Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma

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The influence of vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) on prognosis and the relationship between VEGF expression and MVD in ovarian carcinoma are not well defined. We studied VEGF expression in parallel with MVD by immunohistochemistry in 94 ovarian tumours (64 malignant, 13 borderline, and 17 benign) and correlated the results with the clinicopathologic prognostic factors of the disease to clarify their significance in this disease. Assessment of VEGF mRNA isoforms by RT-PCR was also performed. Of the malignant, borderline, and benign ovarian tumours respectively, two (3%), four (31%) and 16 (94%) were negative, 31 (48%), seven (54%) and one (6%) had low expressions, and 31 (48%), two (15%) and none (0%) had high expressions of VEGF. There were significant associations between the VEGF expression and disease stage (P = 0.002), histologic grade (P = 0.0004), and patient outcome (P = 0.0002). MVD did not correlate significantly with the clinicopathologic parameters. Likewise, no correlation was found between MVD and VEGF expression. The survival of patients with high VEGF expression was significantly worse than that of patients with low and negative VEGF expression (P = 0.0004). Multivariate analysis revealed that disease stage and VEGF expression were significant and independent prognostic indicators of overall survival time (P = 0.008 and P = 0.006 respectively). These findings suggest that in conjunction with the established clinicopathologic prognostic parameters of ovarian carcinoma, VEGF expression may enhance the predictability of patients at high risk for tumour progression who are potential candidates for further aggressive therapy. © 2000 Cancer Research Campaign


  1. Abu-Jawdeh GM, Faix JD, Niloff J, Tognazzi K and Manseau E (1996) Strong expression of vascular permeability factor (vascular endothelial growth factor) and its receptor in ovarian borderline and malignant neoplasms. Lab Invest 74: 1105–1115

  2. Boocock CA, Charnock-Jones DS, Sharkey AM, McLaren J and Barker PJ (1995) Expression of vascular endothelial growth factor and its receptor fit and KDR in ovarian carcinoma. J Natl Cancer Inst 87: 506–516

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

  4. Ferrara N and Hanzel WJ (1989) Pituitary folicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161: 851–858

  5. Ferrara N (1995) The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat 36: 127–137

  6. Ferrara N (2000) Vascular endothelial growth factor: molecular and biological aspects. Curr Top Microbiol Immunol 237: 1–30

  7. Folkman J (1986) How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes Memorial Award Lecture. Cancer Res 46: 467–473

  8. Folkman J (1990) What is the evidence that tumours are angiogenesis-dependent?. J Natl Cancer Inst 82: 4–6

  9. Fujimoto J, Sakaguchi H, Hirose R, Ichigo S and Tamaya T (1998) Biologic implications of the expression of vascular endothelial growth factor subtypes in ovarian carcinoma. Cancer 83: 2528–2533

  10. Garzetti GG, Ciavattini A, Lucarini G, Pugnaloni A and De Nictolis M 1999 a) Expression of vascular endothelial growth factor related to 72-kilodalton metalloproteinase immunostaining in patients with serous ovarian tumours. Cancer 85: 2219–2225

  11. Garzetti GG, Ciavattini A, Lucarini G, Pugnaloni A and De Nictolis M 1999 b) Vascular endothelial growth factor expression as a prognostic index in serous ovarian cystadenocarcinomas: relationship with MIB1 immunostaining. Gynecol Oncol 73: 396–401

  12. Ghazizadeh M, Ogawa H, Sasaki Y, Araki T and Aihara K (1997) Mucin carbohydrate antigens (T, Tn, and sialyl-Tn) in human ovarian carcinoma: Relationship with histopathology and prognosis. Hum Pathol 28: 960–966

  13. Hartenbach EM, Olson TA, Goswitz JJ, Mohanraj D, Twiggs LB, Carson LF and Ramakrishnan S (1997) Vascular endothelial growth factor (VEGF) expression and survival in human epithelial ovarian carcinomas. Cancer Lett 121: 169–175

  14. Hazelton D, Nicosia RF and Nicosia SV (2000) Vascular endothelial growth factor levels in ovarian cyst fluid correlate with malignancy. Clin Cancer Res 5: 823–829

  15. Hollingsworth HC, Kohn EC, Steinberg SM, Rothenberg ML and Merino MJ (1995) Tumour angiogenesis in advanced stage ovarian carcinoma. Am J Pathol 147: 33–41

  16. Kamat BR, Brown LF, Manseau EJ, Senger DR and Dvorak HF (1995) Expression of vascular permeability factor/vascular endothelial growth factor by human granulosa and theca lutein. Am J Pathol 146: 157–165

  17. Keck PJ, Hauser SD, Krivi G, Sanzo K and Warren T (1989) Vascular permeability factor: an endothelial cell mitogen related to PDGF. Science 246: 1309–1312

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

  19. Kraft A, Weindel K, Ochs A, Marth C, Zmija J and Schumacher P (2000) Vascular endothelial growth factor in sera and effusions of patients with malignant and nonmalignant disease. Cancer 85: 178–187

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

  21. Nakanishi Y, Kodama J, Yoshinouchi M, Tokumo K, Kamimura S, Okuda H and Kudo T (1997) The expression of vascular endothelial growth factor and transforming growth facotor-beta associates with angiogenesis in epithelial ovarian cancer. Int J Gynecol Pathol 16: 256–262

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

  23. Orre M, Lotfi-Miri M, Mamers P and Rogers PAW (1998) Increased microvessel density in mucinous compared with malignant serous and benign tumours of the ovary. Br J Cancer 77: 2204–2209

  24. Orre M and Rogers P (2000) VEGF, VEDFR-1, VEGFR-2, mivcrovessel density and endothelial cell proliferation in tumours of the ovary. Intl J Cancer 84: 101–108

  25. Paley PJ, Staskus KA, Gebhard K, Mohanraj D and Twiggs LB (1997) Vascular endothelial growth factor expression in early stage ovarian carcinoma. Cancer 80: 98–106

  26. Peterson F (1988) Annual Report on Gynecological Cancer of FIGO. 20, Panorama Press: Stockholm

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

  28. Serov SF, Scully RE and Sobin LH (1973) Histological typing of ovarian tumours. International Histological Classification of Tumors, No 9, World Health Organization: Geneva

  29. Sowter HM, Corps AN, Evans AL, Clark DE, Charnock-Jones DS and Smith SK (1997) Expression and localization of the vascular endothelial growth factor family in ovarian epithelial tumours. Lab Invest 77: 607–614

  30. Tempfer C, Obermair A, Hefler L, Haeusler G, Gitsch G and Kainz C (1998) Vascular endothelial growth factor serum concentrations in ovarian cancer. Obstet Gynecol 92: 360–363

  31. Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarwics D and Bohlen P (1992) Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Science 255: 989–991

  32. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC and Abraham JA (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative axon splicing. J Biol Chem 266: 26031–26037

  33. Weidner N, Semple JP, Welch WR and Folkman J (1991) Tumour angiogenesis and metastasis: correlation in invasive breast carcinoma. N Engl J Med 324: 1–8

  34. Weidner N and Folkman J (1996) Tumour vascularity as a prognostic factors in cancer. In: Important Advances in Oncology, VT DeVita VT, Hellman S, SA Rosenberg SA. (eds), pp. 167–190., Lippincott-Raven: Philadelphia

  35. Yamamoto S, Konishi I, Mandai M, Kuroda H and Komatsu T (1997) Expression of vascular growth factor (VEGF) in epithelial ovarian neoplasms: Correlation with clinicopathology and patient survival, and analysis of serum VEGF levels. Br J Cancer 76: 1221–1227

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  • ovarian tumours
  • vascular endothelial growth factor
  • microvessel density
  • angiogenesis
  • disease stage
  • prognosis

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