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Spatial Expression of VEGF-A in Human Glioma

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Abstract

Astrocytoma, especially of high grade, is dependent on neovascularization for its growth and progression. The expression of vascular endothelial growth factor (VEGF-A), an important angiogenesis factor, has been demonstrated in perinecrotic cells in glioblastoma. In order to achieve more knowledge regarding the process of astrocytoma angiogenesis and growth we have investigated the expression of VEGF-A immunohistochemically in different areas of tumors.

In 21 patients with astrocytomas of varying grade serial stereotactic biopsies were performed. Biopsies were taken from brain adjacent to tumor (BAT), tumor periphery, and tumor center. In the BAT region of high-grade astrocytomas, we found a frequent expression of VEGF-A in tumor cells and less frequent in blood vessels. In the periphery, there was an expression mainly in tumor cells while in the center of grade IV tumors VEGF-A was also frequently expressed in cells adjacent to necrosis. VEGF-A in astrocytoma grade II was demonstrated in viable tumor cells preferentially in the periphery but also in peripheral vessels and in centrally located tumor cells.

The findings indicate that, in addition to hypoxia in necrotic areas there may be other factors that stimulate the expression of VEGF-A. It is suggested that VEGF-A may be a prerequisite for the aggressive and infiltrative growth of astrocytomas. Therefore, when operating high-grade astrocytomas it may be of importance to resect this aggressive peripheral part of the tumor and also to take this finding into account when planning radiotherapy.

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References

  1. Cavallo T, Sade R, Folkman J, Cotran RS: Tumor angiogenesis. Rapid induction of endothelial mitoses demonstrated by autoradiography. J Cell Biol 54: 408–420, 1972

    Google Scholar 

  2. Folkman J, Klagsburn M: Angiogenic factors. Science 235(0036–8075): 442–447, 1987

    Google Scholar 

  3. Leon SP, Folkerth RD, Black PM: Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 77: 362–372, 1996

    Google Scholar 

  4. Abdulrauf SI, Edvardsen K, Ho KL, Yang XY, Rock JP, Rosenblum ML: Vascular endothelial growth factor expression and vascular density as prognostic markers of survival in patients with low-grade astrocytoma. J Neurosurg 88: 513–520, 1998

    Google Scholar 

  5. Machein MR, Plate KH: VEGF in brain tumors. J Neuro-Oncol 50: 109–120, 2000

    Google Scholar 

  6. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K: A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR(VEGFR-2) receptor tyrosine kinases. EMBO J 15: 290–298, 1996

    Google Scholar 

  7. Olofsson B, Pajusola K, Kaipainen A, von Euler G, Joukov V, Saksela O, Orpana A, Pettersson RF, Alitalo K, Eriksson U: Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93: 2576–2581, 1996

    Google Scholar 

  8. Yamada Y, Nezu J, Shimane M, Hirata Y: Molecular cloning of a novel vascular endothelial growth factor, VEGF-D. Genomics 42: 483–488, 1997

    Google Scholar 

  9. Ferrara N, Henzel WJ: Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161: 851–858, 1989

    Google Scholar 

  10. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF: Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219: 983–985, 1983

    Google Scholar 

  11. Bitzer M, Opitz H, Popp J, Morgalla M, Gruber A, Heiss E, Voigt K: Angiogenesis and brain oedema in intracranial meningiomas: influence of vascular endothelial growth factor. Acta Neurochir 140: 333–340, 1998

    Google Scholar 

  12. Machein MR, Kullmer J, Fiebich BL, Plate KH, Warnke PC: Vascular endothelial growth factor expression, vascular volume, and, capillary permeability in human brain tumors. Neurosurgery 44: 732–740; discussion 740–741, 1999

    Google Scholar 

  13. Ferrara N: Vascular endothelial growth factor. Eur J Cancer 32a: 2413–2422, 1996

    Google Scholar 

  14. Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359: 843–845, 1992

    Google Scholar 

  15. Stein I, Neeman M, Shweiki D, Itin A, Keshet E: Stabilization of vascular endothelial growth factormRNAby hypoxia and hypoglycemia and coregulation with other ischemia-induced genes. Mol Cell Biol 15: 5363–5368, 1995

    Google Scholar 

  16. Shweiki D, Neeman M, Itin A, Keshet E: Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. Proc Natl Acad Sci USA 92: 768–772, 1995

    Google Scholar 

  17. Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY: Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Mol Biol Cell 4: 121–133, 1993

    Google Scholar 

  18. Tsai JC, Goldman CK, Gillespie GY: Vascular endothelial growth factor in human glioma cell lines: induced secretion by EGF, PDGF-BB, and bFGF. J Neurosurg 82: 864–873, 1995

    Google Scholar 

  19. Kieser A, Weich HA, Brandner G, Marme D, Kolch W: Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9: 963–969, 1994

    Google Scholar 

  20. Plate KH, Breier G, Weich HA, Mennel HD, Risau W: Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms. Int J Cancer 59: 520–529, 1994

    Google Scholar 

  21. Ambs S, Bennett WP, Merriam WG, Ogunfusika MO, Oser SM, Khan MA, Jones RT, Harris CC: Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p53. Br J Cancer 78: 233–239, 1998

    Google Scholar 

  22. Plate KH, Breier G, Weich HA, Risau W: Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359: 845–848, 1992

    Google Scholar 

  23. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362: 841–844, 1993

    Google Scholar 

  24. Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L, Winkler M, Ferrara N: Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57: 4593–4599, 1997

    Google Scholar 

  25. Fong TA, Shawver LK, Sun L, Tang C, App H, Powell TJ, Kim YH, Schreck R, Wang X, Risau W, Ullrich A, Hirth KP, McMahon G: SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 59: 99–106, 1999

    Google Scholar 

  26. Laird AD, Vajkoczy P, Shawver LK, Thurnher A, Liang C, Mohammadi M, Schlessinger J, Ullrich A, Hubbard SR, Blake RA, Fong TA, Strawn LM, Sun L, Tang C, Hawtin R, Tang F, Shenoy N, Hirth KP, McMahon G, Cherrington: SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res 60: 4152–4160, 2000

    Google Scholar 

  27. Saleh M, Stacker SA, Wilks AF: Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence. Cancer Res 56: 393–401, 1996

    Google Scholar 

  28. Puduvalli VK, Sawaya R: Antiangiogenesis-therapeutic strategies and clinical implications for brain tumors. J Neuro-Oncol 50: 189–200, 2000

    Google Scholar 

  29. Hariz MI, Bergenheim AT, DeSalles AA, Rabow L, Trojanowski T: Percutaneous stereotactic brain tumour biopsy and cyst aspiration with a non-invasive frame. Br J Neurosurg 4: 397–406, 1990

    Google Scholar 

  30. Kleihues P, Burger PC, Scheithauer BW: Histological Typing of Tumours of the Central Nervous System. Berlin, Springer-Verlag, 1993

    Google Scholar 

  31. Hatva E, Kaipainen A, Mentula P, Jaaskelainen J, Paetau A, Haltia M, Alitalo K: Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. Am J Pathol 146: 368–378, 1995

    Google Scholar 

  32. Lindgren M, Johansson M, Sandstrom J, Jonsson Y, Bergenheim AT, Henriksson R: VEGF and tPAco-expressed in malignant glioma. Acta Oncol 36: 615–618, 1997

    Google Scholar 

  33. McLendon RE, Enterline D, Tien R, Thorstad W, Broner J: Tumours of central neuroepithelial origin. Arnold, London, 1998, pp 307–571

    Google Scholar 

  34. Pedersen PH, Marienhagen K, Mork S, Bjerkvig R: Migratory pattern of fetal rat brain cells and human glioma cells in the adult rat brain. Cancer Res 53: 5158–5165, 1993

    Google Scholar 

  35. Giese A, Rief MD, Loo MA, Berens ME: Determinants of human astrocytoma migration. Cancer Res 54: 3897–3904, 1994

    Google Scholar 

  36. Tysnes BB, Larsen LF, Ness GO, Mahesparan R, Edvardsen K, Garcia-Cabrera I, Bjerkvig R: Stimulation of glioma-cell migration by laminin and inhibition by anti-alpha3 and anti-beta1 integrin antibodies. Int J Cancer 67: 777–784, 1996

    Google Scholar 

  37. Knott JC, Mahesparan R, Garcia-Cabrera I, Bolge Tysnes B, Edvardsen K, Ness GO, Mork S, Lund-Johansen M, Bjerkvig R: Stimulation of extracellular matrix components in the normal brain by invading glioma cells. Int J Cancer 75: 864–872, 1998

    Google Scholar 

  38. Bernstein JJ, Woodard CA: Glioblastoma cells do not intravasate into blood vessels. Neurosurgery 36: 124–132, 1995

    Google Scholar 

  39. Pedersen PH, Rucklidge GJ, Mork SJ, Terzis AJ, Engebraaten O, Lund-Johansen M, Backlund EO, Laerum OD, Bjerkvig R: Leptomeningeal tissue: a barrier against brain tumor cell invasion. J Natl Cancer Inst 86: 1593–1599, 1994

    Google Scholar 

  40. Giordana MT, Germano I, Giaccone G, Mauro A, Migheli A, Schiffer D: The distribution of laminin in human brain tumors: an immunohistochemical study. Acta Neuropathol 67: 51–57, 1985

    Google Scholar 

  41. Criscuolo GR: The genesis of peritumoral vasogenic brain edema and tumor cysts: a hypothetical role for tumor derived vascular permeability factor. Yale J Biol Med 66: 277–314, 1993

    Google Scholar 

  42. Albert FK, Forsting M, Sartor K, Adams HP, Kunze S: Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 34: 45–60, 1994

    Google Scholar 

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Johansson, M., Brännström, T., Tommy Bergenheim, A. et al. Spatial Expression of VEGF-A in Human Glioma. J Neurooncol 59, 1–6 (2002). https://doi.org/10.1023/A:1016317407043

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