Hypoxia in a human intracerebral glioma model

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Object. The development of hypoxia in human gliomas is closely related to functional vasculature and the presence of hypoxia has important biological and therapeutic consequences. Assessment of hypoxia is necessary to understand its role in treatment response and to evaluate treatment strategies to improve tumor oxygenation. In this study, the authors report findings of their analysis of the degree of hypoxia in relation to other vascular parameters in a human intracerebral glioma xenograft.

Methods. In sections of tumor, hypoxic regions were identified immunohistochemically by using the hypoxic marker pimonidazole. The S-phase marker bromodeoxyuridine was used to detect cell proliferation, and the perfusion marker Hoechst 33342 was used to delineate perfused vessels. Vascular structures were stained with an endothelial marker.

Hypoxic tumor regions were clearly present in this human intracerebral glioma model. Hypoxic areas were usually found in nonperfused regions, whereas tumor cell proliferation was especially marked in perfused tumor areas. Furthermore, by using in situ hybridization the authors identified infiltrating tumor cells in the normal brain. This feature is often observed in gliomas in patients.

Conclusions. This model is a representative human glioma model that provides the researcher with the opportunity to analyze the relationship between the degree of hypoxia and vascular parameters, as well as to examine the effects of treatments aimed at modification of the oxygenation status of a tumor.

Article Information

Contributor Notes

Address reprint requests to: Albert J. van der Kogel, Institute of Radiotherapy, University of Nijmegen, Geert Grooteplein 32, 6525 GA, Nijmegen, The Netherlands.
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References
  • 1.

    Arteel GEThurman RGYates JMet al: Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver. Br J Cancer 72:8898951995Arteel GE Thurman RG Yates JM et al: Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver. Br J Cancer 72:889–895 1995

    • Search Google Scholar
    • Export Citation
  • 2.

    Bernsen HJJARijken PFJWOostendorp Tet al: Vascularity and perfusion of human gliomas xenografted in the athymic nude mouse. Br J Cancer 71:7217261995Bernsen HJJA Rijken PFJW Oostendorp T et al: Vascularity and perfusion of human gliomas xenografted in the athymic nude mouse. Br J Cancer 71:721–726 1995

    • Search Google Scholar
    • Export Citation
  • 3.

    Evans SMJenkins WTJoiner Bet al: 2-Nitroimidazole (EF5) binding predicts radiation resistance to individual 9L s.c. tumors. Cancer Res 56:4054111996Evans SM Jenkins WT Joiner B et al: 2-Nitroimidazole (EF5) binding predicts radiation resistance to individual 9L s.c. tumors. Cancer Res 56:405–411 1996

    • Search Google Scholar
    • Export Citation
  • 4.

    Fatigante LDucci FCartei Fet al: Carbogen and nicotinamide combined with unconventional radiotherapy in glioblastoma multiforme: a new modality treatment. Int J Radiat Oncol Biol Phys 37:4995041997Fatigante L Ducci F Cartei F et al: Carbogen and nicotinamide combined with unconventional radiotherapy in glioblastoma multiforme: a new modality treatment. Int J Radiat Oncol Biol Phys 37:499–504 1997

    • Search Google Scholar
    • Export Citation
  • 5.

    Gulledge CJDewhirst MW: Tumor oxygenation: a matter of supply and demand. Anticancer Res 16:7417501996Gulledge CJ Dewhirst MW: Tumor oxygenation: a matter of supply and demand. Anticancer Res 16:741–750 1996

    • Search Google Scholar
    • Export Citation
  • 6.

    Hirst DGDenekamp J: Tumour cell proliferation in relation to the vasculature. Cell Tissue Kinet 12:31421979Hirst DG Denekamp J: Tumour cell proliferation in relation to the vasculature. Cell Tissue Kinet 12:31–42 1979

    • Search Google Scholar
    • Export Citation
  • 7.

    Jeuken JWMSprenger SHEWesseling Pet al: Genetic reflection of glioblastoma biopsy material in xenografts: characterization of 11 glioblastoma xenograft lines by comparative genomic hybridization. J Neurosurg 92:6526582000Jeuken JWM Sprenger SHE Wesseling P et al: Genetic reflection of glioblastoma biopsy material in xenografts: characterization of 11 glioblastoma xenograft lines by comparative genomic hybridization. J Neurosurg 92:652–658 2000

    • Search Google Scholar
    • Export Citation
  • 8.

    Kayama TYoshimoto TFuijmoto Set al: Intratumoral oxygen pressure in malignant brain tumor. J Neurosurg 74:55591991Kayama T Yoshimoto T Fuijmoto S et al: Intratumoral oxygen pressure in malignant brain tumor. J Neurosurg 74:55–59 1991

    • Search Google Scholar
    • Export Citation
  • 9.

    Kennedy ASRaleigh JAPerez GMet al: Proliferation and hypoxia in human squamous cell carcinoma of the cervix: first report of combined immunohistochemical assays. Int J Radiat Oncol Biol Phys 37:8979051997Kennedy AS Raleigh JA Perez GM et al: Proliferation and hypoxia in human squamous cell carcinoma of the cervix: first report of combined immunohistochemical assays. Int J Radiat Oncol Biol Phys 37:897–905 1997

    • Search Google Scholar
    • Export Citation
  • 10.

    Kligerman MMHeidenreich WFGreene S: Distribution of tritiated thymidine about a capillary sinusoid in a transplanted mouse tumour. Nature 196:2822831962Kligerman MM Heidenreich WF Greene S: Distribution of tritiated thymidine about a capillary sinusoid in a transplanted mouse tumour. Nature 196:282–283 1962

    • Search Google Scholar
    • Export Citation
  • 11.

    Knott JCAMahesparan RGarcia-Cabrera Iet al: Stimulation of extracellulair matrix components in the normal brain by invading glioma cells. Int J Cancer 75:8648721998Knott JCA Mahesparan R Garcia-Cabrera I et al: Stimulation of extracellulair matrix components in the normal brain by invading glioma cells. Int J Cancer 75:864–872 1998

    • Search Google Scholar
    • Export Citation
  • 12.

    Olive PLViske CTrotter AAet al: Measurement of oxygen diffusion distance in tumor cubes using a fluorescent hypoxia probe. Int J Radiat Oncol Biol Phys 22:3974021992Olive PL Viske C Trotter AA et al: Measurement of oxygen diffusion distance in tumor cubes using a fluorescent hypoxia probe. Int J Radiat Oncol Biol Phys 22:397–402 1992

    • Search Google Scholar
    • Export Citation
  • 13.

    Parliament MBFranko AJAllalunis-Turner MJet al: Anomalous patterns of nitroimidazole binding adjacent to necrosis in human glioma xenografts: possible role of decreased oxygen consumption. Br J Cancer 75:3113181997Parliament MB Franko AJ Allalunis-Turner MJ et al: Anomalous patterns of nitroimidazole binding adjacent to necrosis in human glioma xenografts: possible role of decreased oxygen consumption. Br J Cancer 75:311–318 1997

    • Search Google Scholar
    • Export Citation
  • 14.

    Pilkington GJBjerkvig Rde Ridder Let al: In vitro and in vivo models for the study of brain tumour invasion. Anticancer Res 17:410741101997Pilkington GJ Bjerkvig R de Ridder L et al: In vitro and in vivo models for the study of brain tumour invasion. Anticancer Res 17:4107–4110 1997

    • Search Google Scholar
    • Export Citation
  • 15.

    Plate KHMennel HD: Vascular morphology and angiogenesis in glial tumors. Exp Toxic Pathol 47:89941995Plate KH Mennel HD: Vascular morphology and angiogenesis in glial tumors. Exp Toxic Pathol 47:89–94 1995

    • Search Google Scholar
    • Export Citation
  • 16.

    Poddighe PJBringuier PPVallinga Met al: Loss of chromosome 9 in tissue sections of transitional cell carcinomas as detected by interphase cytogenetics. A comparison with RFLP analysis. J Pathol 179:1691761996Poddighe PJ Bringuier PP Vallinga M et al: Loss of chromosome 9 in tissue sections of transitional cell carcinomas as detected by interphase cytogenetics. A comparison with RFLP analysis. J Pathol 179:169–176 1996

    • Search Google Scholar
    • Export Citation
  • 17.

    Pötgens AJGLubsen NHvan Altena MCet al: Vascular permeability factor expression influences tumor angiogenesis in human melanoma lines xenografted to nude mice. Am J Pathol 146:1972091995Pötgens AJG Lubsen NH van Altena MC et al: Vascular permeability factor expression influences tumor angiogenesis in human melanoma lines xenografted to nude mice. Am J Pathol 146:197–209 1995

    • Search Google Scholar
    • Export Citation
  • 18.

    Rockwell S: Oxygen delivery: implications for the biology and therapy of solid tumors. Oncol Res 9:3833901997Rockwell S: Oxygen delivery: implications for the biology and therapy of solid tumors. Oncol Res 9:383–390 1997

    • Search Google Scholar
    • Export Citation
  • 19.

    Tannock IF: The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer 22:2582731968Tannock IF: The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer 22:258–273 1968

    • Search Google Scholar
    • Export Citation
  • 20.

    Tannock IFSteel GG: Quantitative techniques for study of the anatomy and function of small blood vessels in tumors. J Natl Cancer Inst 42:7717821969Tannock IF Steel GG: Quantitative techniques for study of the anatomy and function of small blood vessels in tumors. J Natl Cancer Inst 42:771–782 1969

    • Search Google Scholar
    • Export Citation
  • 21.

    Thorsen FTysnes BB: Brain tumor cell invasion, anatomical and biological considerations. Anticancer Res 17:412141261997Thorsen F Tysnes BB: Brain tumor cell invasion anatomical and biological considerations. Anticancer Res 17:4121–4126 1997

    • Search Google Scholar
    • Export Citation
  • 22.

    Trotter MJChaplin DJOlive PL: Possible mechanisms for intermittent blood flow in the murine SCCVII carcinoma. Int J Radiother Biol 60:1391461991Trotter MJ Chaplin DJ Olive PL: Possible mechanisms for intermittent blood flow in the murine SCCVII carcinoma. Int J Radiother Biol 60:139–146 1991

    • Search Google Scholar
    • Export Citation
  • 23.

    Valk PEMathis CAPrados MDet al: Hypoxia in human gliomas: demonstration by PET with fluorine-18-fluoromisonidazole. J Nucl Med 33:213321371992Valk PE Mathis CA Prados MD et al: Hypoxia in human gliomas: demonstration by PET with fluorine-18-fluoromisonidazole. J Nucl Med 33:2133–2137 1992

    • Search Google Scholar
    • Export Citation
  • 24.

    van der Maazen RWMThijssen HOMKaanders JHAMet al: Conventional radiotherapy combined with carbogen breathing and nicotinamide for malignant gliomas. Radiother Oncol 35:1181221995van der Maazen RWM Thijssen HOM Kaanders JHAM et al: Conventional radiotherapy combined with carbogen breathing and nicotinamide for malignant gliomas. Radiother Oncol 35:118–122 1995

    • Search Google Scholar
    • Export Citation
  • 25.

    Vaupel P: Blood flow and metabolic microenvironment of brain tumors. J Neurooncol 22:2612671994Vaupel P: Blood flow and metabolic microenvironment of brain tumors. J Neurooncol 22:261–267 1994

    • Search Google Scholar
    • Export Citation
  • 26.

    Vaupel PKallinowski FOkunieff P: Blood flow, oxygen and nutrient supply and metabolic microenvironment of human tumors, a review. Cancer Res 49:644964651989Vaupel P Kallinowski F Okunieff P: Blood flow oxygen and nutrient supply and metabolic microenvironment of human tumors a review. Cancer Res 49:6449–6465 1989

    • Search Google Scholar
    • Export Citation
  • 27.

    Wesseling Pvan der Laak JAWMde Leeuw Het al: Quantitative immunohistochemical analysis of the microvasculature in untreated human glioblastoma multiforme. Computer-assisted image analysis of whole-tumor sections. J Neurosurg 81:9029091994Wesseling P van der Laak JAWM de Leeuw H et al: Quantitative immunohistochemical analysis of the microvasculature in untreated human glioblastoma multiforme. Computer-assisted image analysis of whole-tumor sections. J Neurosurg 81:902–909 1994

    • Search Google Scholar
    • Export Citation
  • 28.

    Westphal JRvan't Hullenaar RGMvan der Laak JAWMet al: Vascular density in melanoma xenografts correlates with vascular permeability factor expression but not with metastatic potential. Br J Cancer 76:5615701997Westphal JR van't Hullenaar RGM van der Laak JAWM et al: Vascular density in melanoma xenografts correlates with vascular permeability factor expression but not with metastatic potential. Br J Cancer 76:561–570 1997

    • Search Google Scholar
    • Export Citation
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