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PMID: 7680247 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology.

Molecular biology of the cell ·Vol. 4 ·No. 1 ·1993-01-00 ·Pages 121-33

Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY

Abstract

Hypervascularity, focal necrosis, persistent cerebral edema, and rapid cellular proliferation are key histopathologic features of glioblastoma multiforme (GBM), the most common and malignant of human brain tumors. By immunoperoxidase and immunofluorescence, we definitively have demonstrated the presence of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFr) in five out of five human glioma cell lines (U-251MG, U-105MG, D-65MG, D-54MG, and CH-235MG) and in eight human GBM tumor surgical specimens. In vitro experiments with glioma cell lines revealed a consistent and reliable relation between EGFr activation and VEGF production; namely, EGF (1-20 ng/ml) stimulation of glioma cells resulted in a 25-125% increase in secretion of bioactive VEGF. Conditioned media (CM) prepared from EGF-stimulated glioma cell lines produced significant increases in cytosolic free intracellular concentrations of Ca2+ ([Ca2+]i) in human umbilical vein endothelial cells (HUVECs). Neither EGF alone or CM from glioma cultures prepared in the absence of EGF induced [Ca2+]i increases in HUVECs. Preincubation of glioma CM with A4.6.1, a monoclonal antibody to VEGF, completely abolished VEGF-mediated [Ca2+]i transients in HUVECs. Likewise, induction by glioma-derived CM of von Willebrand factor release from HUVECs was completely blocked by A4.6.1 pretreatment. These observations provide a key link in understanding the basic cellular pathophysiology of GBM tumor angiogenesis, increased vascular permeability, and cellular proliferation. Specifically, EGF activation of EGFr expressed on glioma cells leads to enhanced secretion of VEGF by glioma cells. VEGF released by glioma cells in situ most likely accounts for pathognomonic histopathologic and clinical features of GBM tumors in patients, including striking tumor angiogenesis, increased cerebral edema and hypercoagulability manifesting as focal tumor necrosis, deep vein thrombosis, or pulmonary embolism.

MeSH Terms
Brain Neoplasms/blood supply,pathology,physiopathology Endothelial Growth Factors/biosynthesis Epidermal Growth Factor/pharmacology ErbB Receptors/metabolism Glioblastoma/blood supply,pathology,physiopathology Glioma/metabolism Humans Immunohistochemistry Lymphokines/biosynthesis Models, Biological Neovascularization, Pathologic/physiopathology Tumor Cells, Cultured/drug effects,metabolism Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors
Chemicals
Endothelial Growth Factors Lymphokines Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors Epidermal Growth Factor ErbB Receptors
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Goldman C K
Brain Tumor Research Laboratories, Division of Neurosurgery, University of Alabama, Birmingham 35294-0006.
Kim J
Wong W L
King V
Brock T
Gillespie G Y
References (46)
46 references, click to expand
  1. Enhancement of epidermal growth factor receptor expression on glioma cells by recombinant tumor necrosis factor alpha.
    Cancer Immunol Immunother. 1992;34(6):370-6 PMID: 1563013
  2. Vascular permeability factor: a unique regulator of blood vessel function.
    J Cell Biochem. 1991 Nov;47(3):219-23 PMID: 1791186
  3. The vascular endothelial growth factor proteins: identification of biologically relevant regions by neutralizing monoclonal antibodies.
    Growth Factors. 1992;7(1):53-64 PMID: 1380254
  4. Thromboembolic phenomena in neurosurgical patients operated upon for primary and metastatic brain tumors.
    Acta Neurochir (Wien). 1991;109(3-4):93-7 PMID: 1858538
  5. Fibrinopeptide A and fibrinogen fragment B beta 15-42 and their relation to the operative trauma and post-operative thromboembolism in neurosurgical patients.
    Acta Neurochir (Wien). 1987;88(1-2):49-55 PMID: 2447755
  6. Thrombin and histamine activate phospholipase C in human endothelial cells via a phorbol ester-sensitive pathway.
    J Cell Physiol. 1988 Jul;136(1):54-62 PMID: 3260903
  7. The effects of platelet-derived growth factor in cultured microvessel endothelial cells.
    Endocrinology. 1989 Apr;124(4):1841-8 PMID: 2924726
  8. Long term culture of normal and neoplastic human glia.
    Acta Pathol Microbiol Scand. 1968;74(4):465-86 PMID: 4313504
  9. Anti-angiogenesis: new concept for therapy of solid tumors.
    Ann Surg. 1972 Mar;175(3):409-16 PMID: 5077799
  10. In situ detection of mycoplasma contamination in cell cultures by fluorescent Hoechst 33258 stain.
    Exp Cell Res. 1977 Feb;104(2):255-62 PMID: 65285
  11. Properties of human malignant glioma cells in vitro.
    Med Biol. 1978 Aug;56(4):184-93 PMID: 359950
  12. Heterogeneity of Genotypic and phenotypic characteristics of fifteen permanent cell lines derived from human gliomas.
    J Neuropathol Exp Neurol. 1981 May;40(3):201-29 PMID: 6260907
  13. Chromosome and chromosomal progression of human gliomas in vivo, in vitro and in athymic nude mice.
    Prog Exp Tumor Res. 1984;27:67-82 PMID: 6091178
  14. A new generation of Ca2+ indicators with greatly improved fluorescence properties.
    J Biol Chem. 1985 Mar 25;260(6):3440-50 PMID: 3838314
  15. Antigenic heterogeneity of human anaplastic gliomas and glioma-derived cell lines defined by monoclonal antibodies.
    J Neuropathol Exp Neurol. 1985 May;44(3):229-41 PMID: 2580959
  16. Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells.
    Biochemistry. 1985 Sep 24;24(20):5480-6 PMID: 4074709
  17. Transforming growth factor-alpha: a more potent angiogenic mediator than epidermal growth factor.
    Science. 1986 Jun 6;232(4755):1250-3 PMID: 2422759
  18. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro.
    Proc Natl Acad Sci U S A. 1986 Jun;83(12):4167-71 PMID: 2424019
  19. Post-operative thromboembolism in neurosurgery. A study on the prophylactic effect of calf muscle stimulation plus dextran compared to low-dose heparin.
    Acta Neurochir (Wien). 1986;80(3-4):83-9 PMID: 2424279
  20. Binding of an antagonistic monoclonal antibody to an intact and fragmented EGF-receptor polypeptide.
    Arch Biochem Biophys. 1987 Feb 1;252(2):549-60 PMID: 2434025
  21. Patient age, histologic features, and length of survival in patients with glioblastoma multiforme.
    Cancer. 1987 May 1;59(9):1617-25 PMID: 3030531
  22. Structural characterization and biological functions of fibroblast growth factor.
    Endocr Rev. 1987 May;8(2):95-114 PMID: 2440668
  23. Cerebral astrocytic neoplasms in the adult: contribution of histologic examination to the assessment of prognosis.
    Semin Diagn Pathol. 1984 May;1(2):152-63 PMID: 6100972
  24. Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor.
    Nature. 1989 Apr 13;338(6216):557-62 PMID: 2467210
  25. Cytologic composition of the untreated glioblastoma with implications for evaluation of needle biopsies.
    Cancer. 1989 May 15;63(10):2014-23 PMID: 2539242
  26. Proto-oncogene abnormalities and their relationship to tumorigenicity in some human glioblastomas.
    J Neurosurg. 1989 Jul;71(1):83-90 PMID: 2738645
  27. Expression and control of vascular endothelial cells: proliferation and differentiation by fibroblast growth factors.
    J Invest Dermatol. 1989 Aug;93(2 Suppl):39S-47S PMID: 2474036
  28. Cytosolic calcium changes in endothelial cells induced by a protein product of human gliomas containing vascular permeability factor activity.
    J Neurosurg. 1989 Dec;71(6):884-91 PMID: 2585081
  29. Vascular endothelial growth factor is a secreted angiogenic mitogen.
    Science. 1989 Dec 8;246(4935):1306-9 PMID: 2479986
  30. Response of microvascular endothelial cells to biological response modifiers.
    Immunol Cell Biol. 1989 Oct;67 ( Pt 5):271-7 PMID: 2613275
  31. 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):1323-7 PMID: 2406719
  32. Epidermal growth factor concentrations in submandibular salivary gland, plasma, liver, bile, kidneys and urine of male mice: dynamics after phenylephrine injection.
    Life Sci. 1990;46(17):1197-206 PMID: 2338885
  33. Immunohistochemical localization of basic fibroblast growth factor in astrocytomas.
    Cancer Res. 1990 Nov 15;50(22):7393-8 PMID: 2171762
  34. Tumor necrosis factor production and receptor expression by a human malignant glioma cell line, D54-MG.
    J Neuroimmunol. 1990 Nov;30(1):1-13 PMID: 2172302
  35. 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):1535-45 PMID: 2258694
  36. Occult cancer in patients with deep venous thrombosis. A systematic approach.
    Cancer. 1991 Jan 15;67(2):541-5 PMID: 1985747
  37. Tumor-secreted vascular permeability factor increases cytosolic Ca2+ and von Willebrand factor release in human endothelial cells.
    Am J Pathol. 1991 Jan;138(1):213-21 PMID: 1987767
  38. Expression of angiogenic growth factor genes in primary human astrocytomas may contribute to their growth and progression.
    Cancer Res. 1991 Feb 15;51(4):1345-51 PMID: 1705174
  39. Increased capillary permeability in rat brain induced by factors secreted by cultured C6 glioma cells: role in peritumoral brain edema.
    J Neurooncol. 1991 Feb;10(1):13-25 PMID: 2022971
  40. Transforming growth factor-alpha, epidermal growth factor receptor, and proliferating potential in benign and malignant gliomas.
    J Neurosurg. 1991 Jul;75(1):97-102 PMID: 2045927
  41. 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):11947-54 PMID: 1711045
  42. In contrast to EGFr gene overexpression, H-ras gene expression decreases in human gliomas.
    Anticancer Res. 1991 May-Jun;11(3):1353-7 PMID: 1888172
  43. Malignant astrocytomas treated with iodine-125 labeled monoclonal antibody 425 against epidermal growth factor receptor: a phase II trial.
    Int J Radiat Oncol Biol Phys. 1992;22(1):225-30 PMID: 1309204
  44. Interleukin-1 beta induction of tumor necrosis factor-alpha gene expression in human astroglioma cells.
    J Neuroimmunol. 1992 Feb;36(2-3):179-91 PMID: 1732280
  45. The vascular endothelial growth factor family of polypeptides.
    J Cell Biochem. 1991 Nov;47(3):211-8 PMID: 1791185
  46. Interleukin-1 beta induction of TNF-alpha gene expression: involvement of protein kinase C.
    J Cell Physiol. 1992 Aug;152(2):264-73 PMID: 1639861
Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.4.1.121
Published
1993-01-00
Pages
121-33
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC300905
Subset
IM
Grants
NHLBI NIH HHS · HL-41180 · United States
NINDS NIH HHS · NS31096 · United States
NINDS NIH HHS · T32NSO7335 · United States
External Links
PubMed source DOI: 10.1091/mbc.4.1.121 PMC Full Text View journal details
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