Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Aug 16;83(5):620–625. doi: 10.1054/bjoc.2000.1319

Vascular endothelial growth factor (VEGF) expression is a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix

J A Loncaster 1, R A Cooper 2, J P Logue 2, S E Davidson 2, R D Hunter 2, C M L West 1
PMCID: PMC2363503  PMID: 10944602

Abstract

The aim of the study was to evaluate VEGF expression in tumour biopsies as a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix. A retrospective study was carried out on 100 patients. Pre-treatment tumour VEGF expression was examined immunohistochemically in formalin-fixed, paraffin-embedded biopsies using a widely available commercial antibody. A semi-quantitative analysis was made using a scoring system of 0, 1, 2, and 3, for increasing intensity of staining. High VEGF expression was associated with a poor prognosis. A univariate log rank analysis found a significant relationship with overall survival (P = 0.0008) and metastasis-free survival (P = 0.0062), but not local control (P = 0.23). There was no correlation between VEGF expression and disease stage, tumour differentiation, patient age, or tumour radiosensitivity (SF2). In a Cox multivariate analysis of survival VEGF expression was the most significant independent prognostic factor (P = 0.001). After allowing for VEGF only SF2 was a significant prognostic factor (P = 0.003). In conclusion, immunohistochemical analysis of VEGF expression is a highly significant and independent prognostic indicator of overall and metastasis-free survival for patients treated with radiotherapy for advanced carcinoma of the cervix. It is also a rapid and easy method that could be used in the clinical setting, to identify patients at high risk of failure with conventional radiotherapy who may benefit from novel approaches or chemoradiotherapy. © 2000 Cancer Research Campaign

Keywords: cervical carcinoma, vascular endothelial growth factor (VEGF), immunohistochemistry, prognosis

Full Text

The Full Text of this article is available as a PDF (121.9 KB).

Selected References

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

  1. 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]
  2. Bouvet M., Ellis L. M., Nishizaki M., Fujiwara T., Liu W., Bucana C. D., Fang B., Lee J. J., Roth J. A. Adenovirus-mediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer. Cancer Res. 1998 Jun 1;58(11):2288–2292. [PubMed] [Google Scholar]
  3. Chiarotto J. A., Hill R. P. A quantitative analysis of the reduction in oxygen levels required to induce up-regulation of vascular endothelial growth factor (VEGF) mRNA in cervical cancer cell lines. Br J Cancer. 1999 Jul;80(10):1518–1524. doi: 10.1038/sj.bjc.6690555. [DOI] [PMC free article] [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. 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]
  6. Fontanini G., Boldrini L., Chinè S., Pisaturo F., Basolo F., Calcinai A., Lucchi M., Mussi A., Angeletti C. A., Bevilacqua G. Expression of vascular endothelial growth factor mRNA in non-small-cell lung carcinomas. Br J Cancer. 1999 Jan;79(2):363–369. doi: 10.1038/sj.bjc.6690058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Guidi A. J., Abu-Jawdeh G., Berse B., Jackman R. W., Tognazzi K., Dvorak H. F., Brown L. F. Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia. J Natl Cancer Inst. 1995 Aug 16;87(16):1237–1245. doi: 10.1093/jnci/87.16.1237. [DOI] [PubMed] [Google Scholar]
  8. Hawighorst H., Weikel W., Knapstein P. G., Knopp M. V., Zuna I., Schönberg S. O., Vaupel P., van Kaick G. Angiogenic activity of cervical carcinoma: assessment by functional magnetic resonance imaging-based parameters and a histomorphological approach in correlation with disease outcome. Clin Cancer Res. 1998 Oct;4(10):2305–2312. [PubMed] [Google Scholar]
  9. Inoue K., Ozeki Y., Suganuma T., Sugiura Y., Tanaka S. Vascular endothelial growth factor expression in primary esophageal squamous cell carcinoma. Association with angiogenesis and tumor progression. Cancer. 1997 Jan 15;79(2):206–213. doi: 10.1002/(sici)1097-0142(19970115)79:2<206::aid-cncr2>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  10. Ishigami S. I., Arii S., Furutani M., Niwano M., Harada T., Mizumoto M., Mori A., Onodera H., Imamura M. Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer. 1998 Nov;78(10):1379–1384. doi: 10.1038/bjc.1998.688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Itakura J., Ishiwata T., Friess H., Fujii H., Matsumoto Y., Büchler M. W., Korc M. Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin Cancer Res. 1997 Aug;3(8):1309–1316. [PubMed] [Google Scholar]
  12. Keys H. M., Bundy B. N., Stehman F. B., Muderspach L. I., Chafe W. E., Suggs C. L., 3rd, Walker J. L., Gersell D. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 1999 Apr 15;340(15):1154–1161. doi: 10.1056/NEJM199904153401503. [DOI] [PubMed] [Google Scholar]
  13. Kieser A., Weich H. A., Brandner G., Marmé D., Kolch W. Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene. 1994 Mar;9(3):963–969. [PubMed] [Google Scholar]
  14. Kuhnen C., Lehnhardt M., Tolnay E., Muehlberger T., Vogt P. M., Müller K. M. Patterns of expression and secretion of vascular endothelial growth factor in malignant soft-tissue tumours. J Cancer Res Clin Oncol. 2000 Apr;126(4):219–225. doi: 10.1007/s004320050036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lee Y. H., Tokunaga T., Oshika Y., Suto R., Yanagisawa K., Tomisawa M., Fukuda H., Nakano H., Abe S., Tateishi A. Cell-retained isoforms of vascular endothelial growth factor (VEGF) are correlated with poor prognosis in osteosarcoma. Eur J Cancer. 1999 Jul;35(7):1089–1093. doi: 10.1016/s0959-8049(99)00073-8. [DOI] [PubMed] [Google Scholar]
  16. Linderholm B., Tavelin B., Grankvist K., Henriksson R. Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma. J Clin Oncol. 1998 Sep;16(9):3121–3128. doi: 10.1200/JCO.1998.16.9.3121. [DOI] [PubMed] [Google Scholar]
  17. Maeda K., Chung Y. S., Ogawa Y., Takatsuka S., Kang S. M., Ogawa M., Sawada T., Sowa M. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer. 1996 Mar 1;77(5):858–863. doi: 10.1002/(sici)1097-0142(19960301)77:5<858::aid-cncr8>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Morris M., Eifel P. J., Lu J., Grigsby P. W., Levenback C., Stevens R. E., Rotman M., Gershenson D. M., Mutch D. G. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999 Apr 15;340(15):1137–1143. doi: 10.1056/NEJM199904153401501. [DOI] [PubMed] [Google Scholar]
  20. Nagy J. A., Masse E. M., Herzberg K. T., Meyers M. S., Yeo K. T., Yeo T. K., Sioussat T. M., Dvorak H. F. Pathogenesis of ascites tumor growth: vascular permeability factor, vascular hyperpermeability, and ascites fluid accumulation. Cancer Res. 1995 Jan 15;55(2):360–368. [PubMed] [Google Scholar]
  21. Obermair A., Bancher-Todesca D., Bilgi S., Kaider A., Kohlberger P., Müllauer-Ertl S., Leodolter S., Gitsch G. Correlation of vascular endothelial growth factor expression and microvessel density in cervical intraepithelial neoplasia. J Natl Cancer Inst. 1997 Aug 20;89(16):1212–1217. doi: 10.1093/jnci/89.16.1212. [DOI] [PubMed] [Google Scholar]
  22. Ohta Y., Endo Y., Tanaka M., Shimizu J., Oda M., Hayashi Y., Watanabe Y., Sasaki T. Significance of vascular endothelial growth factor messenger RNA expression in primary lung cancer. Clin Cancer Res. 1996 Aug;2(8):1411–1416. [PubMed] [Google Scholar]
  23. 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]
  24. Parliament M. B., Allalunis-Turner M. J., Franko A. J., Olive P. L., Mandyam R., Santos C., Wolokoff B. Vascular endothelial growth factor expression is independent of hypoxia in human malignant glioma spheroids and tumours. Br J Cancer. 2000 Feb;82(3):635–641. doi: 10.1054/bjoc.1999.0975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pepper M. S., 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. 1991 Dec 16;181(2):902–906. doi: 10.1016/0006-291x(91)91276-i. [DOI] [PubMed] [Google Scholar]
  26. Presta L. G., Chen H., O'Connor S. J., Chisholm V., Meng Y. G., Krummen L., Winkler M., Ferrara N. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997 Oct 15;57(20):4593–4599. [PubMed] [Google Scholar]
  27. Rak J., Filmus J., Kerbel R. S. Reciprocal paracrine interactions between tumour cells and endothelial cells: the 'angiogenesis progression' hypothesis. Eur J Cancer. 1996 Dec;32A(14):2438–2450. doi: 10.1016/s0959-8049(96)00396-6. [DOI] [PubMed] [Google Scholar]
  28. Rak J., Mitsuhashi Y., Bayko L., Filmus J., Shirasawa S., Sasazuki T., Kerbel R. S. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res. 1995 Oct 15;55(20):4575–4580. [PubMed] [Google Scholar]
  29. Raleigh J. A., Calkins-Adams D. P., Rinker L. H., Ballenger C. A., Weissler M. C., Fowler W. C., Jr, Novotny D. B., Varia M. A. Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker. Cancer Res. 1998 Sep 1;58(17):3765–3768. [PubMed] [Google Scholar]
  30. 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]
  31. Takahashi Y., Cleary K. R., Mai M., Kitadai Y., Bucana C. D., Ellis L. M. Significance of vessel count and vascular endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer. Clin Cancer Res. 1996 Oct;2(10):1679–1684. [PubMed] [Google Scholar]
  32. Uchida S., Shimada Y., Watanabe G., Tanaka H., Shibagaki I., Miyahara T., Ishigami S., Imamura M. In oesophageal squamous cell carcinoma vascular endothelial growth factor is associated with p53 mutation, advanced stage and poor prognosis. Br J Cancer. 1998 May;77(10):1704–1709. doi: 10.1038/bjc.1998.281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Vaccine compromise. Nature. 1993 Apr 15;362(6421):576–576. doi: 10.1038/362576a0. [DOI] [PubMed] [Google Scholar]
  34. Warren R. S., Yuan H., Matli M. R., Gillett N. A., Ferrara N. 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):1789–1797. doi: 10.1172/JCI117857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. West C. M., Davidson S. E., Roberts S. A., Hunter R. D. Intrinsic radiosensitivity and prediction of patient response to radiotherapy for carcinoma of the cervix. Br J Cancer. 1993 Oct;68(4):819–823. doi: 10.1038/bjc.1993.434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Whitney C. W., Sause W., Bundy B. N., Malfetano J. H., Hannigan E. V., Fowler W. C., Jr, Clarke-Pearson D. L., Liao S. Y. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol. 1999 May;17(5):1339–1348. doi: 10.1200/JCO.1999.17.5.1339. [DOI] [PubMed] [Google Scholar]
  37. 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]

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

RESOURCES