Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Aug;85(4):576–583. doi: 10.1054/bjoc.2001.1971

Correlation of vascular endothelial growth factor expression with fibroblast growth factor-8 expression and clinico-pathologic parameters in human prostate cancer

A F West 1, M O'Donnell 2, R G Charlton 2, D E Neal 1, H Y Leung 1
PMCID: PMC2364102  PMID: 11506499

Abstract

Vascular endothelial growth factor (VEGF) mediates neo-angiogenesis during tumour progression and is known to cooperate with the fibroblast growth factor (FGF) system to facilitate angiogenesis in a synergistic manner. In view of this, we have investigated VEGF expression in 67 cases of prostate cancer previously characterized for fibroblast growth factor-8 (FGF-8) expression. Cytoplasmic VEGF staining was detected in malignant cells in 45 out of 67 cases. Cytoplasmic staining was found in adjacent stromal cells in 32 cases, being particularly strong around nests of invasive tumour. Positive VEGF immunoreactivity in benign glands was restricted to basal epithelium. A significant association was observed between tumour VEGF and FGF-8 expression (P = 0.004). We identified increased VEGF immunoreactivity in both malignant epithelium and adjacent stroma and both were found to be significantly associated with high tumour stage (P = 0.0047 and P = 0.0002, respectively). VEGF expression also correlated with increased serum PSA levels (P = 0.01). Among positively stained tumours, VEGF expression showed a significant association with Gleason score (P = 0.04). Cases showing positive VEGF immunoreactivity in the stroma had a significantly reduced survival rate compared to those with negative staining (P = 0.037). Cases with tumours expressing both FGF-8 in the malignant epithelium and VEGF in the adjacent stroma had a significantly worse survival rate than those with tumours negative for both, or only expressing one of the two growth factors (P = 0.029). Cox multivariate regression analysis of survival demonstrated that stromal VEGF and tumour stage were the most significant independent predictors of survival. In conclusion, we report for the first time a correlation of both tumour and stromal VEGF expression in prostate cancer with clinical parameters as well as its correlation to FGF-8 expression. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: prostate cancer, benign prostatic hyperplasia (BPH), vascular endothelial growth factor (VEGF), fibroblast growth factor-8 (FGF-8), immunohistochemistry, survival

Full Text

The Full Text of this article is available as a PDF (131.9 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. Borre M., Nerstrøm B., Overgaard J. Association between immunohistochemical expression of vascular endothelial growth factor (VEGF), VEGF-expressing neuroendocrine-differentiated tumor cells, and outcome in prostate cancer patients subjected to watchful waiting. Clin Cancer Res. 2000 May;6(5):1882–1890. [PubMed] [Google Scholar]
  3. Bouck N., Stellmach V., Hsu S. C. How tumors become angiogenic. Adv Cancer Res. 1996;69:135–174. doi: 10.1016/s0065-230x(08)60862-3. [DOI] [PubMed] [Google Scholar]
  4. Brawer M. K., Deering R. E., Brown M., Preston S. D., Bigler S. A. Predictors of pathologic stage in prostatic carcinoma. The role of neovascularity. Cancer. 1994 Feb 1;73(3):678–687. doi: 10.1002/1097-0142(19940201)73:3<678::aid-cncr2820730329>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  5. Byrne R. L., Leung H., Neal D. E. Peptide growth factors in the prostate as mediators of stromal epithelial interaction. Br J Urol. 1996 May;77(5):627–633. doi: 10.1046/j.1464-410x.1996.09721.x. [DOI] [PubMed] [Google Scholar]
  6. Connolly D. T., Heuvelman D. M., Nelson R., Olander J. V., Eppley B. L., Delfino J. J., Siegel N. R., Leimgruber R. M., Feder J. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest. 1989 Nov;84(5):1470–1478. doi: 10.1172/JCI114322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dorkin T. J., Robinson M. C., Marsh C., Bjartell A., Neal D. E., Leung H. Y. FGF8 over-expression in prostate cancer is associated with decreased patient survival and persists in androgen independent disease. Oncogene. 1999 Apr 29;18(17):2755–2761. doi: 10.1038/sj.onc.1202624. [DOI] [PubMed] [Google Scholar]
  8. Dorkin T. J., Robinson M. C., Marsh C., Neal D. E., Leung H. Y. aFGF immunoreactivity in prostate cancer and its co-localization with bFGF and FGF8. J Pathol. 1999 Dec;189(4):564–569. doi: 10.1002/(SICI)1096-9896(199912)189:4<564::AID-PATH480>3.0.CO;2-1. [DOI] [PubMed] [Google Scholar]
  9. Ferrara N., Houck K., Jakeman L., Leung D. W. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev. 1992 Feb;13(1):18–32. doi: 10.1210/edrv-13-1-18. [DOI] [PubMed] [Google Scholar]
  10. Ferrer F. A., Miller L. J., Andrawis R. I., Kurtzman S. H., Albertsen P. C., Laudone V. P., Kreutzer D. L. Vascular endothelial growth factor (VEGF) expression in human prostate cancer: in situ and in vitro expression of VEGF by human prostate cancer cells. J Urol. 1997 Jun;157(6):2329–2333. [PubMed] [Google Scholar]
  11. Ferrer F. A., Miller L. J., Lindquist R., Kowalczyk P., Laudone V. P., Albertsen P. C., Kreutzer D. L. Expression of vascular endothelial growth factor receptors in human prostate cancer. Urology. 1999 Sep;54(3):567–572. doi: 10.1016/s0090-4295(99)00156-9. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Gemel J., Gorry M., Ehrlich G. D., MacArthur C. A. Structure and sequence of human FGF8. Genomics. 1996 Jul 1;35(1):253–257. doi: 10.1006/geno.1996.0349. [DOI] [PubMed] [Google Scholar]
  14. Harper M. E., Glynne-Jones E., Goddard L., Thurston V. J., Griffiths K. Vascular endothelial growth factor (VEGF) expression in prostatic tumours and its relationship to neuroendocrine cells. Br J Cancer. 1996 Sep;74(6):910–916. doi: 10.1038/bjc.1996.456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Heikinheimo M., Lawshé A., Shackleford G. M., Wilson D. B., MacArthur C. A. Fgf-8 expression in the post-gastrulation mouse suggests roles in the development of the face, limbs and central nervous system. Mech Dev. 1994 Nov;48(2):129–138. doi: 10.1016/0925-4773(94)90022-1. [DOI] [PubMed] [Google Scholar]
  16. Häggström S., Bergh A., Damber J. E. Vascular endothelial growth factor content in metastasizing and nonmetastasizing Dunning prostatic adenocarcinoma. Prostate. 2000 Sep 15;45(1):42–50. doi: 10.1002/1097-0045(20000915)45:1<42::aid-pros5>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
  17. Jackson M. W., Bentel J. M., Tilley W. D. Vascular endothelial growth factor (VEGF) expression in prostate cancer and benign prostatic hyperplasia. J Urol. 1997 Jun;157(6):2323–2328. [PubMed] [Google Scholar]
  18. Joseph I. B., Nelson J. B., Denmeade S. R., Isaacs J. T. Androgens regulate vascular endothelial growth factor content in normal and malignant prostatic tissue. Clin Cancer Res. 1997 Dec;3(12 Pt 1):2507–2511. [PubMed] [Google Scholar]
  19. Klein L. A. Prostatic carcinoma. N Engl J Med. 1979 Apr 12;300(15):824–833. doi: 10.1056/NEJM197904123001504. [DOI] [PubMed] [Google Scholar]
  20. Kumar-Singh S., Weyler J., Martin M. J., Vermeulen P. B., Van Marck E. Angiogenic cytokines in mesothelioma: a study of VEGF, FGF-1 and -2, and TGF beta expression. J Pathol. 1999 Sep;189(1):72–78. doi: 10.1002/(SICI)1096-9896(199909)189:1<72::AID-PATH401>3.0.CO;2-0. [DOI] [PubMed] [Google Scholar]
  21. Lee A. H., Dublin E. A., Bobrow L. G., Poulsom R. Invasive lobular and invasive ductal carcinoma of the breast show distinct patterns of vascular endothelial growth factor expression and angiogenesis. J Pathol. 1998 Aug;185(4):394–401. doi: 10.1002/(SICI)1096-9896(199808)185:4<394::AID-PATH117>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Mazzucchelli R., Montironi R., Santinelli A., Lucarini G., Pugnaloni A., Biagini G. Vascular endothelial growth factor expression and capillary architecture in high-grade PIN and prostate cancer in untreated and androgen-ablated patients. Prostate. 2000 Sep 15;45(1):72–79. doi: 10.1002/1097-0045(20000915)45:1<72::aid-pros9>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
  24. Pepper M. S., Ferrara N., Orci L., Montesano R. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun. 1992 Dec 15;189(2):824–831. doi: 10.1016/0006-291x(92)92277-5. [DOI] [PubMed] [Google Scholar]
  25. Quinn T. P., Peters K. G., De Vries C., Ferrara N., Williams L. T. Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7533–7537. doi: 10.1073/pnas.90.16.7533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Scott W. W., Menon M., Walsh P. C. Hormonal therapy of prostatic cancer. Cancer. 1980 Apr 15;45(7 Suppl):1929–1936. [PubMed] [Google Scholar]
  27. Seghezzi G., Patel S., Ren C. J., Gualandris A., Pintucci G., Robbins E. S., Shapiro R. L., Galloway A. C., Rifkin D. B., Mignatti P. Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol. 1998 Jun 29;141(7):1659–1673. doi: 10.1083/jcb.141.7.1659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. Siegal J. A., Yu E., Brawer M. K. Topography of neovascularity in human prostate carcinoma. Cancer. 1995 May 15;75(10):2545–2551. doi: 10.1002/1097-0142(19950515)75:10<2545::aid-cncr2820751022>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  30. Song Z., Powell W. C., Kasahara N., van Bokhoven A., Miller G. J., Roy-Burman P. The effect of fibroblast growth factor 8, isoform b, on the biology of prostate carcinoma cells and their interaction with stromal cells. Cancer Res. 2000 Dec 1;60(23):6730–6736. [PubMed] [Google Scholar]
  31. Strohmeyer D., Rössing C., Bauerfeind A., Kaufmann O., Schlechte H., Bartsch G., Loening S. Vascular endothelial growth factor and its correlation with angiogenesis and p53 expression in prostate cancer. Prostate. 2000 Nov 1;45(3):216–224. doi: 10.1002/1097-0045(20001101)45:3<216::aid-pros3>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  32. Takahashi Y., Kitadai Y., Bucana C. D., Cleary K. R., Ellis L. M. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995 Sep 15;55(18):3964–3968. [PubMed] [Google Scholar]
  33. Tanaka A., Furuya A., Yamasaki M., Hanai N., Kuriki K., Kamiakito T., Kobayashi Y., Yoshida H., Koike M., Fukayama M. High frequency of fibroblast growth factor (FGF) 8 expression in clinical prostate cancers and breast tissues, immunohistochemically demonstrated by a newly established neutralizing monoclonal antibody against FGF 8. Cancer Res. 1998 May 15;58(10):2053–2056. [PubMed] [Google Scholar]
  34. Tanaka A., Miyamoto K., Minamino N., Takeda M., Sato B., Matsuo H., Matsumoto K. Cloning and characterization of an androgen-induced growth factor essential for the androgen-dependent growth of mouse mammary carcinoma cells. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):8928–8932. doi: 10.1073/pnas.89.19.8928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Tennant M. K., Thrasher J. B., Twomey P. A., Drivdahl R. H., Birnbaum R. S., Plymate S. R. Protein and messenger ribonucleic acid (mRNA) for the type 1 insulin-like growth factor (IGF) receptor is decreased and IGF-II mRNA is increased in human prostate carcinoma compared to benign prostate epithelium. J Clin Endocrinol Metab. 1996 Oct;81(10):3774–3782. doi: 10.1210/jcem.81.10.8855837. [DOI] [PubMed] [Google Scholar]
  36. Terman B. I., Dougher-Vermazen M., Carrion M. E., Dimitrov D., Armellino D. C., Gospodarowicz D., Böhlen P. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun. 1992 Sep 30;187(3):1579–1586. doi: 10.1016/0006-291x(92)90483-2. [DOI] [PubMed] [Google Scholar]
  37. Toi M., Inada K., Suzuki H., Tominaga T. Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res Treat. 1995;36(2):193–204. doi: 10.1007/BF00666040. [DOI] [PubMed] [Google Scholar]
  38. Weidner N., Carroll P. R., Flax J., Blumenfeld W., Folkman J. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol. 1993 Aug;143(2):401–409. [PMC free article] [PubMed] [Google Scholar]
  39. Zhang L., Scott P. A., Turley H., Leek R., Lewis C. E., Gatter K. C., Harris A. L., Mackenzie I. Z., Rees M. C., Bicknell R. Validation of anti-vascular endothelial growth factor (anti-VEGF) antibodies for immunohistochemical localization of VEGF in tissue sections: expression of VEGF in the human endometrium. J Pathol. 1998 Aug;185(4):402–408. doi: 10.1002/(SICI)1096-9896(199808)185:4<402::AID-PATH112>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]
  40. 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