Skip to main content
Log in

Tumor angiogenesis: the pivotal role of vascular endothelial growth factor

  • I. The Biologic Basis Of Metastasis
  • Published:
World Journal of Urology Aims and scope Submit manuscript

Summary

There is considerable evidence that vascular endothelial growth factor is involved in the vascularization and growth of primary tumors and in the formation of metastases. The expression of vascular endothelial growth factor depends on activated oncogenes and inactivated tumor-suppressor genes as well as several other factors, e.g., growth factors, hypoxia, and tumor promoters. Substantial expression of vascular endothelial growth factor receptors is mainly restricted to tumor vessels. The causal involvement of this angiogenic factor in the progression of the disease has been successfully evaluated using monoclonal antibodies against vascular endothelial growth factor, dominant negative receptor mutants, and antisense oligonucleotides against the messenger RNA of vascular endothelial growth factor. Thus, the vascular endothelial growth factor-signaling system seems to be an appropriate target for inhibition of tumor angiogenesis and metastasis formation.

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.

Similar content being viewed by others

References

  1. Auerbach W, Auerbach R (1994) Angiogenesis inhibition: a review. Pharmacol Ther 63:265–311

    Google Scholar 

  2. Barleon B, Weich HA, Marmé D (1994) Differential regulation of the two VEGF receptor genes flt-1 and kdr by cytokines and growth factors. J Cell Biochem [Suppl] 18A:323

    Google Scholar 

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

    Google Scholar 

  4. Bicknell R (1994) Vascular targeting and the inhibition of angiogenesis. Ann Oncol 5 [Suppl]:S45-S50

    Google Scholar 

  5. Brogi E, Wu T, Namiki A, Isner JM (1994) Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. Circulation 90:649–652

    Google Scholar 

  6. Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Dvorak HF, Senger DR (1993) Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder. Am J Pathol 143:1255–1262

    Google Scholar 

  7. Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Senger DR, Dvorak HF (1993) Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res 53:4727–4735

    Google Scholar 

  8. Brown LF, Berse B, Jackman RW, Tognazzi K, Guidi AJ, Dvorak HF, Senger DR, Connolly JL, Schnitt SJ (1995) Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol 26:86–91

    Google Scholar 

  9. Claffey KP, Senger DR, Spiegelman BM (1995) Structural requirements for dimerization, glycosylation, secretion, and biological function of VPF/VEGF. Biochim Biophys Acta 1246:1–9

    Google Scholar 

  10. Cullinan-Bove K, Koos RD (1993) Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: rapid stimulation by estrogen correlates with estrogeninduced increases in uterine capillary permeability and growth. Endocrinology 133:829–837

    Google Scholar 

  11. Czubayko F, Smith RV, Chung HC, Wellstein A (1994) Tumor growth and angiogenesis induced by a secreted binding protein for fibroblast growth factors. J Biol Chem 269:28243–28248

    Google Scholar 

  12. Dameron KM, Volpert OV, Tainsky MA, Bouck N (1994) Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265:1582–1584

    Google Scholar 

  13. De Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255:989–991

    Google Scholar 

  14. Dickinson AJ, Fox SB, Persad RA, Hollyer J, Sibley GNA, Harris AL (1994) Quantification of angiogenesis as an independent predictor of prognosis in invasive bladder carcinomas. Br J Urol 74:762–766

    Google Scholar 

  15. Dolecki GJ, Connolly DT (1991) Effects of a variety of cytokines and inducing agents on vascular permeability factor mRNA levels in U937 cells. Biochem Biophys Res Commun 180:572–578

    Google Scholar 

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

    Google Scholar 

  17. Ferrara N, Henzel WJ (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161:851–859

    Google Scholar 

  18. Ferrara N, Houck K, Jakeman L, Leung DW (1992) Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev 13:18–32

    Google Scholar 

  19. Fiebich BL, Jäger B, Schöllmann C, Weindel K, Wilting J, Kochs G, Marmé D, Hug H, Weich HA (1993) Synthesis and assembly of functionally active human vascular endothelial growth factor homodimers in insect cells. Eur J Biochem 211:19–26

    Google Scholar 

  20. Finkenzeller G, Marmé D, Weich HA, Hug H (1992) Platelet-derived growth factor-induced transcription of the vascular endothelial growth factor gene is mediated by protein kinase C. Cancer Res 52:4821–4823

    Google Scholar 

  21. Finkenzeller G, Technau A, Marmé D (1995) Hypoxia-induced transcription of the vascular endothelial growth factor gene is independent of functional AP-1 transcription factor. Biochem Biophys Res Commun 208:432–439

    Google Scholar 

  22. Folkman J, Shing Y (1992) Angiogenesis. J Biol Chem 267: 10931–10934

    Google Scholar 

  23. Folkman J, Watson K, Ingber D, Hanahan D (1989) Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339:58–61

    Google Scholar 

  24. Furukawa T, Yoshimura A, Sumizawa T, Haraguchi M, Akiyama S-I (1992) Angiogenic factor. Nature 356:668

    Google Scholar 

  25. Furusato M, Wakui S, Sasaki H, Ito K, Ushigome S (1994) Tumour angiogenesis in latent prostatic carcinoma. Br J Cancer 70:1244–1246

    Google Scholar 

  26. Goldman CK, Kim J, Wong W-L, King V, Brock T, Gillespie GY (1993) Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiform pathophysiology. Mol Biol Cell 4:121–133

    Google Scholar 

  27. Good DJ, Polverini PJ, Rastinejad F, Le Beau MM, Lemons RS, Frazier WA, Bouck NP (1990) A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci USA 87:6624–6628

    Google Scholar 

  28. Grischke EM, Kaufmann M, Eberlein-Gonska M, Mattfeldt T, Sohn C, Bastert G (1994) Angiogenesis as a diagnostic factor in primary breast cancer: microvessel quantitation by stereological methods and correlation with color Doppler sonography. Onkologie 17:35–42

    Google Scholar 

  29. Grugel S, Finkenzeller G, Weindel K, Barleon B, Marmé D (1995) Both v-Ha-ras and v-raf stimulate expression of the vascular endothelial growth factor. J Biol Chem (in press)

  30. Harada S, Nagy JA, Sullivan KA, Thomas KA, Endo N, Rodan GA, Rodan SB (1994) Induction of vascular endothelial growth factor expression by prostaglandin E2 and E1 in osteoblasts. J Clin Invest 93:2490–2496

    Google Scholar 

  31. Hauser S, Weich HA (1993) A heparin-binding form of placenta growth factor (PIGF-2) is expressed in human umbilical evin endothelial cells and in placentas. Growth Factors 9:259–268

    Google Scholar 

  32. Hori A, Sasada R, Matsutani E, Naito K, Sakura Y, Fujita T, Kozai Y (1991) Suppression of solid tumor growth by immunoneutralizing monoclonal antibody against human basic fibroblast growth factor. Cancer Res 51:6180

    Google Scholar 

  33. Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW (1991) The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 5:1806–1814

    Google Scholar 

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

    Google Scholar 

  35. Iizuka M, Yamauchi M, Ando K, Hori N, Furusawa Y, Itsukaichi H, Fukutsu K, Moriya H (1994) Quantitative RT-PCR assay detecting the transcriptional induction of vascular endothelial growth factor under hypoxia. Biochem Biophys Res Commun 205:1474–1480

    Google Scholar 

  36. Jellinek D, Green LS, Bell C, Janjic N (1994) Inhibition of receptor binding by high-affinity RNA ligands to vascular endothelial growth factor. Biochemistry 33:10450–10456

    Google Scholar 

  37. Kandel J, Bossy-Wetzel E, Radvanyi F, Klagsbrun M, Folkman J, Hanahan D (1991) Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma. Cell 66:1095–1104

    Google Scholar 

  38. Keck PJ, Hause SD, Krivi G, Sanzo K, Warren H, Feder J, Connolly DT (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246:1309–1312

    Google Scholar 

  39. Kendall RL, Thomas KA (1993) Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 90:10705–10709

    Google Scholar 

  40. Kieser A, Weich HA, Brandner G, Marmé D, Kölch W (1994) Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9:963–969

    Google Scholar 

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

    Google Scholar 

  42. Kondo S, Asano M, Suzuki H (1993) Significance of vascular endothelial growth factor/vascular permeability factor for solid tumor growth, and its inhibition by the antibody. Biochem Biophys Res Commun 194:1234–1241

    Google Scholar 

  43. Kondo S, Asano M, Matsuo K, Ohmori I, Suzuki H (1994) Vascular endothelial growth factor/vascular permeability factor is detectable in the sera of tumor-bearing mice and cancer patients. Biochim Biophys Acta 1221:211–214

    Google Scholar 

  44. Kondo S, Matsumoto T, Yokoyama Y, Ohmori I, Suzuki H (1995) The shortest isoform of human vascular endothelial growth factor/vascular permeability factor (VEGF/VPF121) produced by Saccharomyces cerevisiae promotes both angiogenesis and vascular permeability. Biochim Biophys Acta 1243:195–202

    Google Scholar 

  45. Leek RD, Harris AL, Lewis CE (1994) Cytokine networks in solid human tumors: regulation of angiogenesis. J Leukocyte Biol 56:423–435

    Google Scholar 

  46. Maxwell M, Naber SP, Wolfe HJ, Hedley-Whyte ET, Galanopoulos T, Neville-Golden J, Antoniades HN (1991) Expression of angiogenic growth factor genes in primary human astrocytomas may contribute to their growth and progression. Cancer Res 51:1345–1351

    Google Scholar 

  47. Millauer B, Wizigmann-Voos S, Schnürch H, Martinez R, Møller NPH, Risau W, Ullrich A (1993) High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72:835–846

    Google Scholar 

  48. Millauer B, Shawver KL, Plate KH, Risau W, Ullrich A (1994) Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367:576–579

    Google Scholar 

  49. Minchenko A, Bauer T, Salceda S, Caro J (1994) Hypoxic stimulation of vascular endothelial growth factor expression in vitro and in vivo. Lab Invest 71:374–379

    Google Scholar 

  50. Moghaddam A, Zhang H-T, Fan T-PD, Hu D-E, Lees VC, Turley H, Fox SB, Gatter KC, Harris AL, Bicknell R (1995) Thymidine phosphorylase is angiogenic and promotes tumor growth. PNAS (in press)

  51. Morris PB, Hida T, Blackshear PJ, Klintworth GK, Swain JL (1988) Tumor-promoting phorbol esters induce angiogenesis in vivo. Cell Physiol 23:C318-C322

    Google Scholar 

  52. Moses MA, Langer R (1991) Inhibitors of angiogenesis. Biotechnology 9:630–634

    Google Scholar 

  53. Nabel EG, Yang Z-Y, Plautz G, Forough R, Zhan X, Haudenschild CC, Maciag T, Nabel GJ (1993) Recombinant fibroblast growth factor-1 promotes intimal hyperplasia and angiogenesis in arteries in vivo. Nature 362:844–846

    Google Scholar 

  54. Nicosia RF, Nicosia SV, Smith M (1994) Vascular endothelial growth factor, platelet-derived growth factor, and insulin-like growth factor-1 promote rat aortic angiogenesis in vitro. Am J Pathol 145:1023–1029

    Google Scholar 

  55. Oikawa T, Shimamura M, Ashino H (1992) Inhibition of angiogenesis by staurosporine, a potent protein kinase inhibitor. J Antibiot 45:1155–1160

    Google Scholar 

  56. Olson TA, Mohanraj D, Carson LF, Ramakrishnan S (1994) Vascular permeability factor gene expression in normal and neoplastic human ovaries. Cancer Res 54:276–280

    Google Scholar 

  57. O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315–328

    Google Scholar 

  58. Park JE, Chen H, Winer J, Houck K, Ferrara N (1994) 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 269:25646–25654

    Google Scholar 

  59. Pepper MA, Montesano R (1990) Proteolytic balance and capillary morphogenesis. Cell Differ Dev 32:319–331

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  62. Peters KG, De Vries C, Williams LT (1993) 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 USA 90:8915–8919

    Google Scholar 

  63. Plate KH, Breier G, Weich HA, Risau W (1992) Vascular endothelial growth is a potential tumour angiogenesis factor in vivo. Nature 359:845–847

    Google Scholar 

  64. Plate KH, Breier G, Millauer B, Ullrich A, Risau W (1993) Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res 53:5822–5827

    Google Scholar 

  65. Plate KH, Breier G, Risau W (1994) Molecular mechanisms of developmental and tumor angiogenesis. Brain Pathol 4:207–218

    Google Scholar 

  66. Plouet J, Schilling J, Gospodarowicz D (1989) Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT20 cells. EMBO J 8:3801–3807

    Google Scholar 

  67. Risau W, Drexler H, Mironov V, Smits A, Siegbahn A, Funa K, Heldin CH (1992) Platelet-derived growth factor is angiogenic in vivo. Growth Factors 7:261–266

    Google Scholar 

  68. Rosenthal R, Megyesi JF, Henzel WJ, Ferrara N, Folkman J (1990) Conditioned medium from mouse sarcoma 180 cells contains vascular endothelial growth factor. Growth Factors 4:53–59

    Google Scholar 

  69. Senger D, Perruzzi CA, Feder J, Dvorak HF (1986) A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res 46:5269–5275

    Google Scholar 

  70. Shibuya M, Yamaguchi S, Yamane A, Ikeda T, Tojo A, Matsushime M, Sato M (1990) Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 5:519–524

    Google Scholar 

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

    Google Scholar 

  72. Sidransky D, Mikkelsen T, Schwechheimer K, Rosenblum ML, Cavanee W, Vogelstein B (1992) Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature 355:846–847

    Google Scholar 

  73. Stavri GT, Hung Y, Zachary IC, Breier G, Baskerville PA, Ylä-Herttuala S, Risau W, Martin JF, Erusalimsky JD (1995) Hypoxia and platelet-derived growth factor-BB synergistically upregulate the expression of vascular endothelial growth factor in vascular smooth muscle cells. FEBS Lett 358:311–315

    Google Scholar 

  74. Strugar J, Rothbart D, Harrington W, Criscuolo GR (1994) Vascular permeability factor in brain metastases: correlation with vasogenic brain edema and tumor angiogenesis. J Neurosurg 81:560–566

    Google Scholar 

  75. Takahashi A, Sasaki H, Kim SJ, Tobisu K, Kakizoe T, Tsukamoto T, Kumamoto Y, Sugimura T, Terada M (1994) Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res 54:4233–4237

    Google Scholar 

  76. Takahashi JA, Mori H, Fukumoto M, Igarashi K, Jaye M, Oda Y, Kikuchi H, Hatanaka M (1990) 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 USA 87:5710–5714

    Google Scholar 

  77. Terano H, Shibata T, Otsuka T (1993) Angiogenesis inhibitors of microbial origin. Drugs Future 18:239–247

    Google Scholar 

  78. Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, Shows TB (1991) Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 6:519–524

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  81. Van Meir EG, Poverini PJ, Chazin VR, Su Huang HJ, Tribolet N de, Cavenee WK (1994) Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Nat Genet 8:171–176

    Google Scholar 

  82. Wakui S, Furusato M, Sasaki H, Akiyama A, Kinoshito I, Asano K, Tokuda T, Aizawa S, Ushigome S (1992) Tumor angiogenesis in prostatic carcinoma with and without bone metastases: a morphometric study. J Pathol 168:257–262

    Google Scholar 

  83. Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CR (1994) Different signal transduction properties of KDR and Flt-1, two receptors for vascular endothelial growth factor. J Biol Chem 43:26988–26995

    Google Scholar 

  84. Weidner N (1993) Tumor angiogenesis: review of current applications in tumor prognostication. Semin Diagn Pathol 10:302–313

    Google Scholar 

  85. Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S, Gasparini G (1992) Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst 84:1875–1887

    Google Scholar 

  86. Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J (1993) Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143:401–409

    Google Scholar 

  87. Weindel K, Moringlane JR, Marmé D, Weich HA (1994) Detection and quantification of vascular endothelial growth factor/vascular permeability factor in brain tumor tissue and cyst fluid: the key to angiogenesis? Neurosurgery 35:439–449

    Google Scholar 

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

    Google Scholar 

  89. Wilting J, Christ B, Bokeloh M, Weich HA (1993) In vivo effects of vascular endothelial growth factor on the chicken chorioallantoic membrane. Cell Tissue Res 274:163–172

    Google Scholar 

  90. Yeo TK, Senger DR, Dvorak HF, Freter L, Yeo KT (1991) Glycosylation is essential for efficient secretion but not for permeability-enhancing activity of vascular permeability factor (vascular endothelial growth factor). Biochem Biophys Res Commun 179:1568–1575

    Google Scholar 

  91. Yeo KT, Sioussat TM, Faix JD, Senger DR, Yeo TK (1992) Development of time-resolved immunofluorometric assay of vascular permeability factor. Clin Chem 38:71–75

    Google Scholar 

  92. Yeo KT, Wang HH, Nagy JA, Sioussat TM, Ledbetter SR, Hoogewerf AJ, Zhou Y, Masse EM, Senger DR, Dvorak HF, Yeo TK (1993) Vascular permeability factor (vascular endothelial growth factor) in guinea pig and human tumor and inflammatory effusions. Cancer Res 53:2912–2918

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marmé, D. Tumor angiogenesis: the pivotal role of vascular endothelial growth factor. World J Urol 14, 166–174 (1996). https://doi.org/10.1007/BF00186896

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00186896

Keywords

Navigation