Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Jun 15;83(2):196–203. doi: 10.1054/bjoc.2000.1228

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

G H Shen 1,2, M Ghazizadeh 1, O Kawanami 1, H Shimizu 1, E Jin 1, T Araki 2, Y Sugisaki 3
PMCID: PMC2363477  PMID: 10901370

Abstract

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

Keywords: ovarian tumours, vascular endothelial growth factor, microvessel density, angiogenesis, disease stage, prognosis

Full Text

The Full Text of this article is available as a PDF (325.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abu-Jawdeh G. M., Faix J. D., Niloff J., Tognazzi K., Manseau E., Dvorak H. F., Brown L. F. Strong expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in ovarian borderline and malignant neoplasms. Lab Invest. 1996 Jun;74(6):1105–1115. [PubMed] [Google Scholar]
  2. Boocock C. A., Charnock-Jones D. S., Sharkey A. M., McLaren J., Barker P. J., Wright K. A., Twentyman P. R., Smith S. K. Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Inst. 1995 Apr 5;87(7):506–516. doi: 10.1093/jnci/87.7.506. [DOI] [PubMed] [Google Scholar]
  3. Ferrara N., Henzel W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989 Jun 15;161(2):851–858. doi: 10.1016/0006-291x(89)92678-8. [DOI] [PubMed] [Google Scholar]
  4. Ferrara N. The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat. 1995;36(2):127–137. doi: 10.1007/BF00666035. [DOI] [PubMed] [Google Scholar]
  5. Ferrara N. Vascular endothelial growth factor: molecular and biological aspects. Curr Top Microbiol Immunol. 1999;237:1–30. doi: 10.1007/978-3-642-59953-8_1. [DOI] [PubMed] [Google Scholar]
  6. Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial Award lecture. Cancer Res. 1986 Feb;46(2):467–473. [PubMed] [Google Scholar]
  7. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990 Jan 3;82(1):4–6. doi: 10.1093/jnci/82.1.4. [DOI] [PubMed] [Google Scholar]
  8. Fujimoto J., Sakaguchi H., Hirose R., Ichigo S., Tamaya T. Biologic implications of the expression of vascular endothelial growth factor subtypes in ovarian carcinoma. Cancer. 1998 Dec 15;83(12):2528–2533. doi: 10.1002/(sici)1097-0142(19981215)83:12<2528::aid-cncr18>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  9. Garzetti G. G., Ciavattini A., Lucarini G., Pugnaloni A., De Nictolis M., Amati S., Romanini C., Biagini G. Expression of vascular endothelial growth factor related to 72-kilodalton metalloproteinase immunostaining in patients with serous ovarian tumors. Cancer. 1999 May 15;85(10):2219–2225. doi: 10.1002/(sici)1097-0142(19990515)85:10<2219::aid-cncr17>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  10. Garzetti G. G., Ciavattini A., Lucarini G., Pugnaloni A., De Nictolis M., Amati S., Romanini C., Biagini G. Vascular endothelial growth factor expression as a prognostic index in serous ovarian cystoadenocarcinomas: relationship with MIB1 immunostaining. Gynecol Oncol. 1999 Jun;73(3):396–401. doi: 10.1006/gyno.1999.5377. [DOI] [PubMed] [Google Scholar]
  11. Ghazizadeh M., Ogawa H., Sasaki Y., Araki T., Aihara K. Mucin carbohydrate antigens (T, Tn, and sialyl-Tn) in human ovarian carcinomas: relationship with histopathology and prognosis. Hum Pathol. 1997 Aug;28(8):960–966. doi: 10.1016/s0046-8177(97)90012-5. [DOI] [PubMed] [Google Scholar]
  12. Hartenbach E. M., Olson T. A., Goswitz J. J., Mohanraj D., Twiggs L. B., Carson L. F., Ramakrishnan S. Vascular endothelial growth factor (VEGF) expression and survival in human epithelial ovarian carcinomas. Cancer Lett. 1997 Dec 23;121(2):169–175. doi: 10.1016/s0304-3835(97)00350-9. [DOI] [PubMed] [Google Scholar]
  13. Hazelton D., Nicosia R. F., Nicosia S. V. Vascular endothelial growth factor levels in ovarian cyst fluid correlate with malignancy. Clin Cancer Res. 1999 Apr;5(4):823–829. [PubMed] [Google Scholar]
  14. Hollingsworth H. C., Kohn E. C., Steinberg S. M., Rothenberg M. L., Merino M. J. Tumor angiogenesis in advanced stage ovarian carcinoma. Am J Pathol. 1995 Jul;147(1):33–41. [PMC free article] [PubMed] [Google Scholar]
  15. Kamat B. R., Brown L. F., Manseau E. J., Senger D. R., Dvorak H. F. Expression of vascular permeability factor/vascular endothelial growth factor by human granulosa and theca lutein cells. Role in corpus luteum development. Am J Pathol. 1995 Jan;146(1):157–165. [PMC free article] [PubMed] [Google Scholar]
  16. Keck P. J., Hauser S. D., Krivi G., Sanzo K., Warren T., Feder J., Connolly D. T. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989 Dec 8;246(4935):1309–1312. doi: 10.1126/science.2479987. [DOI] [PubMed] [Google Scholar]
  17. Kim K. J., Li B., Winer J., Armanini M., Gillett N., Phillips H. S., Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993 Apr 29;362(6423):841–844. doi: 10.1038/362841a0. [DOI] [PubMed] [Google Scholar]
  18. Kraft A., Weindel K., Ochs A., Marth C., Zmija J., Schumacher P., Unger C., Marmé D., Gastl G. Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer. 1999 Jan 1;85(1):178–187. [PubMed] [Google Scholar]
  19. Millauer B., Shawver L. K., Plate K. H., Risau W., Ullrich A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature. 1994 Feb 10;367(6463):576–579. doi: 10.1038/367576a0. [DOI] [PubMed] [Google Scholar]
  20. Nakanishi Y., Kodama J., Yoshinouchi M., Tokumo K., Kamimura S., Okuda H., Kudo T. The expression of vascular endothelial growth factor and transforming growth factor-beta associates with angiogenesis in epithelial ovarian cancer. Int J Gynecol Pathol. 1997 Jul;16(3):256–262. doi: 10.1097/00004347-199707000-00011. [DOI] [PubMed] [Google Scholar]
  21. Olson T. A., Mohanraj D., Carson L. F., Ramakrishnan S. Vascular permeability factor gene expression in normal and neoplastic human ovaries. Cancer Res. 1994 Jan 1;54(1):276–280. [PubMed] [Google Scholar]
  22. Orre M., Lotfi-Miri M., Mamers P., Rogers P. A. Increased microvessel density in mucinous compared with malignant serous and benign tumours of the ovary. Br J Cancer. 1998 Jun;77(12):2204–2209. doi: 10.1038/bjc.1998.367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Orre M., Rogers P. A. VEGF, VEGFR-1, VEGFR-2, microvessel density and endothelial cell proliferation in tumours of the ovary. Int J Cancer. 1999 Apr 20;84(2):101–108. doi: 10.1002/(sici)1097-0215(19990420)84:2<101::aid-ijc2>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  24. Paley P. J., Staskus K. A., Gebhard K., Mohanraj D., Twiggs L. B., Carson L. F., Ramakrishnan S. Vascular endothelial growth factor expression in early stage ovarian carcinoma. Cancer. 1997 Jul 1;80(1):98–106. doi: 10.1002/(sici)1097-0142(19970701)80:1<98::aid-cncr13>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  25. Senger D. R., Galli S. J., Dvorak A. M., Perruzzi C. A., Harvey V. S., Dvorak H. F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983 Feb 25;219(4587):983–985. doi: 10.1126/science.6823562. [DOI] [PubMed] [Google Scholar]
  26. Sowter H. M., Corps A. N., Evans A. L., Clark D. E., Charnock-Jones D. S., Smith S. K. Expression and localization of the vascular endothelial growth factor family in ovarian epithelial tumors. Lab Invest. 1997 Dec;77(6):607–614. [PubMed] [Google Scholar]
  27. Tempfer C., Obermair A., Hefler L., Haeusler G., Gitsch G., Kainz C. Vascular endothelial growth factor serum concentrations in ovarian cancer. Obstet Gynecol. 1998 Sep;92(3):360–363. doi: 10.1016/s0029-7844(98)00190-2. [DOI] [PubMed] [Google Scholar]
  28. Weidner N., Folkman J. Tumoral vascularity as a prognostic factor in cancer. Important Adv Oncol. 1996:167–190. [PubMed] [Google Scholar]
  29. Weidner N., Semple J. P., Welch W. R., Folkman J. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med. 1991 Jan 3;324(1):1–8. doi: 10.1056/NEJM199101033240101. [DOI] [PubMed] [Google Scholar]
  30. Yamamoto S., Konishi I., Mandai M., Kuroda H., Komatsu T., Nanbu K., Sakahara H., Mori T. Expression of vascular endothelial growth factor (VEGF) in epithelial ovarian neoplasms: correlation with clinicopathology and patient survival, and analysis of serum VEGF levels. Br J Cancer. 1997;76(9):1221–1227. doi: 10.1038/bjc.1997.537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. de Vries C., Escobedo J. A., Ueno H., Houck K., Ferrara N., Williams L. T. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992 Feb 21;255(5047):989–991. doi: 10.1126/science.1312256. [DOI] [PubMed] [Google Scholar]
  32. de Vries C., Escobedo J. A., Ueno H., Houck K., Ferrara N., Williams L. T. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992 Feb 21;255(5047):989–991. doi: 10.1126/science.1312256. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES