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

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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.

Article Information

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.

© AANS, except where prohibited by US copyright law.

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    Photomicrographs showing immunohistochemical findings for VEGF and HIF-1α in tumor samples. a: Human meningioma stained for VEGF, Grade 4 on a scale of 0 to 4, with 4 being the highest level of expression of this protein. We used DAB as the developing substrate and toluidine blue as the counterstain. Original magnification × 10. b: Negative control, same meningioma, original magnification × 10. c: Human meningioma section stained for HIF-1α, Grade 4 on a scale of 0 to 4, with 4 being the highest level of expression of this protein. We used DAB as a substrate, counterstained with toluidine blue, original magnification × 20. d: Negative control, same tumor, original magnification × 10. e: Different meningioma, Grade 4, with more than 50% of cells with nuclear staining. Similar immunohistochemical method demonstrating nuclear staining for HIF-1α. Original magnification × 40. f: Negative control without nuclear staining, original magnification × 40. g: An MIB-1—labeled atypical meningioma with a proliferation index of approximately 15%.

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    Bar graph showing values for VEGF secretion in primary meningioma cell cultures grown under conditions of normoxia or hypoxia for 4 hours. The five primary meningioma cell lines (M1–M5) were studied. Tumors were subjected to hypoxic conditions and compared with similar cells grown in normoxia, as described earlier. Medium taken from individual culture dishes for each cell line was examined using the ELISA for VEGF protein. Production of VEGF was normalized to total protein in the media. The baseline VEGF was relatively low, especially when compared with glioma cell lines (data not shown). Production of VEGF is significantly increased under hypoxic conditions for all tumors (Student t-test, p < 0.05), but the increase was much less than that demonstrated in the glioma cell lines.

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    Bar graph showing values for VEGF secretion by a primary meningioma cell culture according to ELISA after stimulation by increasing doses of EGF or PDGF under conditions of normoxia or hypoxia for 4 hours using the primary meningioma cell line M5. Production of VEGF is normalized to total protein in the media. Secretion of VEGF is increased by EGF and PDGF in a dose-dependent manner by using concentrations of 5, 10, and 20 ng/ml of growth factor. Secretion of VEGF increases in hypoxic conditions, as it does after stimulation by both EGF and PDGF (p > 0.05), as indicated by one-way analysis of variance and Fisher protected least significant difference tests in control groups.

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    Western blot showing HIF-1α expression in five primary human meningiomas (M1-M5) and U251 glioma cell lines subjected to normoxic and hypoxic conditions. Fifty micrograms of cell protein from each cell group was subjected to 10% SDS-PAGE and probed with HIF-1α antibody. The same blot was analyzed for consistent loading with B-actin antibody (not shown). No expression was seen in the case of the primary meningiomas (only the hypoxic cells are shown). The U251 cells show baseline expression of HIF-1α, which is significantly increased after 4 hours of hypoxic conditions; CoCl-activated HeLa cells were used as a control.

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    Western blots showing HIF-1α expression in the M5 primary meningioma cell line exposed to PDGF-BB (10 ng/ml) over time under normoxic conditions. Fifty micrograms of cell protein from each cell group was subjected to 10% SDS-PAGE and probed with HIF-1α antibody. The same blot was analyzed for consistent loading with B-actin antibody. Meningioma cells show that PDGF-BB induced expression of HIF-1α beginning at 2 hours with maximal expression between 3 and 5 hours. The control group was incubated under conditions similar to those in the 6-hour group, but without PDGF.

References

1.

An WGKanekai MSimon MCet al: Stabilization of wildtype p53 by hypoxia-inducible factor 1α. Nature 392:4054081998An WG Kanekai M Simon MC et al: Stabilization of wildtype p53 by hypoxia-inducible factor 1α. Nature 392:405–408 1998

2.

Berkman RAMerrill MJReinhold WCet al: Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest 91:1531591993Berkman 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

3.

Bitzer MOpitz HPopp Jet al: Angiogenesis and brain oedema in intracranial meningiomas: influence of vascular endothelial growth factor. Acta Neurochir 140:3333401998Bitzer 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

4.

Chamberlain MC: Adjuvant combined modality therapy for malignant meningiomas. J Neurosurg 84:7337361996Chamberlain MC: Adjuvant combined modality therapy for malignant meningiomas. J Neurosurg 84:733–736 1996

5.

Cho SChoi YJKim JMet al: Binding and regulation of HIF-1α by a subunit of the proteasome complex, PSMA7. FEBS Lett 498:62662001Cho 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

6.

Clerici CMatthay MA: Hypoxia regulates gene expression of alveolar epithelial transport proteins. J Appl Physiol 88:189018962000Clerici C Matthay MA: Hypoxia regulates gene expression of alveolar epithelial transport proteins. J Appl Physiol 88:1890–1896 2000

7.

Dietzmann Kvon Bossanyi PWarich-Kirches Met al: Immunohistochemical detection of vascular growth factors in angiomatous and atypical meningiomas, as well as hemangiopericytomas. Pathol Res Pract 193:5035101997Dietzmann 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

8.

Forsythe JAJiang BHIyer NVet al: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor I. Mol Cell Biol 16:460446131996Forsythe 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

9.

Gleadle JMRatcliffe 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 89:5035091997Gleadle 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

10.

Goldman CKBharara SPalmer CAet al: Brain edema in meningiomas is associated with increased vascular endothelial growth factor expression. Neurosurgery 40:126912771997Goldman 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

11.

Hatva EKaipainen AMentula Pet al: Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. Am J Pathol 146:3683781995Hatva 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

12.

Ivan MKondo KYang Het al: HIF-α targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:4644682001Ivan 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

13.

Iyer NVKotch LEAgani Fet al: Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev 12:1491621998Iyer 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

14.

Jaakkola PMole DRTian YMet al: Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:4684722001Jaakkola 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

15.

Jensen RLLee YSGuijarti Met 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 37:9379471995Jensen 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

16.

Jensen RLOrigitano TCLee YSet al: In vitro growth inhibition of growth factor-stimulated meningioma cells by calcium channel antagonists. Neurosurgery 36:3653741995Jensen 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

17.

Jiang BHRue EWang GLet al: Dimerization, DNA binding, and, transactivation properties of hypoxia-inducible factor 1. J Biol Chem 271:17771177781996Jiang 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

18.

Kalkanis SNCarroll RSZhang Jet al: Correlation of vascular endothelial growth factor messenger RNA expression with peritumoral vasogenic cerebral edema in meningiomas. J Neurosurg 85:109511011996Kalkanis 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

19.

Kallio PJWilson WJO'Brien Set al: Regulation of the hypoxia-inducible transcription factor 1α by the ubiquitin-proteasome pathway. J Biol Chem 274:651965251999Kallio 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

20.

Kamura TKoepp DMConrad MNet al: Rbx1, a component of theVHL tumor suppressor complex and SCF ubiquitin ligase. Science 284:6576611999Kamura T Koepp DM Conrad MN et al: Rbx1 a component of theVHL tumor suppressor complex and SCF ubiquitin ligase. Science 284:657–661 1999

21.

Kleihues PBurger PCScheithauer BW: The new WHO classification of brain tumors. Brain Pathol 3:2552681993Kleihues P Burger PC Scheithauer BW: The new WHO classification of brain tumors. Brain Pathol 3:255–268 1993

22.

Lamszus KLengler USchmidt NOet 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 46:9389482000Lamszus 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

23.

Lantos PLVandenBerg SRKleihues P: Tumours of the nervous system in Graham DILantos PL (eds): Greenfield's Neuropathologyed 6. London: Arnold1997 Vol 2 pp 583879Lantos 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

24.

Li JPost MVolk Ret al: PR39, a peptide regulator of angiogenesis. Nat Med 6:49552000Li J Post M Volk R et al: PR39 a peptide regulator of angiogenesis. Nat Med 6:49–55 2000

25.

Louis DNBudka Hvon Deimling A: Meninigomas in Kleihues PCavenee WK (eds): Pathology and Genetics of Tumours of the Nervous System. Lyon: IARC Press1997 pp 134141Louis 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

26.

Maxwell PHDachs GUGleadle JMet al: Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci 94:810481091997Maxwell 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

27.

Maxwell PHWiesener MSChang GWet al: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:2712751999Maxwell 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

28.

McLean CAJolley DCukier Eet al: Atypical and malignant meningiomas: importance of micronecrosis as a prognostic indicator. Histopathology 23:3493531993McLean CA Jolley D Cukier E et al: Atypical and malignant meningiomas: importance of micronecrosis as a prognostic indicator. Histopathology 23:349–353 1993

29.

Michiels CArnould TRemacle J: Endothelial cell responses to hypoxia: initiation of a cascade of cellular interactions. Biochim Biophys Acta 1497:1102000Michiels C Arnould T Remacle J: Endothelial cell responses to hypoxia: initiation of a cascade of cellular interactions. Biochim Biophys Acta 1497:1–10 2000

30.

Ng HKPoon WSGoh Ket al: Histopathology of post-embolized meningiomas. Am J Surg Pathol 20:122412301996Ng HK Poon WS Goh K et al: Histopathology of post-embolized meningiomas. Am J Surg Pathol 20:1224–1230 1996

31.

Nishikawa RCheng SYNagashima Ret al: Expression of vascular endothelial growth factor in human brain tumors. Acta Neuropathol 96:4534621998Nishikawa R Cheng SY Nagashima R et al: Expression of vascular endothelial growth factor in human brain tumors. Acta Neuropathol 96:453–462 1998

32.

Paulus WMeixensberger JHofmann Eet al: Effect of embolisation of meningioma on Ki-67 proliferation index. J Clin Pathol 46:8768771993Paulus W Meixensberger J Hofmann E et al: Effect of embolisation of meningioma on Ki-67 proliferation index. J Clin Pathol 46:876–877 1993

33.

Pause APeterson BSchaffar Get 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 96:953395381999Pause 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

34.

Pietsch TValer MMWolf HKet al: Expression and distribution of vascular endothelial growth factor protein in human brain tumors. Acta Neuropath 93:1091171997Pietsch 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

35.

Provias JClaffey KdelAguila Let al: Meningiomas: role of vascular endothelial growth factor/vascular permeability factor in angiogenesis and peritumoral edema. Neurosurgery 40:101610261997Provias 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

36.

Richard DEBerra EPouyssegur J: Angiogenesis: how a tumor adapts to hypoxia. Biochem Biophys Res Comm 266:7187221999Richard DE Berra E Pouyssegur J: Angiogenesis: how a tumor adapts to hypoxia. Biochem Biophys Res Comm 266:718–722 1999

37.

Richter HPSchachenmayr W: Preoperative embolization of intracranial meningiomas. Neurosurgery 13:2612681983Richter HP Schachenmayr W: Preoperative embolization of intracranial meningiomas. Neurosurgery 13:261–268 1983

38.

Salceda SCaro 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 272:22642226471997Salceda 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

39.

Samoto KIkezaki KOno Met al: Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res 55:118911931995Samoto 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

40.

Semenza GL: Expression of hypoxia-inducible factor 1: mechanisms and consequences. Biochem Pharmacol 59:47532000Semenza GL: Expression of hypoxia-inducible factor 1: mechanisms and consequences. Biochem Pharmacol 59:47–53 2000

41.

Semenza GLJiang BHLeung SWet 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 271:32529325371996Semenza 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

42.

Shono TInamura TTorisu Met al: Vascular endothelial growth factor and malignant transformation of a meningioma: case report. Neurol Res 22:1891932000Shono 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

43.

Shweiki DItin ASoffer Det al: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:8438451992Shweiki D Itin A Soffer D et al: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845 1992

44.

Stebbins CEKaelin WG JrPavletich NP: Structure of the VHL-ElonginC-ElonginB complex: implications for the VHL tumor suppressor function. Science 284:4554611999Stebbins 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

45.

Sutter CHLaughner ESemenza 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 97:474847532000Sutter 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

46.

Takano SYoshii YKondo Set al: Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res 56:218521901996Takano 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

47.

Tsai JCHsiao YYTeng LJet al: Regulation of vascular endothelial growth factor secretion in human meningioma cells. J Formos Med Assoc 98:1111171999Tsai 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

48.

Waleh NSBrody MDKnapp MAet al: Mapping of the vascular endothelial growth factor-producing hypoxic cells in multicellular tumor spheroids using a hypoxia-specific marker. Cancer Res 55:622262261995Waleh 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

49.

Wang GLJiang BHRue EAet al: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Nat Acad Sci USA 92:551055141995Wang 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

50.

Yamasaki FYoskioka HHama Set al: Recurrence of meningiomas. Cancer 89:110211102000Yamasaki F Yoskioka H Hama S et al: Recurrence of meningiomas. Cancer 89:1102–1110 2000

51.

Yoshioka HHama STaniguchi Eet al: Peritumoral brain edema associated with meningioma: influence of vascular endothelial growth factor expression and vascular blood supply. Cancer 85:9369441999Yoshioka 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

52.

Yu AYFrid MGShimoda LAet al: Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. Am J Physiol 275:L818L8261998Yu 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

53.

Zagzag DZhong HScalzitti JMet al: Expression of hypoxiainducible factor 1α in brain tumors: association with angiogenesis, invasion, and progression. Cancer 88:260626182000Zagzag 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

54.

Zhong HDe Marzo AMLaughner Eet al: Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 59:583058351999Zhong 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

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