scholarly journals Regulation of vascular endothelial growth factor by hypoxia and its modulation by the von Hippel-Lindau tumor suppressor gene

1997 ◽  
Vol 51 (2) ◽  
pp. 575-578 ◽  
Author(s):  
Andrew P. Levy ◽  
Nina S. Levy ◽  
Othon Iliopoulos ◽  
Chian Jiang ◽  
William G. Kaelin ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene ◽  
Vascular Endothelial ◽  
Von Hippel Lindau ◽  
Endothelial Growth Factor

Coexpression of Erythropoietin and Vascular Endothelial Growth Factor in Nervous System Tumors Associated With von Hippel-Lindau Tumor Suppressor Gene Loss of Function

Blood ◽  
1998 ◽  
Vol 92 (9) ◽  
pp. 3388-3393 ◽  
Author(s):  
Marion Krieg ◽  
Hugo H. Marti ◽  
Karl H. Plate
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Nervous System ◽  
Growth Factor ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene ◽  
Vascular Tumors ◽  
Vascular Endothelial ◽  
Von Hippel Lindau ◽  
Endothelial Growth Factor

Abstract Hemangioblastomas are highly vascular tumors of the central nervous system that overexpress the hypoxia-inducible gene, vascular endothelial growth factor (VEGF), as a consequence of mutational inactivation of the von Hippel-Lindau tumor suppressor gene (VHL). Previous reports showed that hemangioblastomas can also express erythropoietin (Epo), which is also hypoxia-inducible. However, Epo expression in hemangioblastomas was observed only in individual cases, and the analyses were mainly based on indirect determination of erythropoiesis-stimulating activity. Therefore, we analyzed a series of 11 hemangioblastomas for Epo, VEGF, and VHL expression by Northern blot analysis and compared the results with normal brain and glioblastomas. Surprisingly, we observed Epo mRNA expression in all hemangioblastoma specimens analyzed, but in none of four glioblastomas. In contrast, VEGF mRNA was expressed in all hemangioblastomas and all glioblastomas. In situ hybridization revealed neoplastic stromal cells as Epo- and VEGF-producing cells in hemangioblastomas. These results suggest that in the nonhypoxic microenvironment of hemangioblastoma, Epo, similar to VEGF, might be negatively regulated by the VHL gene product. © 1998 by The American Society of Hematology.

Coexpression of Erythropoietin and Vascular Endothelial Growth Factor in Nervous System Tumors Associated With von Hippel-Lindau Tumor Suppressor Gene Loss of Function

Blood ◽  
1998 ◽  
Vol 92 (9) ◽  
pp. 3388-3393 ◽  
Author(s):  
Marion Krieg ◽  
Hugo H. Marti ◽  
Karl H. Plate
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Nervous System ◽  
Growth Factor ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene ◽  
Vascular Tumors ◽  
Vascular Endothelial ◽  
Von Hippel Lindau ◽  
Endothelial Growth Factor

Hemangioblastomas are highly vascular tumors of the central nervous system that overexpress the hypoxia-inducible gene, vascular endothelial growth factor (VEGF), as a consequence of mutational inactivation of the von Hippel-Lindau tumor suppressor gene (VHL). Previous reports showed that hemangioblastomas can also express erythropoietin (Epo), which is also hypoxia-inducible. However, Epo expression in hemangioblastomas was observed only in individual cases, and the analyses were mainly based on indirect determination of erythropoiesis-stimulating activity. Therefore, we analyzed a series of 11 hemangioblastomas for Epo, VEGF, and VHL expression by Northern blot analysis and compared the results with normal brain and glioblastomas. Surprisingly, we observed Epo mRNA expression in all hemangioblastoma specimens analyzed, but in none of four glioblastomas. In contrast, VEGF mRNA was expressed in all hemangioblastomas and all glioblastomas. In situ hybridization revealed neoplastic stromal cells as Epo- and VEGF-producing cells in hemangioblastomas. These results suggest that in the nonhypoxic microenvironment of hemangioblastoma, Epo, similar to VEGF, might be negatively regulated by the VHL gene product. © 1998 by The American Society of Hematology.

scholarly journals The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity.

1997 ◽  
Vol 17 (9) ◽  
pp. 5629-5639 ◽  
Author(s):  
D Mukhopadhyay ◽  
B Knebelmann ◽  
H T Cohen ◽  
S Ananth ◽  
V P Sukhatme
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Cell Lines ◽  
Promoter Activity ◽  
Suppressor Gene ◽  
Vascular Endothelial ◽  
Vegf Mrna ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Endothelial Growth Factor

The von Hippel-Lindau tumor suppressor gene (VHL) has a critical role in the pathogenesis of clear-cell renal cell carcinoma (RCC), as VHL mutations have been found in both von Hippel-Lindau disease-associated and sporadic RCCs. Recent studies suggest that vascular endothelial growth factor (VEGF) mRNA is upregulated in RCC- and von Hippel-Lindau disease-associated tumors. We have therefore assessed the effect of the VHL gene product on VEGF expression. VEGF promoter-luciferase constructs were transiently cotransfected with a wild-type VHL (wt-VHL) vector in several cell lines, including 293 embryonic kidney and RCC cell lines. wt-VHL protein inhibited VEGF promoter activity in a dose-dependent manner up to 5- to 10-fold. Deletion analysis defined a 144-bp region of the VEGF promoter necessary for VHL repression. This VHL-responsive element is GC rich and specifically binds the transcription factor Sp1 in crude nuclear extracts. In Drosophila cells, cotransfected VHL represses Sp1-mediated activation but not basal activity of the VEGF promoter. We next demonstrated in coimmunoprecipitates that VHL and Sp1 were part of the same complex and, by using a glutathione-S-transferase-VHL fusion protein and purified Sp1, that VHL and Sp1 directly interact. Furthermore, endogenous VEGF mRNA levels were suppressed in permanent RCC cell lines expressing wt-VHL, and nuclear run-on studies indicated that VHL regulation of VEGF occurs at least partly at the transcriptional level. These observations support a new mechanism for VHL-mediated transcriptional repression via a direct inhibitory action on Sp1 and suggest that loss of Sp1 inhibition may be important in the pathogenesis of von Hippel-Lindau disease and RCC.

Continuous angiogenesis inhibition in the treatment for von Hippel–Lindau-related hemangioblastomas of retina and spinal cord

2019 ◽  
Vol 25 (8) ◽  
pp. 2049-2051 ◽  
Author(s):  
Derya Kıvrak Salim
Keyword(s):  
Spinal Cord ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Therapeutic Option ◽  
Suppressor Gene ◽  
Vascular Endothelial ◽  
Pediatric Age ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Endothelial Growth Factor

Hemangioblastomas of central nervous system are rare and indolent. Twenty-five percent of cases are in association with von Hippel–Lindau disease. Surgery is the standard therapy but un-resectable or recurrent cases need radiation or systemic therapy. Defective von Hippel–Lindau tumor suppressor gene leads to vascular endothelial growth factor overexpression and enhance angiogenesis. Here we report a 19-year-old male, diagnosed at pediatric age, who had retinal and spinal cord hemangioblastomas. He was treated 34 months with bevacizumab, afterwards 12 months with thalidomide and tertiary therapy with pazopanib for 9 months which still goes on. In case of need, radiation and surgical procedures were performed. Vascular endothelial growth factor inhibition continuity is a good therapeutic option, which improves outcomes of von Hippel–Lindau-related hemangioblastomas.

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