.1002/cncr.11246 PubMedCrossRefGoogle Scholar
  130. 130.
    Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3:347–361. doi:10.1016/S1535-6108(03)00085-0 PubMedCrossRefGoogle Scholar
  131. 131.
    Ruan H, Su H, Hu L, Lamborn KR, Kan YW, Deen DF (2001) A hypoxia-regulated adeno-associated virus vector for cancer-specific gene therapy. Neoplasia 3:255–263. doi:10.1038/sj.neo.7900157 PubMedCrossRefGoogle Scholar
  132. 132.
    Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W (2003) Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425:307–311. doi:10.1038/nature01874 PubMedCrossRefGoogle Scholar
  133. 133.
    Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E, Keshet E (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490. doi:10.1038/28867 PubMedCrossRefGoogle Scholar
  134. 134.
    Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, Hankinson O, Pugh CW, Ratcliffe PJ (1997) Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA 94:8104–8109. doi:10.1073/pnas.94.15.8104 PubMedCrossRefGoogle Scholar
  135. 135.
    Ryan HE, Lo J, Johnson RS (1998) HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J 17:3005–3015. doi:10.1093/emboj/17.11.3005 PubMedCrossRefGoogle Scholar
  136. 136.
    Ryan HE, Poloni M, McNulty W, Elson D, Gassmann M, Arbeit JM, Johnson RS (2000) Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Res 60:4010–4015PubMedGoogle Scholar
  137. 137.
    Gaddipati JP, Madhavan S, Sidhu GS, Singh AK, Seth P, Maheshwari RK (1999) Picroliv—a natural product protects cells and regulates the gene expression during hypoxia/reoxygenation. Mol Cell Biochem 194:271–281. doi:10.1023/A:1006982028460 PubMedCrossRefGoogle Scholar
  138. 138.
    Kimura H, Weisz A, Kurashima Y, Hashimoto K, Ogura T, D’Acquisto F, Addeo R, Makuuchi M, Esumi H (2000) Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. Blood 95:189–197PubMedGoogle Scholar
  139. 139.
    Gillespie DL, Whang K, Ragel BT, Flynn JR, Kelly DA, Jensen RL (2007) Silencing of hypoxia inducible factor-1alpha by RNA interference attenuates human glioma cell growth in vivo. Clin Cancer Res 13:2441–2448. doi:10.1158/1078-0432.CCR-06-2692 PubMedCrossRefGoogle Scholar
  140. 140.
    Cooper R, Sarioglu S, Sokmen S, Fuzun M, Kupelioglu A, Valentine H, Gorken IB, Airley R, West C (2003) Glucose transporter-1 (GLUT-1): a potential marker of prognosis in rectal carcinoma? Br J Cancer 89:870–876. doi:10.1038/sj.bjc.6601202 PubMedCrossRefGoogle Scholar
  141. 141.
    Potter CP, Harris AL (2003) Diagnostic, prognostic and therapeutic implications of carbonic anhydrases in cancer. Br J Cancer 89:2–7. doi:10.1038/sj.bjc.6600936 PubMedCrossRefGoogle Scholar
  142. 142.
    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 89:271–276. doi:10.1038/sj.bjc.6601122 PubMedCrossRefGoogle Scholar
  143. 143.
    Ihnatko R, Kubes M, Takacova M, Sedlakova O, Sedlak J, Pastorek J, Kopacek J, Pastorekova S (2006) Extracellular acidosis elevates carbonic anhydrase IX in human glioblastoma cells via transcriptional modulation that does not depend on hypoxia. Int J Oncol 29:1025–1033PubMedGoogle Scholar
  144. 144.
    Lund EL, Hog A, Olsen MW, Hansen LT, Engelholm SA, Kristjansen PE (2004) Differential regulation of VEGF, HIF1alpha and angiopoietin-1, -2 and -4 by hypoxia and ionizing radiation in human glioblastoma. Int J Cancer 108:833–838. doi:10.1002/ijc.11662 PubMedCrossRefGoogle Scholar
  145. 145.
    Sondergaard KL, Hilton DA, Penney M, Ollerenshaw M, Demaine AG (2002) Expression of hypoxia-inducible factor 1alpha in tumours of patients with glioblastoma. Neuropathol Appl Neurobiol 28:210–217. doi:10.1046/j.1365-2990.2002.00391.x PubMedCrossRefGoogle Scholar
  146. 146.
    Vidal S, Horvath E, Kovacs K, Kuroki T, Lloyd RV, Scheithauer BW (2003) Expression of hypoxia-inducible factor-1alpha (HIF-1alpha) in pituitary tumours. Histol Histopathol 18:679–686PubMedGoogle Scholar
  147. 147.
    Zagzag D, Zhong H, Scalzitti JM, Laughner E, Simons JW, Semenza GL (2000) Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer 88:2606–2618. doi:10.1002/1097-0142(20000601)88:11<2606::AID-CNCR25>3.0.CO;2-W PubMedCrossRefGoogle Scholar
  148. 148.
    Belkaid A, Fortier S, Cao J, Annabi B (2007) Necrosis induction in glioblastoma cells reveals a new “bioswitch” function for the MT1-MMP/G6PT signaling axis in proMMP-2 activation versus cell death decision. Neoplasia 9:332–340. doi:10.1593/neo.07142 PubMedCrossRefGoogle Scholar
  149. 149.
    Said HM, Polat B, Staab A, Hagemann C, Stein S, Flentje M, Theobald M, Katzer A, Vordermark D (2008) Rapid detection of the hypoxia-regulated CA-IX and NDRG1 gene expression in different glioblastoma cells in vitro. Oncol Rep 20:413–419PubMedGoogle Scholar
  150. 150.
    Tsukamoto H, Boado RJ, Pardridge WM (1996) Differential expression in glioblastoma multiforme and cerebral hemangioblastoma of cytoplasmic proteins that bind two different domains within the 3′-untranslated region of the human glucose transporter 1 (GLUT1) messenger RNA. J Clin Invest 97:2823–2832. doi:10.1172/JCI118738 PubMedCrossRefGoogle Scholar
  151. 151.
    Said HM, Hagemann C, Staab A, Stojic J, Kuhnel S, Vince GH, Flentje M, Roosen K, Vordermark D (2007) Expression patterns of the hypoxia-related genes osteopontin, CA9, erythropoietin, VEGF and HIF-1alpha in human glioma in vitro and in vivo. Radiother Oncol 83:398–405. doi:10.1016/j.radonc.2007.05.003 PubMedCrossRefGoogle Scholar
  152. 152.
    Kaynar MY, Sanus GZ, Hnimoglu H, Kacira T, Kemerdere R, Atukeren P, Gumustas K, Canbaz B, Tanriverdi T (2008) Expression of hypoxia inducible factor-1alpha in tumors of patients with glioblastoma multiforme and transitional meningioma. J Clin Neurosci 15:1036–1042. doi:10.1016/j.jocn.2007.07.080 PubMedCrossRefGoogle Scholar
  153. 153.
    Ragel BT, Couldwell WT, Gillespie DL, Jensen RL (2007) Identification of hypoxia-induced genes in a malignant glioma cell line (U-251) by cDNA microarray analysis. Neurosurg Rev 30:181–187, discussion 187PubMedCrossRefGoogle Scholar
  154. 154.
    Bates S, Rowan S, Vousden KH (1996) Characterisation of human cyclin G1 and G2: DNA damage inducible genes. Oncogene 13:1103–1109PubMedGoogle Scholar
  155. 155.
    Martinez-Gac L, Marques M, Garcia Z, Campanero MR, Carrera AC (2004) Control of cyclin G2 mRNA expression by forkhead transcription factors: novel mechanism for cell cycle control by phosphoinositide 3-kinase and forkhead. Mol Cell Biol 24:2181–2189. doi:10.1128/MCB.24.5.2181-2189.2004 PubMedCrossRefGoogle Scholar
  156. 156.
    Burger AM, Leyland-Jones B, Banerjee K, Spyropoulos DD, Seth AK (2005) Essential roles of IGFBP-3 and IGFBP-rP1 in breast cancer. Eur J Cancer 41:1515–1527. doi:10.1016/j.ejca.2005.04.023 PubMedCrossRefGoogle Scholar
  157. 157.
    Elmlinger MW, Mayer I, Schnabel D, Schuett BS, Diesing D, Romalo G, Wollmann HA, Weidemann W, Spindler KD, Ranke MB, Schweikert HU (2001) Decreased expression of IGF-II and its binding protein, IGF-binding protein-2, in genital skin fibroblasts of patients with complete androgen insensitivity syndrome compared with normally virilized males. J Clin Endocrinol Metab 86:4741–4746. doi:10.1210/jc.86.10.4741 PubMedCrossRefGoogle Scholar
  158. 158.
    Deal C, Ma J, Wilkin F, Paquette J, Rozen F, Ge B, Hudson T, Stampfer M, Pollak M (2001) Novel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators. J Clin Endocrinol Metab 86:1274–1280. doi:10.1210/jc.86.3.1274 PubMedCrossRefGoogle Scholar
  159. 159.
    Ferry RJ Jr, Cerri RW, Cohen P (1999) Insulin-like growth factor binding proteins: new proteins, new functions. Horm Res 51:53–67. doi:10.1159/000023315 PubMedCrossRefGoogle Scholar
  160. 160.
    Nishioka T, Oda Y, Seino Y, Yamamoto T, Inagaki N, Yano H, Imura H, Shigemoto R, Kikuchi H (1992) Distribution of the glucose transporters in human brain tumors. Cancer Res 52:3972–3979PubMedGoogle Scholar
  161. 161.
    Boado RJ, Black KL, Pardridge WM (1994) Gene expression of GLUT3 and GLUT1 glucose transporters in human brain tumors. Brain Res Mol Brain Res 27:51–57. doi:10.1016/0169-328X(94)90183-X PubMedCrossRefGoogle Scholar
  162. 162.
    Nagamatsu S, Sawa H, Wakizaka A, Hoshino T (1993) Expression of facilitative glucose transporter isoforms in human brain tumors. J Neurochem 61:2048–2053. doi:10.1111/j.1471-4159.1993.tb07441.x PubMedCrossRefGoogle Scholar
  163. 163.
    Ciaccio PJ, Shen H, Jaiswal AK, Lyttle MH, Tew KD (1995) Modulation of detoxification gene expression in human colon HT29 cells by glutathione-S-transferase inhibitors. Mol Pharmacol 48:639–647PubMedGoogle Scholar
  164. 164.
    Landi S (2000) Mammalian class theta GST and differential susceptibility to carcinogens: a review. Mutat Res 463:247–283. doi:10.1016/S1383-5742(00)00050-8 PubMedCrossRefGoogle Scholar
  165. 165.
    Ozanne BW, Spence HJ, McGarry LC, Hennigan RF (2006) Invasion is a genetic program regulated by transcription factors. Curr Opin Genet Dev 16:65–70. doi:10.1016/j.gde.2005.12.012 PubMedCrossRefGoogle Scholar
  166. 166.
    Fujimoto M, Sheridan PJ, Sharp ZD, Weaker FJ, Kagan-Hallet S, Story JL (1989) Proto-oncogene analyses in brain tumors. J Neurosurg 70:910–915PubMedGoogle Scholar
  167. 167.
    Fujimoto M, Weaker FJ, Herbert DC, Sharp ZD, Sheridan PJ, Story JL (1988) Expression of three viral oncogenes (v-sis, v-myc, v-fos) in primary human brain tumors of neuroectodermal origin. Neurology 38:289–293PubMedGoogle Scholar
  168. 168.
    Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, Harding H, Novoa I, Varia M, Raleigh J, Scheuner D, Kaufman RJ, Bell J, Ron D, Wouters BG, Koumenis C (2005) ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J 24:3470–3481. doi:10.1038/sj.emboj.7600777 PubMedCrossRefGoogle Scholar
  169. 169.
    Carriere A, Carmona MC, Fernandez Y, Rigoulet M, Wenger RH, Penicaud L, Casteilla L (2004) Mitochondrial reactive oxygen species control the transcription factor CHOP-10/GADD153 and adipocyte differentiation: a mechanism for hypoxia-dependent effect. J Biol Chem 279:40462–40469. doi:10.1074/jbc.M407258200 PubMedCrossRefGoogle Scholar
  170. 170.
    Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP, Ron D (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 18:3066–3077. doi:10.1101/gad.1250704 PubMedCrossRefGoogle Scholar
  171. 171.
    Tajiri S, Oyadomari S, Yano S, Morioka M, Gotoh T, Hamada JI, Ushio Y, Mori M (2004) Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell Death Differ 11:403–415. doi:10.1038/sj.cdd.4401365 PubMedCrossRefGoogle Scholar
  172. 172.
    Mechaly I, Bourane S, Piquemal D, Al-Jumaily M, Venteo S, Puech S, Scamps F, Valmier J, Carroll P (2006) Gene profiling during development and after a peripheral nerve traumatism reveals genes specifically induced by injury in dorsal root ganglia. Mol Cell Neurosci 32:217–229. doi:10.1016/j.mcn.2006.04.004 PubMedCrossRefGoogle Scholar
  173. 173.
    Tajiri S, Yano S, Morioka M, Kuratsu J, Mori M, Gotoh T (2006) CHOP is involved in neuronal apoptosis induced by neurotrophic factor deprivation. FEBS Lett 580:3462–3468. doi:10.1016/j.febslet.2006.05.021 PubMedCrossRefGoogle Scholar
  174. 174.
    Fung KM, Samara EN, Wong C, Metwalli A, Krlin R, Bane B, Liu CZ, Yang JT, Pitha JV, Culkin DJ, Kropp BP, Penning TM, Lin HK (2006) Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma. Endocr Relat Cancer 13:169–180. doi:10.1677/erc.1.01048 PubMedCrossRefGoogle Scholar
  175. 175.
    Khanna M, Qin KN, Klisak I, Belkin S, Sparkes RS, Cheng KC (1995) Localization of multiple human dihydrodiol dehydrogenase (DDH1 and DDH2) and chlordecone reductase (CHDR) genes in chromosome 10 by the polymerase chain reaction and fluorescence in situ hybridization. Genomics 25:588–590. doi:10.1016/0888-7543(95)80066-U PubMedCrossRefGoogle Scholar
  176. 176.
    Penning TM, Steckelbroeck S, Bauman DR, Miller MW, Jin Y, Peehl DM, Fung KM, Lin HK (2006) Aldo-keto reductase (AKR) 1C3: role in prostate disease and the development of specific inhibitors. Mol Cell Endocrinol 248:182–191. doi:10.1016/j.mce.2005.12.009 PubMedCrossRefGoogle Scholar
  177. 177.
    Shin D, Anderson DJ (2005) Isolation of arterial-specific genes by subtractive hybridization reveals molecular heterogeneity among arterial endothelial cells. Dev Dyn 233:1589–1604. doi:10.1002/dvdy.20479 PubMedCrossRefGoogle Scholar
  178. 178.
    Watanabe H, Nonoguchi K, Sakurai T, Masuda T, Itoh K, Fujita J (2005) A novel protein Depp, which is induced by progesterone in human endometrial stromal cells activates Elk-1 transcription factor. Mol Hum Reprod 11:471–476. doi:10.1093/molehr/gah186 PubMedCrossRefGoogle Scholar
  179. 179.
    Eddy EM, Toshimori K, O’Brien DA (2003) Fibrous sheath of mammalian spermatozoa. Microsc Res Tech 61:103–115. doi:10.1002/jemt.10320 PubMedCrossRefGoogle Scholar
  180. 180.
    Davare MA, Dong F, Rubin CS, Hell JW (1999) The A-kinase anchor protein MAP2B and cAMP-dependent protein kinase are associated with class C L-type calcium channels in neurons. J Biol Chem 274:30280–30287. doi:10.1074/jbc.274.42.30280 PubMedCrossRefGoogle Scholar
  181. 181.
    Koch M, Korf HW (2002) Distribution of regulatory subunits of protein kinase A and A kinase anchor proteins (AKAP 95, 150) in rat pinealocytes. Cell Tissue Res 310:331–338. doi:10.1007/s00441-002-0633-9 PubMedCrossRefGoogle Scholar
  182. 182.
    Sik A, Gulacsi A, Lai Y, Doyle WK, Pacia S, Mody I, Freund TF (2000) Localization of the A kinase anchoring protein AKAP79 in the human hippocampus. Eur J NeuroSci 12:1155–1164. doi:10.1046/j.1460-9568.2000.00002.x PubMedCrossRefGoogle Scholar
  183. 183.
    Su Y, Balice-Gordon RJ, Hess DM, Landsman DS, Minarcik J, Golden J, Hurwitz I, Liebhaber SA, Cooke NE (2004) Neurobeachin is essential for neuromuscular synaptic transmission. J Neurosci 24:3627–3636. doi:10.1523/JNEUROSCI.4644-03.2004 PubMedCrossRefGoogle Scholar
  184. 184.
    Lord EM, Harwell L, Koch CJ (1993) Detection of hypoxic cells by monoclonal antibody recognizing 2-nitroimidazole adducts. Cancer Res 53:5721–5726PubMedGoogle Scholar
  185. 185.
    Arteel GE, Thurman RG, Raleigh JA (1998) Reductive metabolism of the hypoxia marker pimonidazole is regulated by oxygen tension independent of the pyridine nucleotide redox state. Eur J Biochem 253:743–750. doi:10.1046/j.1432-1327.1998.2530743.x PubMedCrossRefGoogle Scholar
  186. 186.
    Rijken PF, Bernsen HJ, Peters JP, Hodgkiss RJ, Raleigh JA, van der Kogel AJ (2000) Spatial relationship between hypoxia and the (perfused) vascular network in a human glioma xenograft: a quantitative multi-parameter analysis. Int J Radiat Oncol Biol Phys 48:571–582. doi:10.1016/S0360-3016(00)00686-6 PubMedGoogle Scholar
  187. 187.
    Raleigh JA, Chou SC, Arteel GE, Horsman MR (1999) Comparisons among pimonidazole binding, oxygen electrode measurements, and radiation response in C3H mouse tumors. Radiat Res 151:580–589. doi:10.2307/3580034 PubMedCrossRefGoogle Scholar
  188. 188.
    Wijffels KI, Kaanders JH, Rijken PF, Bussink J, van den Hoogen FJ, Marres HA, de Wilde PC, Raleigh JA, van der Kogel AJ (2000) Vascular architecture and hypoxic profiles in human head and neck squamous cell carcinomas. Br J Cancer 83:674–683. doi:10.1054/bjoc.2000.1325 PubMedCrossRefGoogle Scholar
  189. 189.
    Raleigh JA, Chou SC, Calkins-Adams DP, Ballenger CA, Novotny DB, Varia MA (2000) A clinical study of hypoxia and metallothionein protein expression in squamous cell carcinomas. Clin Cancer Res 6:855–862PubMedGoogle Scholar
  190. 190.
    Vukovic V, Haugland HK, Nicklee T, Morrison AJ, Hedley DW (2001) Hypoxia-inducible factor-1alpha is an intrinsic marker for hypoxia in cervical cancer xenografts. Cancer Res 61:7394–7398PubMedGoogle Scholar
  191. 191.
    Bentzen L, Keiding S, Nordsmark M, Falborg L, Hansen SB, Keller J, Nielsen OS, Overgaard J (2003) Tumour oxygenation assessed by 18F-fluoromisonidazole PET and polarographic needle electrodes in human soft tissue tumours. Radiother Oncol 67:339–344. doi:10.1016/S0167-8140(03)00081-1 PubMedCrossRefGoogle Scholar
  192. 192.
    Collingridge DR, Piepmeier JM, Rockwell S, Knisely JP (1999) Polarographic measurements of oxygen tension in human glioma and surrounding peritumoural brain tissue. Radiother Oncol 53:127–131. doi:10.1016/S0167-8140(99)00121-8 PubMedCrossRefGoogle Scholar
  193. 193.
    Helmlinger G, Yuan F, Dellian M, Jain RK (1997) Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med 3:177–182. doi:10.1038/nm0297-177 PubMedCrossRefGoogle Scholar
  194. 194.
    Kallinowski F, Zander R, Hoeckel M, Vaupel P (1990) Tumor tissue oxygenation as evaluated by computerized-pO2-histography. Int J Radiat Oncol Biol Phys 19:953–961PubMedGoogle Scholar
  195. 195.
    Kayama T, Yoshimoto T, Fujimoto S, Sakurai Y (1991) Intratumoral oxygen pressure in malignant brain tumor. J Neurosurg 74:55–59PubMedCrossRefGoogle Scholar
  196. 196.
    Riesterer O, Milas L, Ang KK (2007) Use of molecular biomarkers for predicting the response to radiotherapy with or without chemotherapy. J Clin Oncol 25:4075–4083. doi:10.1200/JCO.2007.11.8497 PubMedCrossRefGoogle Scholar
  197. 197.
    Vordermark D, Brown JM (2003) Evaluation of hypoxia-inducible factor-1alpha (HIF-1alpha) as an intrinsic marker of tumor hypoxia in U87 MG human glioblastoma: in vitro and xenograft studies. Int J Radiat Oncol Biol Phys 56:1184–1193. doi:10.1016/S0360-3016(03)00289-X PubMedCrossRefGoogle Scholar
  198. 198.
    Airley RE, Loncaster J, Raleigh JA, Harris AL, Davidson SE, Hunter RD, West CM, Stratford IJ (2003) GLUT-1 and CAIX as intrinsic markers of hypoxia in carcinoma of the cervix: relationship to pimonidazole binding. Int J Cancer 104:85–91. doi:10.1002/ijc.10904 PubMedCrossRefGoogle Scholar
  199. 199.
    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
  200. 200.
    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
  201. 201.
    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
  202. 202.
    Brown JM, Le QT (2002) Tumor hypoxia is important in radiotherapy, but how should we measure it? Int J Radiat Oncol Biol Phys 54:1299–1301. doi:10.1016/S0360-3016(02)03936-6 PubMedGoogle Scholar
  203. 203.
    Abramovitch R, Dafni H, Smouha E, Benjamin LE, Neeman M (1999) In vivo prediction of vascular susceptibility to vascular susceptibility endothelial growth factor withdrawal: magnetic resonance imaging of C6 rat glioma in nude mice. Cancer Res 59:5012–5016PubMedGoogle Scholar
  204. 204.
    Abramovitch R, Marikovsky M, Meir G, Neeman M (1998) Stimulation of tumour angiogenesis by proximal wounds: spatial and temporal analysis by MRI. Br J Cancer 77:440–447PubMedGoogle Scholar
  205. 205.
    Brasch R, Pham C, Shames D, Roberts T, van Dijke K, van Bruggen N, Mann J, Ostrowitzki S, Melnyk O (1997) Assessing tumor angiogenesis using macromolecular MR imaging contrast media. J Magn Reson Imaging 7:68–74. doi:10.1002/jmri.1880070110 PubMedCrossRefGoogle Scholar
  206. 206.
    Daldrup H, Shames DM, Wendland M, Okuhata Y, Link TM, Rosenau W, Lu Y, Brasch RC (1998) Correlation of dynamic contrast-enhanced MR imaging with histologic tumor grade: comparison of macromolecular and small-molecular contrast media. AJR Am J Roentgenol 171:941–949PubMedGoogle Scholar
  207. 207.
    Gossmann A, Okuhata Y, Shames DM, Helbich TH, Roberts TP, Wendland MF, Huber S, Brasch RC (1999) Prostate cancer tumor grade differentiation with dynamic contrast-enhanced MR imaging in the rat: comparison of macromolecular and small-molecular contrast media–preliminary experience. Radiology 213:265–272PubMedGoogle Scholar
  208. 208.
    Griffiths JR, Taylor NJ, Howe FA, Saunders MI, Robinson SP, Hoskin PJ, Powell ME, Thoumine M, Caine LA, Baddeley H (1997) The response of human tumors to carbogen breathing, monitored by Gradient-Recalled Echo Magnetic Resonance Imaging. Int J Radiat Oncol Biol Phys 39:697–701. doi:10.1016/S0360-3016(97)00326-X PubMedGoogle Scholar
  209. 209.
    Knopp EA, Cha S, Johnson G, Mazumdar A, Golfinos JG, Zagzag D, Miller DC, Kelly PJ, Kricheff II (1999) Glial neoplasms: dynamic contrast-enhanced T2*-weighted MR imaging. Radiology 211:791–798PubMedGoogle Scholar
  210. 210.
    Sugahara T, Korogi Y, Tomiguchi S, Shigematsu Y, Ikushima I, Kira T, Liang L, Ushio Y, Takahashi M (2000) Posttherapeutic intraaxial brain tumor: the value of perfusion-sensitive contrast-enhanced MR imaging for differentiating tumor recurrence from nonneoplastic contrast-enhancing tissue. AJNR Am J Neuroradiol 21:901–909PubMedGoogle Scholar
  211. 211.
    Bhujwalla ZM, Artemov D, Natarajan K, Ackerstaff E, Solaiyappan M (2001) Vascular differences detected by MRI for metastatic versus nonmetastatic breast and prostate cancer xenografts. Neoplasia 3:143–153. doi:10.1038/sj.neo.7900129 PubMedCrossRefGoogle Scholar
  212. 212.
    Fisher MJ, Adamson PC (2002) Anti-angiogenic agents for the treatment of brain tumors. Neuroimaging Clin N Am 12:477–499. doi:10.1016/S1052-5149(02)00035-7 PubMedCrossRefGoogle Scholar
  213. 213.
    McDonald DM, Choyke PL (2003) Imaging of angiogenesis: from microscope to clinic. Nat Med 9:713–725. doi:10.1038/nm0603-713 PubMedCrossRefGoogle Scholar
  214. 214.
    Pathak AP, Schmainda KM, Ward BD, Linderman JR, Rebro KJ, Greene AS (2001) MR-derived cerebral blood volume maps: issues regarding histological validation and assessment of tumor angiogenesis. Magn Reson Med 46:735–747. doi:10.1002/mrm.1252 PubMedCrossRefGoogle Scholar
  215. 215.
    Pham CD, Roberts TP, van Bruggen N, Melnyk O, Mann J, Ferrara N, Cohen RL, Brasch RC (1998) Magnetic resonance imaging detects suppression of tumor vascular permeability after administration of antibody to vascular endothelial growth factor. Cancer Invest 16:225–230. doi:10.3109/07357909809039771 PubMedCrossRefGoogle Scholar
  216. 216.
    Su MY, Najafi AA, Nalcioglu O (1995) Regional comparison of tumor vascularity and permeability parameters measured by albumin-Gd-DTPA and Gd-DTPA. Magn Reson Med 34:402–411. doi:10.1002/mrm.1910340318 PubMedCrossRefGoogle Scholar
  217. 217.
    Turetschek K, Roberts TP, Floyd E, Preda A, Novikov V, Shames DM, Carter WO, Brasch RC (2001) Tumor microvascular characterization using ultrasmall superparamagnetic iron oxide particles (USPIO) in an experimental breast cancer model. J Magn Reson Imaging 13:882–888. doi:10.1002/jmri.1126 PubMedCrossRefGoogle Scholar
  218. 218.
    McMillan KM, Rogers BP, Field AS, Laird AR, Fine JP, Meyerand ME (2006) Physiologic characterisation of glioblastoma multiforme using MRI-based hypoxia mapping, chemical shift imaging, perfusion and diffusion maps. J Clin Neurosci 13:811–817. doi:10.1016/j.jocn.2005.12.025 PubMedCrossRefGoogle Scholar
  219. 219.
    Moller-Hartmann W, Herminghaus S, Krings T, Marquardt G, Lanfermann H, Pilatus U, Zanella FE (2002) Clinical application of proton magnetic resonance spectroscopy in the diagnosis of intracranial mass lesions. Neuroradiology 44:371–381. doi:10.1007/s00234-001-0760-0 PubMedCrossRefGoogle Scholar
  220. 220.
    Alger JR, Frank JA, Bizzi A, Fulham MJ, DeSouza BX, Duhaney MO, Inscoe SW, Black JL, van Zijl PC, Moonen CT et al (1990) Metabolism of human gliomas: assessment with H-1 MR spectroscopy and F-18 fluorodeoxyglucose PET. Radiology 177:633–641PubMedGoogle Scholar
  221. 221.
    Go KG, Kamman RL, Mooyaart EL, Heesters MA, Pruim J, Vaalburg W, Paans AM (1995) Localised proton spectroscopy and spectroscopic imaging in cerebral gliomas, with comparison to positron emission tomography. Neuroradiology 37:198–206. doi:10.1007/BF01578258 PubMedCrossRefGoogle Scholar
  222. 222.
    Yetkin FZ, Mendelsohn D (2002) Hypoxia imaging in brain tumors. Neuroimaging Clin N Am 12:537–552. doi:10.1016/S1052-5149(02)00029-1 PubMedCrossRefGoogle Scholar
  223. 223.
    DeSouza BX, Alger JR, Frank JA, Bizzi A, Fulham MJ, Duhaney MO, Inscoe SW, Black JL, van Zijl PC, Moonen CT et al (1990) Metabolism of human gliomas: assessment with H-1 MR spectroscopy and F-18 fluorodeoxyglucose PET. Radiology 177:633–641PubMedGoogle Scholar
  224. 224.
    Bruehlmeier M, Roelcke U, Schubiger PA, Ametamey SM (2004) Assessment of hypoxia and perfusion in human brain tumors using PET with 18F-fluoromisonidazole and 15O–H2O. J Nucl Med 45:1851–1859PubMedGoogle Scholar
  225. 225.
    Rischin D, Peters L, Hicks R, Hughes P, Fisher R, Hart R, Sexton M, D’Costa I, von Roemeling R (2001) Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. J Clin Oncol 19:535–542PubMedGoogle Scholar
  226. 226.
    Tochon-Danguy HJ, Sachinidis JI, Chan F, Chan JG, Hall C, Cher L, Stylli S, Hill J, Kaye A, Scott AM (2002) Imaging and quantitation of the hypoxic cell fraction of viable tumor in an animal model of intracerebral high grade glioma using [18F]fluoromisonidazole (FMISO). Nucl Med Biol 29:191–197. doi:10.1016/S0969-8051(01)00298-0 PubMedCrossRefGoogle Scholar
  227. 227.
    Rasey JS, Casciari JJ, Hofstrand PD, Muzi M, Graham MM, Chin LK (2000) Determining hypoxic fraction in a rat glioma by uptake of radiolabeled fluoromisonidazole. Radiat Res 153:84–92. doi:10.1667/0033-7587(2000)153[0084:DHFIAR]2.0.CO;2 PubMedCrossRefGoogle Scholar
  228. 228.
    Rasey JS, Hofstrand PD, Chin LK, Tewson TJ (1999) Characterization of [18F]fluoroetanidazole, a new radiopharmaceutical for detecting tumor hypoxia. J Nucl Med 40:1072–1079PubMedGoogle Scholar
  229. 229.
    Rasey JS, Koh WJ, Evans ML, Peterson LM, Lewellen TK, Graham MM, Krohn KA (1996) Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients. Int J Radiat Oncol Biol Phys 36:417–428. doi:10.1016/S0360-3016(96)00325-2 PubMedGoogle Scholar
  230. 230.
    Troost EG, Laverman P, Kaanders JH, Philippens M, Lok J, Oyen WJ, van der Kogel AJ, Boerman OC, Bussink J (2006) Imaging hypoxia after oxygenation-modification: comparing [18F]FMISO autoradiography with pimonidazole immunohistochemistry in human xenograft tumors. Radiother Oncol 80:157–164. doi:10.1016/j.radonc.2006.07.023 PubMedCrossRefGoogle Scholar
  231. 231.
    Lewis JS, McCarthy DW, McCarthy TJ, Fujibayashi Y, Welch MJ (1999) Evaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic tumor model. J Nucl Med 40:177–183PubMedGoogle Scholar
  232. 232.
    Lewis JS, Sharp TL, Laforest R, Fujibayashi Y, Welch MJ (2001) Tumor uptake of copper-diacetyl-bis(N(4)-methylthiosemicarbazone): effect of changes in tissue oxygenation. J Nucl Med 42:655–661PubMedGoogle Scholar
  233. 233.
    Obata A, Yoshimi E, Waki A, Lewis JS, Oyama N, Welch MJ, Saji H, Yonekura Y, Fujibayashi Y (2001) Retention mechanism of hypoxia selective nuclear imaging/radiotherapeutic agent Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) in tumor cells. Ann Nucl Med 15:499–504. doi:10.1007/BF02988502 PubMedCrossRefGoogle Scholar
  234. 234.
    Blankenberg FG, Eckelman WC, Strauss HW, Welch MJ, Alavi A, Anderson C, Bacharach S, Blasberg RG, Graham MM, Weber W (2000) Role of radionuclide imaging in trials of antiangiogenic therapy. Acad Radiol 7:851–867. doi:10.1016/S1076-6332(00)80633-9 PubMedCrossRefGoogle Scholar
  235. 235.
    Dehdashti F, Grigsby PW, Mintun MA, Lewis JS, Siegel BA, Welch MJ (2003) Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response—a preliminary report. Int J Radiat Oncol Biol Phys 55:1233–1238. doi:10.1016/S0360-3016(02)04477-2 PubMedGoogle Scholar
  236. 236.
    Fujibayashi Y, Taniuchi H, Yonekura Y, Ohtani H, Konishi J, Yokoyama A (1997) Copper-62-ATSM: a new hypoxia imaging agent with high membrane permeability and low redox potential. J Nucl Med 38:1155–1160PubMedGoogle Scholar
  237. 237.
    Hoffman WF, Levin VA, Wilson CB (1979) Evaluation of malignant glioma patients during the postirradiation period. J Neurosurg 50:624–628PubMedGoogle Scholar
  238. 238.
    De Wit D, Olislagers V, Goriely S, Vermeulen F, Wagner H, Goldman M, Willems F (2004) Blood plasmacytoid dendritic cell responses to CpG oligodeoxynucleotides are impaired in human newborns. Blood 103:1030–1032. doi:10.1182/blood-2003-04-1216 PubMedCrossRefGoogle Scholar
  239. 239.
    Chamberlain MC (2008) Pseudoprogression in glioblastoma. J Clin Oncol 26:4359 author reply 4359–4360PubMedCrossRefGoogle Scholar
  240. 240.
    Chamberlain MC, Glantz MJ, Chalmers L, Van Horn A, Sloan AE (2007) Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. J Neurooncol 82:81–83. doi:10.1007/s11060-006-9241-y PubMedCrossRefGoogle Scholar
  241. 241.
    Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, Bertorelle R, Bartolini S, Calbucci F, Andreoli A, Frezza G, Leonardi M, Spagnolli F, Ermani M (2008) MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol 26:2192–2197. doi:10.1200/JCO.2007.14.8163 PubMedCrossRefGoogle Scholar
  242. 242.
    Brandes AA, Tosoni A, Franceschi E, Reni M, Gatta G, Vecht C (2008) Glioblastoma in adults. Crit Rev Oncol Hematol 67:139–152. doi:10.1016/j.critrevonc.2008.02.005 PubMedCrossRefGoogle Scholar
  243. 243.
    Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ (2008) Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 9:453–461. doi:10.1016/S1470-2045(08)70125-6 PubMedCrossRefGoogle Scholar
  244. 244.
    Taal W, Brandsma D, de Bruin HG, Bromberg JE, Swaak-Kragten AT, Smitt PA, van Es CA, van den Bent MJ (2008) Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer 113:405–410. doi:10.1002/cncr.23562 PubMedCrossRefGoogle Scholar
  245. 245.
    Parney IF, Kunwar S, McDermott M, Berger M, Prados M, Cha S, Croteau D, Puri RK, Chang SM (2005) Neuroradiographic changes following convection-enhanced delivery of the recombinant cytotoxin interleukin 13-PE38QQR for recurrent malignant glioma. J Neurosurg 102:267–275PubMedGoogle Scholar
  246. 246.
    Patel SJ, Shapiro WR, Laske DW, Jensen RL, Asher AL, Wessels BW, Carpenter SP, Shan JS (2005) Safety and feasibility of convection-enhanced delivery of Cotara for the treatment of malignant glioma: initial experience in 51 patients. Neurosurgery 56:1243–1252 discussion 1252–1253PubMedCrossRefGoogle Scholar
  247. 247.
    Fujiwara K, Iwado E, Mills GB, Sawaya R, Kondo S, Kondo Y (2007) Akt inhibitor shows anticancer and radiosensitizing effects in malignant glioma cells by inducing autophagy. Int J Oncol 31:753–760PubMedGoogle Scholar
  248. 248.
    Tan C, de Noronha RG, Roecker AJ, Pyrzynska B, Khwaja F, Zhang Z, Zhang H, Teng Q, Nicholson AC, Giannakakou P, Zhou W, Olson JJ, Pereira MM, Nicolaou KC, Van Meir EG (2005) Identification of a novel small-molecule inhibitor of the hypoxia-inducible factor 1 pathway. Cancer Res 65:605–612PubMedGoogle Scholar
  249. 249.
    Greenberger LM, Horak ID, Filpula D, Sapra P, Westergaard M, Frydenlund HF, Albaek C, Schroder H, Orum H (2008) A RNA antagonist of hypoxia-inducible factor-1alpha, EZN-2968, inhibits tumor cell growth. Mol Cancer Ther 7:3598–3608. doi:10.1158/1535-7163.MCT-08-0510 PubMedCrossRefGoogle Scholar
  250. 250.
    Ozawa T, Hu JL, Hu LJ, Kong EL, Bollen AW, Lamborn KR, Deen DF (2005) Functionality of hypoxia-induced BAX expression in a human glioblastoma xenograft model. Cancer Gene Ther 12:449–455PubMedGoogle Scholar
  251. 251.
    Wang D, Ruan H, Hu L, Lamborn KR, Kong EL, Rehemtulla A, Deen DF (2005) Development of a hypoxia-inducible cytosine deaminase expression vector for gene-directed prodrug cancer therapy. Cancer Gene Ther 12:276–283. doi:10.1038/sj.cgt.7700748 PubMedCrossRefGoogle Scholar
  252. 252.
    Chen JK, Hu LJ, Wang D, Lamborn KR, Deen DF (2007) Cytosine deaminase/5-fluorocytosine exposure induces bystander and radiosensitization effects in hypoxic glioblastoma cells in vitro. Int J Radiat Oncol Biol Phys 67:1538–1547. doi:10.1016/j.ijrobp.2006.12.020 PubMedGoogle Scholar
  253. 253.
    Albertella MR, Loadman PM, Jones PH, Phillips RM, Rampling R, Burnet N, Alcock C, Anthoney A, Vjaters E, Dunk CR, Harris PA, Wong A, Lalani AS, Twelves CJ (2008) Hypoxia-selective targeting by the bioreductive prodrug AQ4N in patients with solid tumors: results of a phase I study. Clin Cancer Res 14:1096–1104. doi:10.1158/1078-0432.CCR-07-4020 PubMedCrossRefGoogle Scholar
  254. 254.
    Koshikawa N, Takenaga K (2005) Hypoxia-regulated expression of attenuated diphtheria toxin A fused with hypoxia-inducible factor-1alpha oxygen-dependent degradation domain preferentially induces apoptosis of hypoxic cells in solid tumor. Cancer Res 65:11622–11630. doi:10.1158/0008-5472.CAN-05-0111 PubMedCrossRefGoogle Scholar
  255. 255.
    Shibata T, Giaccia AJ, Brown JM (2000) Development of a hypoxia-responsive vector for tumor-specific gene therapy. Gene Ther 7:493–498. doi:10.1038/sj.gt.3301124 PubMedCrossRefGoogle Scholar
  256. 256.
    Binley K, Iqball S, Kingsman A, Kingsman S, Naylor S (1999) An adenoviral vector regulated by hypoxia for the treatment of ischaemic disease and cancer. Gene Ther 6:1721–1727. doi:10.1038/sj.gt.3301001 PubMedCrossRefGoogle Scholar
  257. 257.
    Ruan H, Wang J, Hu L, Lin CS, Lamborn KR, Deen DF (1999) Killing of brain tumor cells by hypoxia-responsive element mediated expression of BAX. Neoplasia 1:431–437. doi:10.1038/sj.neo.7900059 PubMedCrossRefGoogle Scholar
  258. 258.
    Shibata T, Akiyama N, Noda M, Sasai K, Hiraoka M (1998) Enhancement of gene expression under hypoxic conditions using fragments of the human vascular endothelial growth factor and the erythropoietin genes. Int J Radiat Oncol Biol Phys 42:913–916. doi:10.1016/S0360-3016(98)00298-3 PubMedGoogle Scholar
  259. 259.
    Boast K, Binley K, Iqball S, Price T, Spearman H, Kingsman S, Kingsman A, Naylor S (1999) Characterization of physiologically regulated vectors for the treatment of ischemic disease. Hum Gene Ther 10:2197–2208. doi:10.1089/10430349950017185 PubMedCrossRefGoogle Scholar
  260. 260.
    Cao YJ, Shibata T, Rainov NG (2001) Hypoxia-inducible transgene expression in differentiated human NT2 N neurons—a cell culture model for gene therapy of postischemic neuronal loss. Gene Ther 8:1357–1362. doi:10.1038/sj.gt.3301536 PubMedCrossRefGoogle Scholar
  261. 261.
    Shibata T, Giaccia AJ, Brown JM (2002) Hypoxia-inducible regulation of a prodrug-activating enzyme for tumor-specific gene therapy. Neoplasia 4:40–48. doi:10.1038/sj.neo.7900189 PubMedCrossRefGoogle Scholar
  262. 262.
    Post DE, Van Meir EG (2001) Generation of bidirectional hypoxia/HIF-responsive expression vectors to target gene expression to hypoxic cells. Gene Ther 8:1801–1807. doi:10.1038/sj.gt.3301605 PubMedCrossRefGoogle Scholar
  263. 263.
    Post DE, Khuri FR, Simons JW, Van Meir EG (2003) Replicative oncolytic adenoviruses in multimodal cancer regimens. Hum Gene Ther 14:933–946. doi:10.1089/104303403766682205 PubMedCrossRefGoogle Scholar
  264. 264.
    Post DE, Van Meir EG (2003) A novel hypoxia-inducible factor (HIF) activated oncolytic adenovirus for cancer therapy. Oncogene 22:2065–2072. doi:10.1038/sj.onc.1206464 PubMedCrossRefGoogle Scholar
  265. 265.
    Aghi MK, Liu TC, Rabkin S, Martuza RL (2009) Hypoxia enhances the replication of oncolytic herpes simplex virus. Mol Ther 17:51–56. doi:10.1038/mt.2008.232 Google Scholar
  266. 266.
    Liu Y, Liu R, Mao SC, Morgan JB, Jekabsons MB, Zhou YD, Nagle DG (2008) Molecular-targeted antitumor agents. 19. Furospongolide from a marine Lendenfeldia sp. sponge inhibits hypoxia-inducible factor-1 activation in breast tumor cells. J Nat Prod 71:1854–1860. doi:10.1021/np800342s Google Scholar
  267. 267.
    Zou GM, Maitra A (2008) Small-molecule inhibitor of the AP endonuclease 1/REF-1 E3330 inhibits pancreatic cancer cell growth and migration. Mol Cancer Ther 7:2012–2021. doi:10.1158/1535-7163.MCT-08-0113 PubMedCrossRefGoogle Scholar
  268. 268.
    Huang XZ, Wang J, Huang C, Chen YY, Shi GY, Hu QS, Yi J (2008) Emodin enhances cytotoxicity of chemotherapeutic drugs in prostate cancer cells: the mechanisms involve ROS-mediated suppression of multidrug resistance and hypoxia inducible factor-1. Cancer Biol Ther 7:468–475PubMedCrossRefGoogle Scholar
  269. 269.
    Meng F, Nguyen XT, Cai X, Duan J, Matteucci M, Hart CP (2007) ARC-111 inhibits hypoxia-mediated hypoxia-inducible factor-1alpha accumulation. Anticancer Drugs 18:435–445. doi:10.1097/CAD.0b013e328013ffed PubMedCrossRefGoogle Scholar
  270. 270.
    Creighton-Gutteridge M, Cardellina JH 2nd, Stephen AG, Rapisarda A, Uranchimeg B, Hite K, Denny WA, Shoemaker RH, Melillo G (2007) Cell type-specific, topoisomerase II-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation by NSC 644221. Clin Cancer Res 13:1010–1018. doi:10.1158/1078-0432.CCR-06-2301 PubMedCrossRefGoogle Scholar
  271. 271.
    Carroll VA, Ashcroft M (2006) Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Res 66:6264–6270. doi:10.1158/0008-5472.CAN-05-2519 PubMedCrossRefGoogle Scholar
  272. 272.
    Chau NM, Rogers P, Aherne W, Carroll V, Collins I, McDonald E, Workman P, Ashcroft M (2005) Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1alpha induction in response to hypoxic stress and growth factors. Cancer Res 65:4918–4928. doi:10.1158/0008-5472.CAN-04-4453 PubMedCrossRefGoogle Scholar
  273. 273.
    Hwang II, Watson IR, Der SD, Ohh M (2006) Loss of VHL confers hypoxia-inducible factor (HIF)-dependent resistance to vesicular stomatitis virus: role of HIF in antiviral response. J Virol 80:10712–10723. doi:10.1128/JVI.01014-06 PubMedCrossRefGoogle Scholar
  274. 274.
    Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A, Fisher RJ, Shoemaker RH, Melillo G (2005) Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res 65:9047–9055. doi:10.1158/0008-5472.CAN-05-1235 PubMedCrossRefGoogle Scholar
  275. 275.
    Mabjeesh NJ, Escuin D, LaVallee TM, Pribluda VS, Swartz GM, Johnson MS, Willard MT, Zhong H, Simons JW, Giannakakou P (2003) 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell 3:363–375. doi:10.1016/S1535-6108(03)00077-1 PubMedCrossRefGoogle Scholar
  276. 276.
    Mooberry SL (2003) New insights into 2-methoxyestradiol, a promising antiangiogenic and antitumor agent. Curr Opin Oncol 15:425–430. doi:10.1097/00001622-200311000-00004 PubMedCrossRefGoogle Scholar
  277. 277.
    Zagzag D, Nomura M, Friedlander DR, Blanco CY, Gagner JP, Nomura N, Newcomb EW (2003) Geldanamycin inhibits migration of glioma cells in vitro: a potential role for hypoxia-inducible factor (HIF-1alpha) in glioma cell invasion. J Cell Physiol 196:394–402. doi:10.1002/jcp.10306 PubMedCrossRefGoogle Scholar
  278. 278.
    Mabjeesh NJ, Post DE, Willard MT, Kaur B, Van Meir EG, Simons JW, Zhong H (2002) Geldanamycin induces degradation of hypoxia-inducible factor 1alpha protein via the proteosome pathway in prostate cancer cells. Cancer Res 62:2478–2482PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  1. 1.Department of Neurosurgery, Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA
  2. 2.Department of Radiation Oncology, Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA
  3. 3.Department of Oncological Sciences, Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA

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