Expression of hypoxia inducible factor—1 alpha and correlation with preoperative embolization of meningiomas

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  • 1 Department of Neurosurgery and Huntsman Cancer Institute, University of Utah; and Surgical Service, Department of Veterans Affairs, Salt Lake City Health Care System, Salt Lake City, Utah
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Object. Vascular endothelial growth factor (VEGF) has been implicated in meningioma tumorigenesis and growth. The production of VEGF is regulated by hypoxia inducible factor—1α (HIF-1α), especially under conditions of hypoxia. In this study, the authors examine the expression of HIF-1α and VEGF in meningiomas, with a special emphasis on conditions of hypoxia, such as preoperative embolization, and on in vitro studies in cultured cells.

Methods. Meningiomas obtained in 142 patients were studied using immunohistochemical methods to detect HIF-1α and the results were correlated with the extent or lack of preoperative embolization and expression of VEGF. Primary meningioma cell cultures were established and cell culture experiments were performed using a hypoxia chamber to stimulate HIF-1α and VEGF production. Expression of HIF-1α in primary meningioma cell cultures was measured using immunoblot assays. The VEGF secretion was measured using enzyme-linked immunosorbent assay.

Half of the meningiomas studied were positive for HIF-1α, with a strong correlation between complete embolization and HIF-1α expression. Most of the meningiomas studied expressed VEGF protein, and VEGF expression did not correlate with the degree of embolization. A strong correlation was found between VEGF and HIF-1α expression in immunohistochemical studies. Secretion of VEGF is increased by hypoxia and growth factor stimulation. In meningiomas, growth factors stimulate HIF-1α expression. The role of hypoxia is less clear.

Conclusions. The expression of HIF-1α is increased by complete preoperative embolization of meningiomas. The expression of HIF-1α also correlates with VEGF secretion in meningiomas. Growth factor and hypoxic stimulation both contribute to VEGF control, but which is most important (or whether both are equally important) will require further studies.

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Contributor Notes

Address reprint requests to: Randy Jensen, M.D. Ph.D., Department of Neurosurgery, University of Utah, 3B-409 SOM, 30 North 1900 East, Salt Lake City, Utah 84132–2303. email: randy.jensen@hsc.utah.edu.
  • 1.

    An WG, , Kanekai M, & Simon MC, et al: Stabilization of wildtype p53 by hypoxia-inducible factor 1α. Nature 392:405408, 1998 An WG, Kanekai M, Simon MC, et al: Stabilization of wildtype p53 by hypoxia-inducible factor 1α. Nature 392:405–408, 1998

    • Search Google Scholar
    • Export Citation
  • 2.

    Berkman RA, , Merrill MJ, & Reinhold WC, et al: Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest 91:153159, 1993 Berkman RA, Merrill MJ, Reinhold WC, et al: Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest 91:153–159, 1993

    • Search Google Scholar
    • Export Citation
  • 3.

    Bitzer M, , Opitz H, & Popp J, et al: Angiogenesis and brain oedema in intracranial meningiomas: influence of vascular endothelial growth factor. Acta Neurochir 140:333340, 1998 Bitzer M, Opitz H, Popp J, et al: Angiogenesis and brain oedema in intracranial meningiomas: influence of vascular endothelial growth factor. Acta Neurochir 140:333–340, 1998

    • Search Google Scholar
    • Export Citation
  • 4.

    Chamberlain MC: Adjuvant combined modality therapy for malignant meningiomas. J Neurosurg 84:733736, 1996 Chamberlain MC: Adjuvant combined modality therapy for malignant meningiomas. J Neurosurg 84:733–736, 1996

    • Search Google Scholar
    • Export Citation
  • 5.

    Cho S, , Choi YJ, & Kim JM, et al: Binding and regulation of HIF-1α by a subunit of the proteasome complex, PSMA7. FEBS Lett 498:6266, 2001 Cho S, Choi YJ, Kim JM, et al: Binding and regulation of HIF-1α by a subunit of the proteasome complex, PSMA7. FEBS Lett 498:62–66, 2001

    • Search Google Scholar
    • Export Citation
  • 6.

    Clerici C, & Matthay MA: Hypoxia regulates gene expression of alveolar epithelial transport proteins. J Appl Physiol 88:18901896, 2000 Clerici C, Matthay MA: Hypoxia regulates gene expression of alveolar epithelial transport proteins. J Appl Physiol 88:1890–1896, 2000

    • Search Google Scholar
    • Export Citation
  • 7.

    Dietzmann K, , von Bossanyi P, & Warich-Kirches M, et al: Immunohistochemical detection of vascular growth factors in angiomatous and atypical meningiomas, as well as hemangiopericytomas. Pathol Res Pract 193:503510, 1997 Dietzmann K, von Bossanyi P, Warich-Kirches M, et al: Immunohistochemical detection of vascular growth factors in angiomatous and atypical meningiomas, as well as hemangiopericytomas. Pathol Res Pract 193:503–510, 1997

    • Search Google Scholar
    • Export Citation
  • 8.

    Forsythe JA, , Jiang BH, & Iyer NV, et al: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor I. Mol Cell Biol 16:46044613, 1996 Forsythe JA, Jiang BH, Iyer NV, et al: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor I. Mol Cell Biol 16:4604–4613, 1996

    • Search Google Scholar
    • Export Citation
  • 9.

    Gleadle JM, & Ratcliffe PJ: Induction of hypoxia-inducible factor-1, erythropoietin, vascular endothelial growth factor, and glucose transporter-1 by hypoxia: evidence against a regulatory role for Src kinase. Blood 89:503509, 1997 Gleadle JM, Ratcliffe PJ: Induction of hypoxia-inducible factor-1, erythropoietin, vascular endothelial growth factor, and glucose transporter-1 by hypoxia: evidence against a regulatory role for Src kinase. Blood 89:503–509, 1997

    • Search Google Scholar
    • Export Citation
  • 10.

    Goldman CK, , Bharara S, & Palmer CA, et al: Brain edema in meningiomas is associated with increased vascular endothelial growth factor expression. Neurosurgery 40:12691277, 1997 Goldman CK, Bharara S, Palmer CA, et al: Brain edema in meningiomas is associated with increased vascular endothelial growth factor expression. Neurosurgery 40:1269–1277, 1997

    • Search Google Scholar
    • Export Citation
  • 11.

    Hatva E, , Kaipainen A, & Mentula P, et al: Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. Am J Pathol 146:368378, 1995 Hatva E, Kaipainen A, Mentula P, et al: Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. Am J Pathol 146:368–378, 1995

    • Search Google Scholar
    • Export Citation
  • 12.

    Ivan M, , Kondo K, & Yang H, et al: HIF-α targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464468, 2001 Ivan M, Kondo K, Yang H, et al: HIF-α targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468, 2001

    • Search Google Scholar
    • Export Citation
  • 13.

    Iyer NV, , Kotch LE, & Agani F, et al: Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev 12:149162, 1998 Iyer NV, Kotch LE, Agani F, et al: Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev 12:149–162, 1998

    • Search Google Scholar
    • Export Citation
  • 14.

    Jaakkola P, , Mole DR, & Tian YM, et al: Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468472, 2001 Jaakkola P, Mole DR, Tian YM, et al: Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472, 2001

    • Search Google Scholar
    • Export Citation
  • 15.

    Jensen RL, , Lee YS, & Guijarti M, et al: Inhibition of in vitro meningioma proliferation after growth factor stimulation by calcium channel antagonists: Part II—additional growth factors, growth factor receptor immunohistochemistry, and intracellular calcium measurements. Neurosurgery 37:937947, 1995 Jensen RL, Lee YS, Guijarti M, et al: Inhibition of in vitro meningioma proliferation after growth factor stimulation by calcium channel antagonists: Part II—additional growth factors, growth factor receptor immunohistochemistry, and intracellular calcium measurements. Neurosurgery 37:937–947, 1995

    • Search Google Scholar
    • Export Citation
  • 16.

    Jensen RL, , Origitano TC, & Lee YS, et al: In vitro growth inhibition of growth factor-stimulated meningioma cells by calcium channel antagonists. Neurosurgery 36:365374, 1995 Jensen RL, Origitano TC, Lee YS, et al: In vitro growth inhibition of growth factor-stimulated meningioma cells by calcium channel antagonists. Neurosurgery 36:365–374, 1995

    • Search Google Scholar
    • Export Citation
  • 17.

    Jiang BH, , Rue E, & Wang GL, et al: Dimerization, DNA binding, and, transactivation properties of hypoxia-inducible factor 1. J Biol Chem 271:1777117778, 1996 Jiang BH, Rue E, Wang GL, et al: Dimerization, DNA binding, and, transactivation properties of hypoxia-inducible factor 1. J Biol Chem 271:17771–17778, 1996

    • Search Google Scholar
    • Export Citation
  • 18.

    Kalkanis SN, , Carroll RS, & Zhang J, et al: Correlation of vascular endothelial growth factor messenger RNA expression with peritumoral vasogenic cerebral edema in meningiomas. J Neurosurg 85:10951101, 1996 Kalkanis SN, Carroll RS, Zhang J, et al: Correlation of vascular endothelial growth factor messenger RNA expression with peritumoral vasogenic cerebral edema in meningiomas. J Neurosurg 85:1095–1101, 1996

    • Search Google Scholar
    • Export Citation
  • 19.

    Kallio PJ, , Wilson WJ, & O'Brien S, et al: Regulation of the hypoxia-inducible transcription factor 1α by the ubiquitin-proteasome pathway. J Biol Chem 274:65196525, 1999 Kallio PJ, Wilson WJ, O'Brien S, et al: Regulation of the hypoxia-inducible transcription factor 1α by the ubiquitin-proteasome pathway. J Biol Chem 274:6519–6525, 1999

    • Search Google Scholar
    • Export Citation
  • 20.

    Kamura T, , Koepp DM, & Conrad MN, et al: Rbx1, a component of theVHL tumor suppressor complex and SCF ubiquitin ligase. Science 284:657661, 1999 Kamura T, Koepp DM, Conrad MN, et al: Rbx1, a component of theVHL tumor suppressor complex and SCF ubiquitin ligase. Science 284:657–661, 1999

    • Search Google Scholar
    • Export Citation
  • 21.

    Kleihues P, , Burger PC, & Scheithauer BW: The new WHO classification of brain tumors. Brain Pathol 3:255268, 1993 Kleihues P, Burger PC, Scheithauer BW: The new WHO classification of brain tumors. Brain Pathol 3:255–268, 1993

    • Search Google Scholar
    • Export Citation
  • 22.

    Lamszus K, , Lengler U, & Schmidt NO, et al: Vascular endothelial growth factor, hepatocyte growth factor/scatter factor, basic fibroblast growth factor, and placenta growth factor in human meningiomas and their relation to angiogenesis and malignancy. Neurosurgery 46:938948, 2000 Lamszus K, Lengler U, Schmidt NO, et al: Vascular endothelial growth factor, hepatocyte growth factor/scatter factor, basic fibroblast growth factor, and placenta growth factor in human meningiomas and their relation to angiogenesis and malignancy. Neurosurgery 46:938–948, 2000

    • Search Google Scholar
    • Export Citation
  • 23.

    Lantos PL, , VandenBerg SR, & Kleihues P: Tumours of the nervous system, in Graham DI, & Lantos PL (eds): Greenfield's Neuropathology, ed 6. London: Arnold, 1997, Vol 2, pp 583879 Lantos PL, VandenBerg SR, Kleihues P: Tumours of the nervous system, in Graham DI, Lantos PL (eds): Greenfield's Neuropathology, ed 6. London: Arnold, 1997, Vol 2, pp 583–879

    • Search Google Scholar
    • Export Citation
  • 24.

    Li J, , Post M, & Volk R, et al: PR39, a peptide regulator of angiogenesis. Nat Med 6:4955, 2000 Li J, Post M, Volk R, et al: PR39, a peptide regulator of angiogenesis. Nat Med 6:49–55, 2000

    • Search Google Scholar
    • Export Citation
  • 25.

    Louis DN, , Budka H, & von Deimling A: Meninigomas, in Kleihues P, & Cavenee WK (eds): Pathology and Genetics of Tumours of the Nervous System. Lyon: IARC Press, 1997, pp 134141 Louis DN, Budka H, von Deimling A: Meninigomas, in Kleihues P, Cavenee WK (eds): Pathology and Genetics of Tumours of the Nervous System. Lyon: IARC Press, 1997, pp 134–141

    • Search Google Scholar
    • Export Citation
  • 26.

    Maxwell PH, , Dachs GU, & Gleadle JM, et al: Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci 94:81048109, 1997 Maxwell PH, Dachs GU, Gleadle JM, et al: Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci 94:8104–8109, 1997

    • Search Google Scholar
    • Export Citation
  • 27.

    Maxwell PH, , Wiesener MS, & Chang GW, et al: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271275, 1999 Maxwell PH, Wiesener MS, Chang GW, et al: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275, 1999

    • Search Google Scholar
    • Export Citation
  • 28.

    McLean CA, , Jolley D, & Cukier E, et al: Atypical and malignant meningiomas: importance of micronecrosis as a prognostic indicator. Histopathology 23:349353, 1993 McLean CA, Jolley D, Cukier E, et al: Atypical and malignant meningiomas: importance of micronecrosis as a prognostic indicator. Histopathology 23:349–353, 1993

    • Search Google Scholar
    • Export Citation
  • 29.

    Michiels C, , Arnould T, & Remacle J: Endothelial cell responses to hypoxia: initiation of a cascade of cellular interactions. Biochim Biophys Acta 1497:110, 2000 Michiels C, Arnould T, Remacle J: Endothelial cell responses to hypoxia: initiation of a cascade of cellular interactions. Biochim Biophys Acta 1497:1–10, 2000

    • Search Google Scholar
    • Export Citation
  • 30.

    Ng HK, , Poon WS, & Goh K, et al: Histopathology of post-embolized meningiomas. Am J Surg Pathol 20:12241230, 1996 Ng HK, Poon WS, Goh K, et al: Histopathology of post-embolized meningiomas. Am J Surg Pathol 20:1224–1230, 1996

    • Search Google Scholar
    • Export Citation
  • 31.

    Nishikawa R, , Cheng SY, & Nagashima R, et al: Expression of vascular endothelial growth factor in human brain tumors. Acta Neuropathol 96:453462, 1998 Nishikawa R, Cheng SY, Nagashima R, et al: Expression of vascular endothelial growth factor in human brain tumors. Acta Neuropathol 96:453–462, 1998

    • Search Google Scholar
    • Export Citation
  • 32.

    Paulus W, , Meixensberger J, & Hofmann E, et al: Effect of embolisation of meningioma on Ki-67 proliferation index. J Clin Pathol 46:876877, 1993 Paulus W, Meixensberger J, Hofmann E, et al: Effect of embolisation of meningioma on Ki-67 proliferation index. J Clin Pathol 46:876–877, 1993

    • Search Google Scholar
    • Export Citation
  • 33.

    Pause A, , Peterson B, & Schaffar G, et al: Studying interactions of four proteins in the yeast two-hybrid system: Structural resemblance of the pVHL/elongin BC/hCUL-2 complex with the ubiquitin ligase complex SKP1/cullin/F-box protein. Proc Natl Acad Sci USA 96:95339538, 1999 Pause A, Peterson B, Schaffar G, et al: Studying interactions of four proteins in the yeast two-hybrid system: Structural resemblance of the pVHL/elongin BC/hCUL-2 complex with the ubiquitin ligase complex SKP1/cullin/F-box protein. Proc Natl Acad Sci USA 96:9533–9538, 1999

    • Search Google Scholar
    • Export Citation
  • 34.

    Pietsch T, , Valer MM, & Wolf HK, et al: Expression and distribution of vascular endothelial growth factor protein in human brain tumors. Acta Neuropath 93:109117, 1997 Pietsch T, Valer MM, Wolf HK, et al: Expression and distribution of vascular endothelial growth factor protein in human brain tumors. Acta Neuropath 93:109–117, 1997

    • Search Google Scholar
    • Export Citation
  • 35.

    Provias J, , Claffey K, & delAguila L, et al: Meningiomas: role of vascular endothelial growth factor/vascular permeability factor in angiogenesis and peritumoral edema. Neurosurgery 40:10161026, 1997 Provias J, Claffey K, delAguila L, et al: Meningiomas: role of vascular endothelial growth factor/vascular permeability factor in angiogenesis and peritumoral edema. Neurosurgery 40:1016–1026, 1997

    • Search Google Scholar
    • Export Citation
  • 36.

    Richard DE, , Berra E, & Pouyssegur J: Angiogenesis: how a tumor adapts to hypoxia. Biochem Biophys Res Comm 266:718722, 1999 Richard DE, Berra E, Pouyssegur J: Angiogenesis: how a tumor adapts to hypoxia. Biochem Biophys Res Comm 266:718–722, 1999

    • Search Google Scholar
    • Export Citation
  • 37.

    Richter HP, & Schachenmayr W: Preoperative embolization of intracranial meningiomas. Neurosurgery 13:261268, 1983 Richter HP, Schachenmayr W: Preoperative embolization of intracranial meningiomas. Neurosurgery 13:261–268, 1983

    • Search Google Scholar
    • Export Citation
  • 38.

    Salceda S, & Caro J: Hypoxia-inducible factor 1α (HIF-1α) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends upon redox-induced changes. J Biol Chem 272:2264222647, 1997 Salceda S, Caro J: Hypoxia-inducible factor 1α (HIF-1α) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends upon redox-induced changes. J Biol Chem 272:22642–22647, 1997

    • Search Google Scholar
    • Export Citation
  • 39.

    Samoto K, , Ikezaki K, & Ono M, et al: Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res 55:11891193, 1995 Samoto K, Ikezaki K, Ono M, et al: Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res 55:1189–1193, 1995

    • Search Google Scholar
    • Export Citation
  • 40.

    Semenza GL: Expression of hypoxia-inducible factor 1: mechanisms and consequences. Biochem Pharmacol 59:4753, 2000 Semenza GL: Expression of hypoxia-inducible factor 1: mechanisms and consequences. Biochem Pharmacol 59:47–53, 2000

    • Search Google Scholar
    • Export Citation
  • 41.

    Semenza GL, , Jiang BH, & Leung SW, et al: Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271:3252932537, 1996 Semenza GL, Jiang BH, Leung SW, et al: Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271:32529–32537, 1996

    • Search Google Scholar
    • Export Citation
  • 42.

    Shono T, , Inamura T, & Torisu M, et al: Vascular endothelial growth factor and malignant transformation of a meningioma: case report. Neurol Res 22:189193, 2000 Shono T, Inamura T, Torisu M, et al: Vascular endothelial growth factor and malignant transformation of a meningioma: case report. Neurol Res 22:189–193, 2000

    • Search Google Scholar
    • Export Citation
  • 43.

    Shweiki D, , Itin A, & Soffer D, et al: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843845, 1992 Shweiki D, Itin A, Soffer D, et al: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845, 1992

    • Search Google Scholar
    • Export Citation
  • 44.

    Stebbins CE, , Kaelin WG Jr, & Pavletich NP: Structure of the VHL-ElonginC-ElonginB complex: implications for the VHL tumor suppressor function. Science 284:455461, 1999 Stebbins CE, Kaelin WG Jr, Pavletich NP: Structure of the VHL-ElonginC-ElonginB complex: implications for the VHL tumor suppressor function. Science 284:455–461, 1999

    • Search Google Scholar
    • Export Citation
  • 45.

    Sutter CH, , Laughner E, & Semenza GL: Hypoxia-inducible factor 1α protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations. Proc Natl Acad Sci USA 97:47484753, 2000 Sutter CH, Laughner E, Semenza GL: Hypoxia-inducible factor 1α protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations. Proc Natl Acad Sci USA 97:4748–4753, 2000

    • Search Google Scholar
    • Export Citation
  • 46.

    Takano S, , Yoshii Y, & Kondo S, et al: Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res 56:21852190, 1996 Takano S, Yoshii Y, Kondo S, et al: Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res 56:2185–2190, 1996

    • Search Google Scholar
    • Export Citation
  • 47.

    Tsai JC, , Hsiao YY, & Teng LJ, et al: Regulation of vascular endothelial growth factor secretion in human meningioma cells. J Formos Med Assoc 98:111117, 1999 Tsai JC, Hsiao YY, Teng LJ, et al: Regulation of vascular endothelial growth factor secretion in human meningioma cells. J Formos Med Assoc 98:111–117, 1999

    • Search Google Scholar
    • Export Citation
  • 48.

    Waleh NS, , Brody MD, & Knapp MA, et al: Mapping of the vascular endothelial growth factor-producing hypoxic cells in multicellular tumor spheroids using a hypoxia-specific marker. Cancer Res 55:62226226, 1995 Waleh NS, Brody MD, Knapp MA, et al: Mapping of the vascular endothelial growth factor-producing hypoxic cells in multicellular tumor spheroids using a hypoxia-specific marker. Cancer Res 55:6222–6226, 1995

    • Search Google Scholar
    • Export Citation
  • 49.

    Wang GL, , Jiang BH, & Rue EA, et al: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Nat Acad Sci USA 92:55105514, 1995 Wang GL, Jiang BH, Rue EA, et al: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Nat Acad Sci USA 92:5510–5514, 1995

    • Search Google Scholar
    • Export Citation
  • 50.

    Yamasaki F, , Yoskioka H, & Hama S, et al: Recurrence of meningiomas. Cancer 89:11021110, 2000 Yamasaki F, Yoskioka H, Hama S, et al: Recurrence of meningiomas. Cancer 89:1102–1110, 2000

    • Search Google Scholar
    • Export Citation
  • 51.

    Yoshioka H, , Hama S, & Taniguchi E, et al: Peritumoral brain edema associated with meningioma: influence of vascular endothelial growth factor expression and vascular blood supply. Cancer 85:936944, 1999 Yoshioka H, Hama S, Taniguchi E, et al: Peritumoral brain edema associated with meningioma: influence of vascular endothelial growth factor expression and vascular blood supply. Cancer 85:936–944, 1999

    • Search Google Scholar
    • Export Citation
  • 52.

    Yu AY, , Frid MG, & Shimoda LA, et al: Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. Am J Physiol 275:L818L826, 1998 Yu AY, Frid MG, Shimoda LA, et al: Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. Am J Physiol 275:L818–L826, 1998

    • Search Google Scholar
    • Export Citation
  • 53.

    Zagzag D, , Zhong H, & Scalzitti JM, et al: Expression of hypoxiainducible factor 1α in brain tumors: association with angiogenesis, invasion, and progression. Cancer 88:26062618, 2000 Zagzag D, Zhong H, Scalzitti JM, et al: Expression of hypoxiainducible factor 1α in brain tumors: association with angiogenesis, invasion, and progression. Cancer 88:2606–2618, 2000

    • Search Google Scholar
    • Export Citation
  • 54.

    Zhong H, , De Marzo AM, & Laughner E, et al: Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 59:58305835, 1999 Zhong H, De Marzo AM, Laughner E, et al: Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 59:5830–5835, 1999

    • Search Google Scholar
    • Export Citation

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