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PMID: 8534862 Published · ppublish English Comparative Study Journal Article Review

The role of vascular endothelial growth factor in pathological angiogenesis.

Breast cancer research and treatment ·Vol. 36 ·No. 2 ·1995-00-00 ·Pages 127-37

Ferrara N

Abstract

Vascular endothelial growth factor (VEGF) is a diffusible endothelial cell-specific mitogen and angiogenic factor that can also increase vascular permeability. By alternative splicing of mRNA, VEGF may exist as one of four different isoforms that have similar biological activities but differ markedly in targeting and bioavailability. The VEGF receptors are specifically expressed in the cell surface of vascular endothelial cells. Recent studies point to VEGF as a major regulator of physiological angiogenesis, such as developmental and reproductive angiogenesis. Furthermore, VEGF appears to be a crucial mediator of blood vessel growth associated with tumors and proliferative retinopathies. The VEGF mRNA is up-regulated in the majority of human tumors and the VEGF protein is increased in the aqueous and vitreous humors of patients with proliferative retinopathies. Anti-VEGF antibodies have the ability to suppress the growth of a variety of tumor cell lines in nude mice and also can inhibit angiogenesis in animal models of intraocular neovascularization. Therefore, strategies aimed at antagonizing VEGF may form the basis for an effective treatment of tumors and retinopathies. Furthermore, VEGF-induced angiogenesis is sufficient to achieve a therapeutic endpoint in models of coronary or limb ischemia.

MeSH Terms
Animals Endothelial Growth Factors/physiology Humans Lymphokines/physiology Mice Neovascularization, Pathologic/physiopathology Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors
Chemicals
Endothelial Growth Factors Lymphokines Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Ferrara N
Department of Cardiovascular Research, Genentech, Inc., South San Francisco CA 94080, USA.
References (86)
86 references, click to expand
  1. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines.
    Cancer Res. 1986 Nov;46(11):5629-32 PMID: 3756910
  2. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders.
    N Engl J Med. 1994 Dec 1;331(22):1480-7 PMID: 7526212
  3. Angiogenic activity as a marker of neoplastic and preneoplastic lesions of the human bladder.
    Ann Surg. 1980 Dec;192(6):762-71 PMID: 6160821
  4. Similarities between the oxygen-sensing mechanisms regulating the expression of vascular endothelial growth factor and erythropoietin.
    J Biol Chem. 1994 Feb 11;269(6):4355-9 PMID: 8308005
  5. Vascular endothelial growth factor messenger ribonucleic acid expression in the primate ovary.
    Endocrinology. 1992 Jul;131(1):254-60 PMID: 1612003
  6. Comparison of microscopic vascularity in benign and malignant prostate tissue.
    Hum Pathol. 1993 Feb;24(2):220-6 PMID: 8432518
  7. Growth factor control of extracellular proteolysis.
    Cell Differ Dev. 1990 Dec 2;32(3):313-8 PMID: 1711916
  8. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis.
    Cancer Res. 1994 Aug 1;54(15):4233-7 PMID: 7518352
  9. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells.
    Biochem Biophys Res Commun. 1989 Jun 15;161(2):851-8 PMID: 2735925
  10. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis.
    Cell. 1993 Mar 26;72(6):835-46 PMID: 7681362
  11. Vitreous levels of the insulin-like growth factors I and II, and the insulin-like growth factor binding proteins 2 and 3, increase in neovascular eye disease. Studies in nondiabetic and diabetic subjects.
    J Clin Invest. 1993 Dec;92(6):2620-5 PMID: 7504689
  12. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer.
    Lancet. 1992 Nov 7;340(8828):1120-4 PMID: 1279332
  13. The significance of atypical vessels and neovascularization in cervical neoplasia.
    Am J Obstet Gynecol. 1981 Jan 15;139(2):154-9 PMID: 6161537
  14. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor.
    Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9267-71 PMID: 1924389
  15. Developmental expression of binding sites and messenger ribonucleic acid for vascular endothelial growth factor suggests a role for this protein in vasculogenesis and angiogenesis.
    Endocrinology. 1993 Aug;133(2):848-59 PMID: 7688292
  16. Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium.
    Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7533-7 PMID: 8356051
  17. Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation.
    Development. 1992 Feb;114(2):521-32 PMID: 1592003
  18. Vascular endothelial growth factor is expressed in rat corpus luteum.
    Endocrinology. 1990 Aug;127(2):965-7 PMID: 2197082
  19. Characterization of vascular permeability factor/vascular endothelial growth factor receptors on mononuclear phagocytes.
    Blood. 1993 May 15;81(10):2767-73 PMID: 8490183
  20. Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue.
    J Exp Med. 1994 Jul 1;180(1):341-6 PMID: 8006592
  21. The potential aggressiveness of synovial tissue in rheumatoid arthritis.
    J Pathol. 1983 Mar;139(3):399-406 PMID: 6834180
  22. Tumour angiogenesis in prostatic carcinoma with and without bone marrow metastasis: a morphometric study.
    J Pathol. 1992 Nov;168(3):257-62 PMID: 1281874
  23. Conditioned medium from mouse sarcoma 180 cells contains vascular endothelial growth factor.
    Growth Factors. 1990;4(1):53-9 PMID: 2085441
  24. 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
  25. In vitro angiogenesis on the human amniotic membrane: requirement for basic fibroblast growth factor-induced proteinases.
    J Cell Biol. 1989 Feb;108(2):671-82 PMID: 2465298
  26. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms.
    J Biol Chem. 1992 Dec 25;267(36):26031-7 PMID: 1464614
  27. 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):1806-14 PMID: 1791831
  28. Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis.
    J Clin Invest. 1993 May;91(5):2235-43 PMID: 7683699
  29. What is the evidence that tumors are angiogenesis dependent?
    J Natl Cancer Inst. 1990 Jan 3;82(1):4-6 PMID: 1688381
  30. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract.
    Cancer Res. 1993 Oct 1;53(19):4727-35 PMID: 8402650
  31. Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues.
    J Clin Invest. 1992 Jan;89(1):244-53 PMID: 1729274
  32. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis.
    J Clin Invest. 1995 Apr;95(4):1789-97 PMID: 7535799
  33. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor.
    Science. 1992 Feb 21;255(5047):989-91 PMID: 1312256
  34. Expression of matrix metalloproteinase genes in transformed rat cell lines of high and low metastatic potential.
    Cancer Res. 1992 Sep 15;52(18):4942-7 PMID: 1325287
  35. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.
    Nature. 1992 Oct 29;359(6398):843-5 PMID: 1279431
  36. Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms.
    J Clin Invest. 1993 Jan;91(1):153-9 PMID: 8380810
  37. Studies on retinal neovascularization. Friedenwald Lecture.
    Invest Ophthalmol Vis Sci. 1980 Oct;19(10):1133-8 PMID: 6158493
  38. Characterization of the receptor to vasculotropin on bovine adrenal cortex-derived capillary endothelial cells.
    J Biol Chem. 1990 Dec 25;265(36):22071-4 PMID: 2266109
  39. Vascular permeability factor, an endothelial cell mitogen related to PDGF.
    Science. 1989 Dec 8;246(4935):1309-12 PMID: 2479987
  40. Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model.
    J Clin Invest. 1994 Feb;93(2):662-70 PMID: 7509344
  41. Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT-20 cells.
    EMBO J. 1989 Dec 1;8(12):3801-6 PMID: 2684646
  42. Angiogenesis.
    J Biol Chem. 1992 Jun 5;267(16):10931-4 PMID: 1375931
  43. Proteolytic balance and capillary morphogenesis.
    Cell Differ Dev. 1990 Dec 2;32(3):319-27 PMID: 1711917
  44. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo.
    Nature. 1993 Apr 29;362(6423):841-4 PMID: 7683111
  45. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family.
    Oncogene. 1990 Apr;5(4):519-24 PMID: 2158038
  46. Specific degradation of the collagen molecule by tadpole collagenolytic enzyme.
    Proc Natl Acad Sci U S A. 1965 Oct;54(4):1197-204 PMID: 4286832
  47. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma.
    J Natl Cancer Inst. 1992 Dec 16;84(24):1875-87 PMID: 1281237
  48. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.
    N Engl J Med. 1986 Dec 25;315(26):1650-9 PMID: 3537791
  49. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant.
    Nature. 1994 Feb 10;367(6463):576-9 PMID: 8107827
  50. The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF.
    Mol Biol Cell. 1993 Dec;4(12):1317-26 PMID: 8167412
  51. Vascular endothelial growth factor is a secreted angiogenic mitogen.
    Science. 1989 Dec 8;246(4935):1306-9 PMID: 2479986
  52. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo.
    Nature. 1992 Oct 29;359(6398):845-8 PMID: 1279432
  53. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis.
    J Clin Invest. 1989 Nov;84(5):1470-8 PMID: 2478587
  54. Association of vascular endothelial growth factor expression with tumor angiogenesis and with early relapse in primary breast cancer.
    Jpn J Cancer Res. 1994 Oct;85(10):1045-9 PMID: 7525523
  55. Regulators of angiogenesis.
    Annu Rev Physiol. 1991;53:217-39 PMID: 1710435
  56. The prognostic significance of tumor vascularity in intermediate-thickness (0.76-4.0 mm thick) skin melanoma. A quantitative histologic study.
    Am J Pathol. 1988 Nov;133(2):419-23 PMID: 3189515
  57. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor.
    Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10705-9 PMID: 8248162
  58. Therapeutic angiogenesis following arterial gene transfer of vascular endothelial growth factor in a rabbit model of hindlimb ischemia.
    Biochem Biophys Res Commun. 1996 Oct 14;227(2):628-35 PMID: 8878563
  59. Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells.
    Biochem Biophys Res Commun. 1991 Dec 16;181(2):902-6 PMID: 1755866
  60. Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs.
    Circulation. 1994 May;89(5):2183-9 PMID: 7514110
  61. Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells.
    J Cell Physiol. 1992 Dec;153(3):557-62 PMID: 1447317
  62. Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth.
    Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8915-9 PMID: 7692439
  63. Intense focal expression of vascular endothelial growth-factor messenger-RNA in human intracranial neoplasms - association with regions of necrosis.
    Int J Oncol. 1993 Jun;2(6):913-9 PMID: 21573646
  64. Altered distribution of basic fibroblast growth factor in diabetic retinopathy.
    Arch Ophthalmol. 1991 Jul;109(7):1005-11 PMID: 2064554
  65. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR.
    J Biol Chem. 1994 Oct 14;269(41):25646-54 PMID: 7929268
  66. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor.
    Biochem Biophys Res Commun. 1992 Sep 30;187(3):1579-86 PMID: 1417831
  67. A heparin-binding form of placenta growth factor (PlGF-2) is expressed in human umbilical vein endothelial cells and in placenta.
    Growth Factors. 1993;9(4):259-68 PMID: 8148155
  68. Demonstration and characterization of the angiogenic properties of cervical dysplasia.
    Cancer Res. 1994 Feb 1;54(3):800-4 PMID: 7508337
  69. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis.
    J Immunol. 1994 Apr 15;152(8):4149-56 PMID: 7511670
  70. Expression of vascular endothelial growth factor does not promote transformation but confers a growth advantage in vivo to Chinese hamster ovary cells.
    J Clin Invest. 1993 Jan;91(1):160-70 PMID: 8423215
  71. Relation of neovascularisation to metastasis of non-small-cell lung cancer.
    Lancet. 1992 Jul 18;340(8812):145-6 PMID: 1378165
  72. Hypothesis: in vitro evidence for the invasive and tumor-like properties of the rheumatoid pannus.
    J Rheumatol. 1983 Dec;10(6):845-51 PMID: 6686611
  73. Vascular permeability factor gene expression in normal and neoplastic human ovaries.
    Cancer Res. 1994 Jan 1;54(1):276-80 PMID: 8261452
  74. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor.
    J Biol Chem. 1994 Oct 28;269(43):26988-95 PMID: 7929439
  75. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro.
    Biochem Biophys Res Commun. 1992 Dec 15;189(2):824-31 PMID: 1281999
  76. Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells.
    J Biol Chem. 1994 Mar 4;269(9):6271-4 PMID: 8119973
  77. Identification of a new endothelial cell growth factor receptor tyrosine kinase.
    Oncogene. 1991 Sep;6(9):1677-83 PMID: 1656371
  78. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy.
    Am J Ophthalmol. 1994 Oct 15;118(4):445-50 PMID: 7943121
  79. Vascular endothelial growth factor.
    Trends Cardiovasc Med. 1993 Nov-Dec;3(6):244-50 PMID: 21244915
  80. Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model.
    Am J Pathol. 1994 Sep;145(3):574-84 PMID: 7521577
  81. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma.
    N Engl J Med. 1991 Jan 3;324(1):1-8 PMID: 1701519
  82. Correlation of intratumoral endothelial cell proliferation with microvessel density (tumor angiogenesis) and tumor cell proliferation in breast carcinoma.
    Am J Pathol. 1994 Jun;144(6):1188-94 PMID: 7515558
  83. A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit.
    Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9026-30 PMID: 1717995
  84. Molecular and biological properties of the vascular endothelial growth factor family of proteins.
    Endocr Rev. 1992 Feb;13(1):18-32 PMID: 1372863
  85. Characterization of the receptors for vascular endothelial growth factor.
    J Biol Chem. 1990 Nov 15;265(32):19461-6 PMID: 2246236
  86. Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries.
    Am J Physiol. 1993 Aug;265(2 Pt 2):H586-92 PMID: 8368362
Article Info
Journal
Breast cancer research and treatment
Abbr.
Breast Cancer Res Treat
ISSN
0167-6806
DOI
10.1007/BF00666035
Published
1995-00-00
Pages
127-37
Language
English
Region
Netherlands
NLM ID
8111104
Subset
IM
External Links
PubMed source DOI: 10.1007/BF00666035 View journal details
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