Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Jan;91(1):153–159. doi: 10.1172/JCI116165

Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms.

R A Berkman 1, M J Merrill 1, W C Reinhold 1, W T Monacci 1, A Saxena 1, W C Clark 1, J T Robertson 1, I U Ali 1, E H Oldfield 1
PMCID: PMC330009  PMID: 8380810

Abstract

Expression of the vascular permeability factor/vascular endothelial growth factor (VEGPF) gene was investigated in human central nervous system (CNS) neoplasms and normal brain. Adsorption of capillary permeability activity from human glioblastoma multiforme (GBM) cell conditioned medium and GBM cyst fluids by anti-VEGPF antibodies demonstrated that VEGPF is secreted by GBM cells and is present in sufficient quantities in vivo to induce vascular permeability. Cloning and sequencing of polymerase chain reaction-amplified GBM and normal brain cDNA demonstrated three forms of the VEGPF coding region (567, 495, and 363 nucleotides), corresponding to mature polypeptides of 189, 165, and 121 amino acids, respectively. VEGPF mRNA levels in CNS tumors vs. normal brain were investigated by the RNase protection assay. Significant elevation of VEGPF gene expression was observed in 81% (22/27) of the highly vascular and edema-associated CNS neoplasms (6/8 GBM, 8/8 capillary hemangioblastomas, 6/7 meningiomas, and 2/4 cerebral metastases). In contrast, only 13% (2/15) of those CNS tumors that are not commonly associated with significant neovascularity or cerebral edema (2/10 pituitary adenomas and 0/5 nonastrocytic gliomas) had significantly increased levels of VEGPF mRNA. The relative abundance of the forms of VEGPF mRNA was consistent in tumor and normal brain: VEGPF495 > VEGPF363 > VEGPF567. In situ hybridization confirmed the presence of VEGPF mRNA in tumor cells and its increased abundance in capillary hemangioblastomas. Our results suggest a significant role for VEGPF in the development of CNS tumor neovascularity and peritumoral edema.

Full text

PDF
153

Images in this article

155Image
on p.155
156Image
on p.156
157Image
on p.157
157Image
on p.157

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akutsu Y., Aida T., Nakazawa S., Asano G. Localization of acidic and basic fibroblast growth factor mRNA in human brain tumors. Jpn J Cancer Res. 1991 Sep;82(9):1022–1027. doi: 10.1111/j.1349-7006.1991.tb01938.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Berse B., Brown L. F., Van de Water L., Dvorak H. F., Senger D. R. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell. 1992 Feb;3(2):211–220. doi: 10.1091/mbc.3.2.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bruce J. N., Criscuolo G. R., Merrill M. J., Moquin R. R., Blacklock J. B., Oldfield E. H. Vascular permeability induced by protein product of malignant brain tumors: inhibition by dexamethasone. J Neurosurg. 1987 Dec;67(6):880–884. doi: 10.3171/jns.1987.67.6.0880. [DOI] [PubMed] [Google Scholar]
  4. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  5. Clauss M., Gerlach M., Gerlach H., Brett J., Wang F., Familletti P. C., Pan Y. C., Olander J. V., Connolly D. T., Stern D. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med. 1990 Dec 1;172(6):1535–1545. doi: 10.1084/jem.172.6.1535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Conn G., Bayne M. L., Soderman D. D., Kwok P. W., Sullivan K. A., Palisi T. M., Hope D. A., Thomas K. A. Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2628–2632. doi: 10.1073/pnas.87.7.2628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Conn G., Soderman D. D., Schaeffer M. T., Wile M., Hatcher V. B., Thomas K. A. Purification of a glycoprotein vascular endothelial cell mitogen from a rat glioma-derived cell line. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1323–1327. doi: 10.1073/pnas.87.4.1323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Connolly D. T., Heuvelman D. M., Nelson R., Olander J. V., Eppley B. L., Delfino J. J., Siegel N. R., Leimgruber R. M., Feder J. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest. 1989 Nov;84(5):1470–1478. doi: 10.1172/JCI114322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Connolly D. T., Olander J. V., Heuvelman D., Nelson R., Monsell R., Siegel N., Haymore B. L., Leimgruber R., Feder J. Human vascular permeability factor. Isolation from U937 cells. J Biol Chem. 1989 Nov 25;264(33):20017–20024. [PubMed] [Google Scholar]
  10. Criscuolo G. R., Merrill M. J., Oldfield E. H. Further characterization of malignant glioma-derived vascular permeability factor. J Neurosurg. 1988 Aug;69(2):254–262. doi: 10.3171/jns.1988.69.2.0254. [DOI] [PubMed] [Google Scholar]
  11. Dvorak H. F., Sioussat T. M., Brown L. F., Berse B., Nagy J. A., Sotrel A., Manseau E. J., Van de Water L., Senger D. R. Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels. J Exp Med. 1991 Nov 1;174(5):1275–1278. doi: 10.1084/jem.174.5.1275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ekstrand A. J., James C. D., Cavenee W. K., Seliger B., Pettersson R. F., Collins V. P. Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res. 1991 Apr 15;51(8):2164–2172. [PubMed] [Google Scholar]
  13. Ferrara N., Henzel W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989 Jun 15;161(2):851–858. doi: 10.1016/0006-291x(89)92678-8. [DOI] [PubMed] [Google Scholar]
  14. Ferrara N., Winer J., Burton T. Aortic smooth muscle cells express and secrete vascular endothelial growth factor. Growth Factors. 1991;5(2):141–148. doi: 10.3109/08977199109000278. [DOI] [PubMed] [Google Scholar]
  15. Gospodarowicz D., Abraham J. A., Schilling J. Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7311–7315. doi: 10.1073/pnas.86.19.7311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hermansson M., Nistér M., Betsholtz C., Heldin C. H., Westermark B., Funa K. Endothelial cell hyperplasia in human glioblastoma: coexpression of mRNA for platelet-derived growth factor (PDGF) B chain and PDGF receptor suggests autocrine growth stimulation. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7748–7752. doi: 10.1073/pnas.85.20.7748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hirano A., Matsui T. Vascular structures in brain tumors. Hum Pathol. 1975 Sep;6(5):611–621. doi: 10.1016/s0046-8177(75)80045-1. [DOI] [PubMed] [Google Scholar]
  18. Houck K. A., Ferrara N., Winer J., Cachianes G., Li B., Leung D. W. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 1991 Dec;5(12):1806–1814. doi: 10.1210/mend-5-12-1806. [DOI] [PubMed] [Google Scholar]
  19. Keck P. J., Hauser S. D., Krivi G., Sanzo K., Warren T., Feder J., Connolly D. T. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989 Dec 8;246(4935):1309–1312. doi: 10.1126/science.2479987. [DOI] [PubMed] [Google Scholar]
  20. Leung D. W., Cachianes G., Kuang W. J., Goeddel D. V., Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989 Dec 8;246(4935):1306–1309. doi: 10.1126/science.2479986. [DOI] [PubMed] [Google Scholar]
  21. Levy A. P., Tamargo R., Brem H., Nathans D. An endothelial cell growth factor from the mouse neuroblastoma cell line NB41. Growth Factors. 1989;2(1):9–19. doi: 10.3109/08977198909069077. [DOI] [PubMed] [Google Scholar]
  22. Long D. M. Capillary ultrastructure and the blood-brain barrier in human malignant brain tumors. J Neurosurg. 1970 Feb;32(2):127–144. doi: 10.3171/jns.1970.32.2.0127. [DOI] [PubMed] [Google Scholar]
  23. Maxwell M., Naber S. P., Wolfe H. J., Galanopoulos T., Hedley-Whyte E. T., Black P. M., Antoniades H. N. Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance. J Clin Invest. 1990 Jul;86(1):131–140. doi: 10.1172/JCI114675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Maxwell M., Naber S. P., Wolfe H. J., Hedley-Whyte E. T., Galanopoulos T., Neville-Golden J., Antoniades H. N. Expression of angiogenic growth factor genes in primary human astrocytomas may contribute to their growth and progression. Cancer Res. 1991 Feb 15;51(4):1345–1351. [PubMed] [Google Scholar]
  25. Merrill M. J., Edwards N. A. Insulin-like growth factor-I receptors in human glial tumors. J Clin Endocrinol Metab. 1990 Jul;71(1):199–209. doi: 10.1210/jcem-71-1-199. [DOI] [PubMed] [Google Scholar]
  26. Plouët J., Schilling J., Gospodarowicz D. Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT-20 cells. EMBO J. 1989 Dec 1;8(12):3801–3806. doi: 10.1002/j.1460-2075.1989.tb08557.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rosenthal R. A., Megyesi J. F., Henzel W. J., Ferrara N., Folkman J. Conditioned medium from mouse sarcoma 180 cells contains vascular endothelial growth factor. Growth Factors. 1990;4(1):53–59. doi: 10.3109/08977199009011010. [DOI] [PubMed] [Google Scholar]
  28. Saxena A., Ali I. U. Increased expression of genes from growth factor signaling pathways in glioblastoma cell lines. Oncogene. 1992 Feb;7(2):243–247. [PubMed] [Google Scholar]
  29. Schlegel U., Moots P. L., Rosenblum M. K., Thaler H. T., Furneaux H. M. Expression of transforming growth factor alpha in human gliomas. Oncogene. 1990 Dec;5(12):1839–1842. [PubMed] [Google Scholar]
  30. Senger D. R., Connolly D. T., Van de Water L., Feder J., Dvorak H. F. Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res. 1990 Mar 15;50(6):1774–1778. [PubMed] [Google Scholar]
  31. Senger D. R., Galli S. J., Dvorak A. M., Perruzzi C. A., Harvey V. S., Dvorak H. F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983 Feb 25;219(4587):983–985. doi: 10.1126/science.6823562. [DOI] [PubMed] [Google Scholar]
  32. Senger D. R., Perruzzi C. A., Feder J., Dvorak H. F. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 1986 Nov;46(11):5629–5632. [PubMed] [Google Scholar]
  33. Takahashi J. A., Mori H., Fukumoto M., Igarashi K., Jaye M., Oda Y., Kikuchi H., Hatanaka M. Gene expression of fibroblast growth factors in human gliomas and meningiomas: demonstration of cellular source of basic fibroblast growth factor mRNA and peptide in tumor tissues. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5710–5714. doi: 10.1073/pnas.87.15.5710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tischer E., Gospodarowicz D., Mitchell R., Silva M., Schilling J., Lau K., Crisp T., Fiddes J. C., Abraham J. A. Vascular endothelial growth factor: a new member of the platelet-derived growth factor gene family. Biochem Biophys Res Commun. 1989 Dec 29;165(3):1198–1206. doi: 10.1016/0006-291x(89)92729-0. [DOI] [PubMed] [Google Scholar]
  35. Tischer E., Mitchell R., Hartman T., Silva M., Gospodarowicz D., Fiddes J. C., Abraham J. A. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991 Jun 25;266(18):11947–11954. [PubMed] [Google Scholar]
  36. Udaka K., Takeuchi Y., Movat H. Z. Simple method for quantitation of enhanced vascular permeability. Proc Soc Exp Biol Med. 1970 Apr;133(4):1384–1387. doi: 10.3181/00379727-133-34695. [DOI] [PubMed] [Google Scholar]
  37. Westermark B., Pontén J., Hugosson R. Determinants for the establishment of permanent tissue culture lines from human gliomas. Acta Pathol Microbiol Scand A. 1973 Nov;81(6):791–805. doi: 10.1111/j.1699-0463.1973.tb03573.x. [DOI] [PubMed] [Google Scholar]
  38. Yeo T. K., Senger D. R., Dvorak H. F., Freter L., Yeo K. T. Glycosylation is essential for efficient secretion but not for permeability-enhancing activity of vascular permeability factor (vascular endothelial growth factor). Biochem Biophys Res Commun. 1991 Sep 30;179(3):1568–1575. doi: 10.1016/0006-291x(91)91752-x. [DOI] [PubMed] [Google Scholar]
  39. Young W. S., 3rd, Bonner T. I., Brann M. R. Mesencephalic dopamine neurons regulate the expression of neuropeptide mRNAs in the rat forebrain. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9827–9831. doi: 10.1073/pnas.83.24.9827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zagzag D., Miller D. C., Sato Y., Rifkin D. B., Burstein D. E. Immunohistochemical localization of basic fibroblast growth factor in astrocytomas. Cancer Res. 1990 Nov 15;50(22):7393–7398. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES