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
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Boocock CA, Charnock-Jones DS, Sharkey AM, McLaren J, Barker PJ, Wright KA, Twentyman PR & Smith SK (1995) Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Institute 87: 506–516
Bouvet M, Ellis LM, Nishizaki M, Fujiwara T, Liu W, Bucana CD, Fang B, Lee J & Roth JA (1998) Adenovirus-mediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer. Cancer Res 58: 2288–2292
Chiarotto JA & Hill RP (1999) A quantitative analysis of the reduction in oxygen levels required to induce up-regulation of vascular endothelial growth factor (VEGF) mRNA in cervical cell lines. Br J Cancer 80: 1518–1524
Ferrara N (1995) The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat 36: 127–137
Folkman J (1990) What is the evidence that tumors are angiogenesis dependent?. J Natl Cancer Institute 82: 4–6
Fontanini G, Boldrini L, Chine S, Pisaturo F, Basalo F, Calcinai A, Lucchi M, Angeletti CA & Bevilacqua G (1999) Expression of vascular endothelial growth factor mRNA in non-small cell lung carcinomas. Br J Cancer 79: 363–369
Guidi A, Abu-Jawdeh G, Berse B, Jackman RW, Tognazzi K, Dvorak HF & Brown LF (1995) Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia. J Natl Cancer Institute 87: 1237–1245
Hawighorst H, Weikel W, Knapstein PG, Knopp MV, Zuna I, Schonberg SO, Vaupel P & van Kaick G (1998) 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 4: 2305–2312
Inoue K, Ozeki Y, Suganuma T, Sugiura T & Tanaka S (1997) Vascular endothelial growth factor expression in primary esophageal squamous cell carcinoma. Cancer 79: 206–213
Ishigami SI, Arii S, Furutani M, Niwano M, Harada T, Mizumoto M, Mori A & Imamura M (1998) Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer 78: 1379–1384
Itakura J, Ishiwata T, Freiss H, Fujii H, Matsumoto Y, Buchler MW & Korc M (1997) Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin Cancer Res 3: 1309–1316
Keiser A, Weich HA, Brandner G, Marme D & Kolch W (1994) Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9: 963–969
Keys HM, Bundy BN & Stehman FB (1999) Cisplatin, radiation, and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340: 1154–1161
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: 576–579
Kuhnen C, Lehnhardt M, Tolnay E, Muehlberger T, Vogt PM & Muller K-M (2000) Patterns of expression and secretion of vascular endothelial growth factor in malignant soft-tissue tumours. J Cancer Res Clin Oncol 126: 219–225
Lee YH, Tokunaga T, Oshika Y, Suto R, Yanagisawa K, Tomisawa M, Fukuda H, Abe S, Tateishi A, Kijima H, Yamazaki H, Tamaoki N, Ueyama Y & Nakamura M (1999) Cell-retained isoforms of vascular endothelial growth factor (VEGF) are correlated with poor prognosis in osteosarcoma. Eur J cancer 35: 1089–1093
Linderholm B, Tavelin B, Grankvist K & Henriksson R (1998) Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma. J Clin Onc 16: 3121–3128
Maeda K, Chung YS, Ogawa Y, Takatsuka S, Kang S, Ogawa M, Sawada T & Sowa M (1996) Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer 77: 858–863
Millaeur B, Shawver KL & Plate KH (1994) Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367: 576–579
Morris M, Eifel PJ & Lu J (1999) Pelvic radiation with concurrent chemotherapy compared with pelvic and paraaortic radiation for high risk cervical cancer. N Engl J Med 340: 1137–1143
Nagy JA, Masse EM, Herzberg KT, Myers MS, Yeo K, Sioussat T & Dvorak H (1995) Pathogenesis of ascites tumour growth: vascular permeability factor, vascular hyperpermeability, and ascites fluid formation. Cancer Res 55: 360–368
Obermair A, Bancher-Todesca D, Bilgi S, Kaider A, Kohlberger P, Mullauer-Ertl S, Leodolter S & Gitsch G (1997) Correlation of vascular endothelial growth factor expression and microvessel density in cervical intraepithelial neoplasia. J Natl Cancer Inst 89: 1212–1217
Ohta Y, Endo Y, Tanaka M, Shimizu J, Oda M, Hayashi Y, Watanabe Y & Sasaki T (1996) Significance of vascular endothelial growth factor messnger RNA expression in primary lung cancer. Clin Cancer Res 2: 1411–1416
Paley PJ, Staskus KA, Gebhard K, Mohanraj D, Twiggs LB & Ramakrishnan S (1997) Vascular endothelial growth factor expression in early stage ovarian carcinoma. Cancer 80: 98–106
Parliament MB, Allalunis-Turner MJ, Franko AJ, Olive PL, Mandyam R, Santos C & Wolokoff B (2000) Vascular endothelial growth factor expression is independent of hypoxia in human malignant glioma spheroids and tumours. Br J Cancer 82: 635–641
Peters WAIII, Liu PY & Barrett R (1999) Cisplatin, 5-fluorouracil plus radiation therapy are superior to radiation therapy as adjunctive therapy in high-risk, early stage carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy. Proc Soc Gynecol Oncol 28: (abstr)
Pepper MS, Ferrara N & Orchi L (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
Presta LG, Chen H, O’Conner SJ, Chisholm V, Winkler M & Ferrara N (1997) Humanisation of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumours and other disorders. Cancer Res 57: 4593–4599
Rak J (1996) Reciprocal paracrine interactions between tumour cells and endothelial cells: the ‘angiogenesis progression’ hypothesis. Eur J Cancer 32A: 2438–2450
Rak J, Mitsuhashi Y & Bayko L (1995) Mutant ras oncogenes up-regulate VEGF/VPF expression-implications for induction and inhibition of tumour angiogenesis. Cancer Res 55: 4574–4580
Raleigh JA, Calkins-Adams DP, Rinker LH, Ballenger CA, Weisser MC, Fowler WC, Novotny D & Varia M (1998) Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker. Cancer Res 58: 3765–3768
Senger DR, Galli SJ, Peruzzi CA, Harvey VS & Dvorak HF (1983) Tumour cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219: 983–985
Takahashi Y, Cleary KR, Mai M, Kitadai Y, Bucana CD & Ellis LM (1996) Significance of vessel count and vascular endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer. Clin Cancer Res 2: 1679–1684
Uchida S, Shimada Y, Watanabe G, Tanaka H, Shobagaki I, Miyahara T, Ishigami S, Arii S & Imamura M (1998) In oesophageal squamous cell carcinoma vascular endothelial growth factor is associated with p53 mutation, advanced stage and poor prognosis. Br J Cancer 77: 1704–1709
Warren RA, Yuan H & Matli MR (1995) Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastases. J Clin Invest 95: 1789–1797
West CML, Davidson SE, Roberts SA & Hunter RD (1993) Intrinsic radiosensitivity and prediction of patient response to radiotherapy for carcinoma of the cervix. Br J Cancer 68: 819–823
Whitney CW, Sause W, Bundy BN, Malfetano JH, Hannigan EV, Fowler WC, Clarke-Pearson DL & Liao S (1999) Randomised comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative paraaortic lymph nodes. J Clin Oncol 17: 1339–1343
Yamamoto S, Konishi I, Mandai M, Kuroda H, Komatsu T, Nanbu K, Sakahara H & Mori T (1997) 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 76: 1221–1227
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Loncaster, J., Cooper, R., Logue, J. et al. Vascular endothelial growth factor (VEGF) expression is a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix. Br J Cancer 83, 620–625 (2000). https://doi.org/10.1054/bjoc.2000.1319
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2000.1319
Keywords
This article is cited by
-
The prognostic significance of pretreatment squamous cell carcinoma antigen levels in cervical cancer patients treated by concurrent chemoradiation therapy and a comparison of dosimetric outcomes and clinical toxicities between tomotherapy and volumetric modulated arc therapy
Radiation Oncology (2022)
-
Radiotherapy resistance: identifying universal biomarkers for various human cancers
Journal of Cancer Research and Clinical Oncology (2022)
-
Expression of CD34, PCNA and VEGF in CIN-3 and Invasive Squamous Cell Carcinoma Cervix: A Pilot Study
Indian Journal of Gynecologic Oncology (2020)
-
Early motor function after local treatment of brain metastases in the motor cortex region with stereotactic radiotherapy/radiosurgery or microsurgical resection: a retrospective study of two consecutive cohorts
Radiation Oncology (2017)
-
SIM2l attenuates resistance to hypoxia and tumor growth by transcriptional suppression of HIF1A in uterine cervical squamous cell carcinoma
Scientific Reports (2017)