Skip to main content
Log in

Vascular permeability factor (VPF, VEGF) in tumor biology

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Summary

Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a multifunctional cytokine expressed and secreted at high levels by many tumor cells of animal and human origin. As secreted by tumor cells, VPF/VEGF is a 34–42 kDa heparin-binding, dimeric, disulfide-bonded glycoprotein that acts directly on endothelial cells (EC) by way of specific receptors to activate phospholipase C and induce [Ca2+]i transients. Two high affinity VPF/VEGF receptors, both tyrosine kinases, have thus far been described. VPF/VEGF is likely to have a number of important roles in tumor biology related, but not limited to, the process of tumor angiogenesis. As a potent permeability factor, VPF/VEGF promotes extravasation of plasma fibrinogen, leading to fibrin deposition which alters the tumor extracellular matrix. This matrix promotes the ingrowth of macrophages, fibroblasts, and endothelial cells. Moreover, VPF/VEGF is a selective endothelial cell (EC) growth factorin vitro, and it presumably stimulates EC proliferationin vivo. Furthermore, VPF/VEGF has been found in animal and human tumor effusions by immunoassay and by functional assays and very likely accounts for the induction of malignant ascites. In addition to its role in tumors, VPF/VEGF has recently been found to have a role in wound healing and its expression by activated macrophages suggests that it probably also participates in certain types of chronic inflammation. VPF/VEGF is expressed in normal development and in certain normal adult organs, notably kidney, heart, adrenal gland and lung. Its functions in normal adult tissues are under investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Underwood JC, Carr I: The ultrastructure and permeability characteristics of the blood vessels of a transplantable rat sarcoma. J Pathol 107: 157–166, 1972

    Google Scholar 

  2. Peterson H-I: Tumor Blood Circulation: Angiogenesis, Vascular Morphology and Blood Flow of Experimental and Human Tumors. CRC Press, Inc., Boca Raton, 1979, 229

    Google Scholar 

  3. Dvorak HF: Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315: 1650–1659, 1986

    Google Scholar 

  4. Nagy JA, Brown LF, Senger DR, Lanir N, Van De Water L, Dvorak AM, Dvorak HF: Pathogenesis of tumor stroma generation: A critical role for leaky blood vessels and fibrin deposition. Biochim Biophys Acta 948: 305–326, 1988

    Google Scholar 

  5. Dvorak HF, Nagy JA, Dvorak JT, Dvorak AM: Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am J Pathol 133: 95–109, 1988

    Google Scholar 

  6. Dvorak HF, Nagy JA, Dvorak AM: Structure of solid tumors and their vasculature: Implications for therapy with monoclonal antibodies. Cancer Cells 3: 77–85, 1991

    Google Scholar 

  7. Dvorak HF, Orenstein NS, Carvalho AC, Churchill WH, Dvorak AM, Galli SJ, Feder J, Bitzer AM, Rypysc J, Giovinco P: Induction of a fibrin-gel investment: An early event in line 10 hepatocarcinoma growth mediated by tumor-secreted products. J Immunol 122: 166–174, 1979

    Google Scholar 

  8. 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 

  9. Senger DR, Perruzzi CA, Feder J, Dvorak HF: A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res 46: 5629–5632, 1986

    Google Scholar 

  10. Dvorak HF, Nagy JA, Berse B, Brown LF, Yeo K-T, Yeo T-K, Dvorak AM, Van De Water L, Sioussat TM, Senger DR: Vascular permeability factor, fibrin, and the pathogenesis of tumor stroma function. Ann NY Acad Sci 667: 101–111, 1992

    Google Scholar 

  11. Ferrara N, Henzel WJ: Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. BBRC 161: 851–858, 1989

    Google Scholar 

  12. Gospodarowicz D, Abraham JA, Schilling J: Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Natl Acad Sci USA 86: 7311–7315, 1989

    Google Scholar 

  13. Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ, Siegel NR, Leimgruber RM, Feder J: Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 84: 1470–1478, 1989

    Google Scholar 

  14. Senger DR, Connolly D, Perruzzi CA, Alsup D, Nelson R, Leimgruber R, Feder J, Dvorak HF: Purification of a vascular permeability factor (VPF) from tumor cell conditioned medium. Federation Proceedings 1987: 2102

  15. Connolly DT, Olander JV, Heuvelman D, Nelson R, Monsell R, Siegel N, Haymore BL, Leimgruber R, Feder J: Human vascular permeability factor. Isolation from U937 cells. J Biol Chem 264: 20017–20024, 1989

    Google Scholar 

  16. Senger DR, Connolly DT, Van De Water L, Feder J, Dvorak HF: Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res 50: 1774–1778, 1990

    Google Scholar 

  17. Conn G, Soderman DD, Schaeffer M-T, Wile M, Hatcher VB, Thomas KA: Purification of a glycoprotein vascular endothelial cell mitogen from a rat glioma-derived cell line. Proc Natl Acad Sci USA 87: 1323–1327, 1990

    Google Scholar 

  18. Myoken Y, Kayada Y, Okamoto T, Kan M, Sato GH, Sato JD: Vascular endothelial cell growth factor (VEGF) produced by A-431 human epidermoid carcinoma cells and identification of VEGF membrane binding sites. Proc Natl Acad Sci USA 88: 5819–5823, 1991

    Google Scholar 

  19. Leung DW, Cachianes G, Kuang W-J, Goeddel DV, Ferrara N: Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246: 1306–1309, 1989

    Google Scholar 

  20. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT: Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246: 1309–1312, 1989

    Google Scholar 

  21. Conn G, Bayne ML, Soderman DD, Kwok PW, Sullivan KA, Palisi TM, Hope DA, Thomas KA: Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor. Proc Natl Acad Sci USA 87: 2628–2632, 1990

    Google Scholar 

  22. Berse B, Brown LF, Van De Water L, Dvorak HF, Senger DR: Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell 3: 211–220, 1992

    Google Scholar 

  23. Claffey KP, Wilkison WO, Spiegelman BM: Vascular endothelial growth factor. Regulation by cell differentiation and activated second messenger pathways. J Biol Chem 267: 16317–16322, 1992

    Google Scholar 

  24. Tischer E, Mitchell R, Hartman T, Silva M, G0spodarowicz D, Fiddes JC, Abraham JA: The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266: 11947–11954, 1991

    Google Scholar 

  25. Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N: Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 267: 26031–26037, 1992

    Google Scholar 

  26. Yeo T-K, Senger DR, Dvorak HF, 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). BBRC 179: 1568–1575, 1991

    Google Scholar 

  27. Peretz D, Gitay-Goren H, Safran M, Kimmel N, Gospodarowicz D, Neufeld G: Glycosylation of vascular endothelial growth factor is not required for its mitogenic activity. Biochem Biophys Res Commun 182: 1340–1347, 1992

    Google Scholar 

  28. Sioussat TM, Dvorak HF, Brock TA, Senger DR: Inhibition of vascular permeability factor (vascular endothelial growth factor) with anti-peptide antibodies. Arch Biochem Biophys 301: 15–20. 1993

    Google Scholar 

  29. Brock TA, Dvorak HF, Senger DR: Tumor-secreted vascular permeability factor increases cytosolic Ca2+ and von Willebrand factor release in human endothelial cells. Am J Pathol 138: 213–221, 1991

    Google Scholar 

  30. Berridge MJ: Inositol trisphosphate and calcium signalling. Nature 361: 315–325, 1993

    Google Scholar 

  31. de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT: Thefms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255: 989–991, 1992

    Google Scholar 

  32. Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, Shows TB: Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 6: 1677–1683, 1991

    Google Scholar 

  33. Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Böhlen P: Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 187: 1579–1586, 1992

    Google Scholar 

  34. Gitay-Goren H, Soker S, Vlodavsky I, Neufeld G: The binding of vascular endothelial growth factor to its receptor is dependent on cell surface-associated heparin-like molecules. J Biol Chem 267: 6093–6098, 1992

    Google Scholar 

  35. Pepper MS, Ferrara N, Orci L, Montesano R: Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesisin vitro. Biochem Biophys Res Commun 189: 824–831, 1992

    Google Scholar 

  36. Wilting J, Christ B, Weich HA: The effects of growth factors on the day 13 chorioallantoic membrane (CAM): A study of VEGF165 and PDGF-BB. Anatomy and Embryology 186: 251–257, 1992

    Google Scholar 

  37. Clauss M, Gerlach M, Gerlach H, Brett J, Wang F, Familletti PC, Pan Y-CE, Olander JV, Connolly DT, Stern D: Vascular permeability factor: A tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med 172: 1535–1545, 1990

    Google Scholar 

  38. Dvorak HF: Abnormalities of hemostasis in malignancy. In: Colman RW, Hirsh J, Marder VJ, Salzman EW (ed) Hemostasis and Thrombosis. Basic Principles and Clinical Practice. 2ed. Philadelphia: J.B. Lippincott Company, 1987: 1143–1157

    Google Scholar 

  39. Frost P, Hart I, Kerbel R (ed): The Hemostatic System in Malignancy. Kluwer Academic Publishers, Dordrecht, 1992, pp 223–431. Cancer and Metastasis Reviews; (vol 11)

    Google Scholar 

  40. Pepper MS, Ferrara N, Orci L, Montesano R: Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun 181: 902–906, 1991

    Google Scholar 

  41. Unemori EN, Ferrara N, Bauer EA, Amento EP: Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 153: 557–562, 1992

    Google Scholar 

  42. Dvorak HF, Sioussat TM, Brown LF, Berse B, Nagy J, Sotrel A, Manseau EJ, Van De Water L, Senger DR: Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: Concentration in tumor blood vessels. J Exp Med 174: 1275–1278, 1991

    Google Scholar 

  43. Dvorak HF, Dvorak AM, Manseau EJ, Wiberg L, Churchill WH: Fibrin gel investment associated with line 1 and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line tumor regression. J Natl Cancer Inst 62: 1459–1472, 1979

    Google Scholar 

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

    Google Scholar 

  45. Ferrara N, Winer J, Burton T, Rowland A, Siegel M, Phillips HS, Terrell T, Keller GA, Levinson AD: Expression of vascular endothelial growth factor does not promote transformation but confers a growth advantagein vivo to Chinese hamster ovary cells. J Clin Invest 91: 160–170, 1993

    Google Scholar 

  46. Yayon A, Klagsbrun M, Esko JD, Leder P, Ornitz DM: Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64: 841–848, 1991

    Google Scholar 

  47. Andres JL, Stanley K, Chiefetz S, Massagué J: Membraneanchored and soluble forms of betaglycan, a polymorphic proteoglycan that binds transforming growth factor-β. J Cell Biol 109: 3137–3145, 1989

    Google Scholar 

  48. Cordon-Cardo C, Vlodavsky I, Haimovitz-Friedman A, Hicklin D, Fuks Z: Expression of basic fibroblast growth factor in normal human tissues. Lab Invest 63: 832–840, 1990

    Google Scholar 

  49. 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 

  50. Koos RD, Olson CE: Hypoxia stimulates expression of the gene for vascular endothelial growth factor (VEGF), a putative angiogenic factor, by granulosa cells of the ovarian follicle, a site of angiogenesis [abstract]. J Cell Biol 115: 421a, 1991

    Google Scholar 

  51. Berkman RA, Merrill MJ, Reinhold WC, Monacci WT, Saxena A, Clark WC, Robertson JT, Ali IU, Oldfield EH: Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest 91: 153–159, 1993

    Google Scholar 

  52. Kohn S, Nagy JA, Dvorak HF, Dvorak AM: Pathways of macromolecular tracer transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels. Lab Invest 67: 596–607, 1992

    Google Scholar 

  53. Palade GE: The microvascular endothelium revisited. In: Simionescu N, Simionescu M (ed) Endothelial Cell Biology in Health and Disease. New York: Plenum Press, 1988: 3–22

    Google Scholar 

  54. Dvorak HF, Senger DR, Dvorak AM: Fibrin as a component of the tumor stroma: Origins and biological significance. Cancer Metastasis Rev 2: 41–73, 1983

    Google Scholar 

  55. Folkman J: The role of angiogenesis in tumor growth. Seminars in Cancer Biology 3: 65–71, 1992

    Google Scholar 

  56. Dvorak HF: Tumor Stroma. In: Colvin RB, Bhan AK, McCluskey RT (ed) Diagnostic Immunopathology. New York: Raven Press, 1988: 401–420

    Google Scholar 

  57. Dvorak HF, Harvey VS, McDonagh J: Quantitation of fibrinogen influx and fibrin deposition and turnover in line 1 and line 10 guinea pig carcinomas. Cancer Res 44: 3348–3354, 1984

    Google Scholar 

  58. Brown LF, Van De Water L, Harvey VS, Dvorak HF: Fibrinogen influx and accumulation of cross-linked fibrin in healing wounds and in tumor stroma. Am J Pathol 130: 455–465, 1988

    Google Scholar 

  59. Brown LF, Asch B, Harvey VS, Buchinski B, Dvorak HF: Fibrinogen influx and accumulation of cross-linked fibrin in mouse carcinomas. Cancer Res 48: 1920–1925, 1988

    Google Scholar 

  60. Costantini V, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Rousseau SM: Fibrinogen deposition without thrombin generation in primary human breast cancer tissue. Cancer Res 51: 349–353, 1991

    Google Scholar 

  61. Hui KY, Haber E, Matsueda GR: Monoclonal antibodies to a synthetic fibrin-like peptide bind to human fibrin but not fibrinogen. Science 222: 1129–1132, 1983

    Google Scholar 

  62. Dvorak HF, Quay SC, Orenstein NS, Dvorak AM, Hahn P, Bitzer AW, Carvelho AC: Tumor shedding and coagulation. Science 212: 923–924, 1981

    Google Scholar 

  63. Van De Water L, Tracy PB, Aronson D, Mann KG, Dvorak HF: Tumor cell generation of thrombin via functional prothrombinase assembly. Cancer Res 45: 5521–5525, 1985

    Google Scholar 

  64. Danø K, Andreasen PA, Grøndahl-Hansen J, Kristensen P, Nielsen LS, Skriver L: Plasminogen activators, tissue degradation, and cancer. In: Klein G, Weinhouse S (ed) Advances in Cancer Research. Orlando, FL: Academic Press, Inc., 1985: 139–266. (vol 44)

    Google Scholar 

  65. Kerbel RS, Greig R, Frost P (ed) The role of cellular proteases and their inhibitors in invasion and metastasis. Kluwer Academic Publishers, Dordrecht, 1990: 285–392. Cancer and Metastasis Reviews; (vol 9)

    Google Scholar 

  66. Dvorak HF, Senger DR, Dvorak AM, Harvey VS, McDonagh J: Regulation of extravascular coagulation by microvascular permeability. Science 227: 1059–1061, 1985

    Google Scholar 

  67. Bissell MJ, Hall HG, Parry G: How does the extracellular matrix direct gene expression? J Theor Biol 99: 31–68, 1982

    Google Scholar 

  68. Hynes RO, Lander AD: Contact and adhesive specificities in the associations, migrations, and targeting of cells and axons. Cell 68: 303–322, 1992

    Google Scholar 

  69. Hynes RO: Integrins: Versatility, modulation, and signaling in cell adhesion. Cell 69: 11–25, 1992

    Google Scholar 

  70. Damsky CH, Werb Z: Signal transduction by integrin receptors for extracellular matrix: Cooperative processing of extracellular information. Cur Opin Cell Biol 4: 772–781, 1992

    Google Scholar 

  71. Dvorak HF, Harvey VS, Estrella P, Brown LF, McDonagh J, Dvorak AM: Fibrin containing gels induce angiogenesis. Implications for tumor stroma generation and wound healing. Lab Invest 57: 673–686, 1987

    Google Scholar 

  72. Lanir N, Ciano PS, Van De Water L, McDonagh J, Dvorak AM, Dvorak HF: Macrophage migration in fibrin gel matrices. II. Effects of clotting factor XIII, fibronectin, and glycosaminoglycan content on cell migration. J Immunol 140: 2340–2349, 1988

    Google Scholar 

  73. Brown LF, Lanir N, McDonagh J, Czarnecki K, Estrella P, Dvorak AM, Dvorak HF: Fibroblast migration in fibrin gel matrices. Am J Pathol 142: 273–283, 1993

    Google Scholar 

  74. Yeo K-T, Sioussat T, Faix JD, Senger DR, Yeo T-K: Development of time-resolved immunofluorometric assay of vascular permeability factor. Clin Chem 38: 71–75, 1992

    Google Scholar 

  75. Yeo K-T, Wang H, Nagy J, Senger D, Dvorak H, Yeo T-K: Vascular Permeability Factor levels in Line 1 and Line 10 ascites tumors and human fluids. J Cell Biol 115: 421a, 1991

    Google Scholar 

  76. Nagy JA, Herzberg KT, Masse EM, Zientara GP, Dvorak HF: Exchange of macromolecules between plasma and peritoneal cavity in ascites tumor-bearing, normal, and serotonin-injected mice. Cancer Res 49: 5448–5458, 1989

    Google Scholar 

  77. Nagy JA, Masse EM, Harvey-Bliss VS, Meyers MS, Sioussat TM, Senger DR, Dvorak HF: Immunochemical localization of vascular permeability factor (vascular endothelial growth factor) in ascites tumors: Distribution in peritoneal wall mi crovasculature. J Cell Biol 115: 264a, 1991

    Google Scholar 

  78. Nagy JA, Herzberg KT, Dvorak JM, Dvorak HF: Pathogenesis of malignant ascites formation: Initiating events that lead to fluid accumulation. Cancer Res ([in press]): 000-000. 1993

  79. Breier G, Albrecht U, Sterrer S, Risau W: Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development 114: 521–532, 1992

    Google Scholar 

  80. Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG: Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 88: 9267–9271, 1991

    Google Scholar 

  81. Phillips HS, Hains J, Leung DW, Ferrara N: Vascular endothelial growth factor is expressed in rat corpus luteum. Endocrinology 127: 965–967, 1990

    Google Scholar 

  82. Ravindranath N, Little-Ihrig L, Phillips HS, Ferrara N, Zeleznik AJ: Vascular endothelial growth factor messenger ribonucleic acid expression in the primate ovary. Endocrinology 131: 254–260, 1992

    Google Scholar 

  83. Brown LF, Yeo K-T, Berse B, Yeo T-K, Senger DR, Dvorak HF, Van De Water L: Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J Experimental medicine 1992: 1375-9: 1375–1379

    Google Scholar 

  84. Brown LF, Berse B, Tognazzi K, Manseau EJ, Van De Water L, Senger DR, Dvorak HF, Rosen S: Vascular permeability factor mRNA and protein expression in human kidney. Kidney International 42: 1457–1461, 1992

    Google Scholar 

  85. Clark RA: Wound repair. Curr Opin Cell Biol 1: 1000–1008, 1989

    Google Scholar 

  86. Breuing K, Eriksson E, Liu P, Miller DR: Healing of partial thickness porcine skin wounds in a liquid environment. J Surg Res 52: 50–58, 1992

    Google Scholar 

  87. Dvorak HF, Galli SJ, Dvorak AM: Cellular and vascular manifestations of cell-mediated immunity. Hum Pathol 17: 122–137, 1986

    Google Scholar 

  88. Yeo K-T, Wang H, Nagy J, Sioussat T, Ledbetter S, Hoogerverf A, Zhou Y, Masse E, Senger D, Dvorak H, Yeo T-K: Vascular permeability factor (vascular endothelial growth factor) in guinea pig and human tumor and inflammatory effusions. Cancer Res 53: 1–7, 1993

    Google Scholar 

  89. Weindel K, Marmé D, Weich HA: AIDS-associated Kaposi's sarcoma cells in culture express vascular endothelial growth factor. BBRC 183: 1167–1174, 1992

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Senger, D.R., Van De Water, L., Brown, L.F. et al. Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metast Rev 12, 303–324 (1993). https://doi.org/10.1007/BF00665960

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00665960

Key words

Navigation