Up-regulation of Vascular Endothelial Growth Factor in Stromal Cells of Hemangioblastomas is Correlated with Up-regulation of the Transcription Factor HRF/HIF-2alpha

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 1998 Jul 17

PMID 9665461

Citations 32

Authors

I Flamme

M Krieg

K H Plate

Affiliations

Soon will be listed here.

Abstract

Hemangioblastomas, the most frequent manifestation of the hereditary von Hippel-Lindau disease (VHL), are highly vascularized tumors of the central nervous system. In previous studies, the endothelial-specific mitogen vascular endothelial growth factor (VEGF) was shown to be up-regulated in the stromal cells, the putative neoplastic cells in hemangioblastomas. Therefore, it was suggested that secretion of VEGF by stromal cells is the pathogenetic cause of the vascular lesions in hemangioblastomas. The novel basic helix loop helix transcription factor HRF/HIF-2alpha is a candidate regulator of VEGF expression during development. We therefore investigated expression of HRF/HIF-2alpha in hemangioblastomas and found the overexpression of VEGF mRNA in stromal cells to be highly correlated with elevated expression levels of HRF/HIF-2alpha mRNA. This finding is suggestive for a role of HRF in VEGF-dependent vascular growth in hemangioblastomas and could provide a link between transcriptional activation of the VEGF gene and loss of function of the VHL gene product.

Citing Articles

Relationship between ZHX2 Expression and VHL Gene Alteration in VHL-associated and Sporadic Hemangioblastomas of the Central Nervous System.

Kanno H, Nakahara K, Yamada S, Fujii S, Murata H, Yamamoto T J Kidney Cancer VHL. 2025; 11(4):39-47.

PMID: 39850947 PMC: 11756601. DOI: 10.15586/jkcvhl.v11i4.355.

ATF4/NUPR1 axis promotes cancer cell survival and mediates immunosuppression in clear cell renal cell carcinoma.

Lu Y, Chen W, Xuan Y, Li X, Wu S, Wang H Discov Oncol. 2024; 15(1):607.

PMID: 39480570 PMC: 11528094. DOI: 10.1007/s12672-024-01485-0.

Benign Spinal Tumors.

Noureldine M, Shimony N, Jallo G Adv Exp Med Biol. 2023; 1405:583-606.

PMID: 37452955 DOI: 10.1007/978-3-031-23705-8_23.

Neurological applications of belzutifan in von Hippel-Lindau disease.

Zhang Y, Nguyen C, Zhang N, Fink N, John J, Venkatesh O Neuro Oncol. 2022; 25(5):827-838.

PMID: 36215167 PMC: 10158112. DOI: 10.1093/neuonc/noac234.

Developmentally Arrested Basket/Stellate Cells in Postnatal Human Brain as Potential Tumor Cells of Origin for Cerebellar Hemangioblastoma in von Hippel-Lindau Patients.

Shively S, Edwards N, MacDonald T, Johnson K, Diaz-Rodriguez N, Merrill M J Neuropathol Exp Neurol. 2022; 81(11):885-899.

PMID: 35980299 PMC: 9803908. DOI: 10.1093/jnen/nlac073.

References

Wenger R, Gassmann M . Oxygen(es) and the hypoxia-inducible factor-1. Biol Chem. 1997; 378(7):609-16. View

Millauer B, Schnurch H, Martinez R, Moller N, Risau W, Ullrich A . High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993; 72(6):835-46. DOI: 10.1016/0092-8674(93)90573-9. View

Sato T, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gridley T . Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature. 1995; 376(6535):70-4. DOI: 10.1038/376070a0. View

Breier G, Risau W . The role of vascular endothelial growth factor in blood vessel formation. Trends Cell Biol. 1996; 6(12):454-6. DOI: 10.1016/0962-8924(96)84935-x. View

Iliopoulos O, Levy A, Jiang C, Kaelin Jr W, Goldberg M . Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A. 1996; 93(20):10595-9. PMC: 38198. DOI: 10.1073/pnas.93.20.10595. View

Plate K . Pathology, genetics and cell biology of hemangioblastomas. Histol Histopathol. 1996; 11(4):1049-61. View

Hatva E, Bohling T, Jaaskelainen J, Persico M, Haltia M, Alitalo K . Vascular growth factors and receptors in capillary hemangioblastomas and hemangiopericytomas. Am J Pathol. 1996; 148(3):763-75. PMC: 1861732. View

Semenza G . Transcriptional regulation by hypoxia-inducible factor 1 molecular mechanisms of oxygen homeostasis. Trends Cardiovasc Med. 2011; 6(5):151-7. DOI: 10.1016/1050-1738(96)00039-4. View

Gnarra J, Zhou S, Merrill M, Wagner J, Krumm A, Papavassiliou E . Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci U S A. 1996; 93(20):10589-94. PMC: 38197. DOI: 10.1073/pnas.93.20.10589. View

10.

Huang L, Arany Z, Livingston D, BUNN H . Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem. 1996; 271(50):32253-9. DOI: 10.1074/jbc.271.50.32253. View

11.

Breier G, Risau W, Plate K . Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res. 1995; 55(6):1358-64. View

12.

Forsythe J, Jiang B, Iyer N, Agani F, Leung S, Koos R . Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996; 16(9):4604-13. PMC: 231459. DOI: 10.1128/MCB.16.9.4604. View

13.

Kibel A, Iliopoulos O, DeCaprio J, Kaelin Jr W . Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science. 1995; 269(5229):1444-6. DOI: 10.1126/science.7660130. View

14.

Flamme I, Frohlich T, von Reutern M, Kappel A, Damert A, Risau W . HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1 alpha and developmentally expressed in blood vessels. Mech Dev. 1997; 63(1):51-60. DOI: 10.1016/s0925-4773(97)00674-6. View

15.

Duan D, Pause A, Burgess W, Aso T, Chen D, Garrett K . Inhibition of transcription elongation by the VHL tumor suppressor protein. Science. 1995; 269(5229):1402-6. DOI: 10.1126/science.7660122. View

16.

Shweiki D, Itin A, Soffer D, Keshet E . Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992; 359(6398):843-5. DOI: 10.1038/359843a0. View

17.

Wang G, Jiang B, Rue E, Semenza G . Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995; 92(12):5510-4. PMC: 41725. DOI: 10.1073/pnas.92.12.5510. View

18.

Damert A, Machein M, Breier G, Fujita M, Hanahan D, Risau W . Up-regulation of vascular endothelial growth factor expression in a rat glioma is conferred by two distinct hypoxia-driven mechanisms. Cancer Res. 1997; 57(17):3860-4. View

19.

Plate K, Breier G, Weich H, Risau W . Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992; 359(6398):845-8. DOI: 10.1038/359845a0. View

20.

Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y . A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci U S A. 1997; 94(9):4273-8. PMC: 20712. DOI: 10.1073/pnas.94.9.4273. View