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
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
Asahara T, Bauters C, Zheng LP, Takeshita S, Bunting S, Ferrara N, Symes JF and Isner JM (1995) Synergistic effect of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in vivo. Circulation 92: 365–371
Boocock CA, Charnock-Jones DS, Sharkey AM, McLaren J, Barker PJ, Wright KA, Twentyman PR and Smith SK (1995) Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian cancer. J Natl Cancer Inst 87: 506–516
Borre M, Nerstrom B and Overgaard J (2000) Association between immunohistochemical expression of vascular endothelial growth factor (VEGF), VEGF-expressing neuroendocrine-differentiated tumour cells, and outcome in prostate cancer patients subjected to watchful waiting. Clin Cancer Res 6: 1882–1890
Bouck N, Stellmach V and Hsu SC (1996) How tumours become angiogenic. Adv Cancer Res 69: 135–174
Brawer MK, Deering RE, Brown M, Preston SD and Bigler SA (1994) Predictors of pathologic stage in prostatic carcinoma. The role of neovascularity. Cancer 73: 678–687
Byrne RL, Leung H and Neal DE (1996) Peptide growth factors in the prostate as mediators of stromal epithelial interaction. Br J Urol 77: 627–633
Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ, Siegel NR, Leimgruber RM and Feder J (1989) Tumour vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 84: 1470
deVries C, Escobedo J, 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
Dorkin TJ, Robinson MC, Marsh C, Bjartell A, Neal DE and Leung HY (1999a) FGF8 over-expression in prostate cancer is associated with decreased patient survival and persists in androgen independent disease. Oncogene 18: 2755–2761
Dorkin TJ, Robinson MC, Marsh C, Neal DE and Leung HY (1996b) aFGF immunoreactivity in prostate cancer and its co-localisation with bFGF and FGF8. J Pathol 189: 564–569
Ferrara N, Houck K, Jakeman L and Leung DW (1992) Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev 13: 18
Ferrer FA, Miller LJ, Andrawis RI, Kurtzman SH, Albertsen PC, Laudone VP and Kreutzer DL (1997) 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 157: 2329–2333
Ferrer FA, Miller LJ, Lindquist R, Kowalczyk P, Laudone VP, Albertsen PC and Kreutzer DL (1999) Expression of vascular endothelial growth factor receptors in human prostate cancer. Urology 54: 567–572
Folkman J (1990) What is the evidence that tumours are angiogenesis dependent?. J Natl Cancer Inst 82: 4–6
Gemel J, Gorry M, Ehrlich GD and MacArthur CA (1996) Structure and sequence of human FGF8. Genomics 35: 253–257
Haggstrom S, Bergh A and Damber J (2000) Vascular endothelial growth factor content in metastasizing and nonmetastasizing Dunning prostatic adenocarcinoma. Prostate 45: 42–50
Harper ME, Glynne-Jones E, Goddard L, Thurston VJ and Griffiths K (1996) Vascular endothelial growth factor (VEGF) expression in prostatic tumours and its relationship to neuroendocrine cells. Br J Cancer 74: 910–916
Heikinheimo M, Lawshe A, Shackleford GM, Wilson DB and MacArthur CA (1994) Fgf-8 expression in the post-gastrulation mouse suggests roles in the development of the face, limbs and central nervous system. Mech Dev 48: 129–138
Jackson MW, Bentel JM and Tilley WD (1997) Vascular endothelial growth factor (VEGF) expression in prostate cancer and benign prostatic hyperplasia. J Urol 157: 2323–2328
Joseph IB, Nelson JB, Denmeade SR and Isaac JT (1997) Androgens regulate vascular endothelial growth factor content in normal and malignant prostatic tissue. Clin Cancer Res 3: 2507–2511
Klein L (1979) Prostatic carcinoma. N Engl J Med 300: 824–833
Kumar-Singh S, Weyler J, Martin MJH, Vermeulen PB and Van Marck E (1999) Angiogenic cytokines in mesothelioma: a study of VEGF, FGF-1 and -2, and TGFbeta expression. J Pathol 189: 72–78
Lee AHS, Dublin EA, Bobrow LG and Poulsom R (1998) Invasive lobular and invasive ductal carcinoma of the breast show distinct patterns of vascular endothelial growth factor expression and angiogenesis. J Pathol 185: 394–401
Maeda K, Chung Y-S, Ogawa Y, Takatsuka S, Kang SM, Ogawa M, Sawada T and Sowa M (1996) Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer 77: 858–863
Mazzuchelli R, Montironi R, Santinelli A, Lucarini G, Pugnaloni A and Biagini G (2000) Vascular endothelial growth factor expression and capillary architecture in high-grade PIN and prostate cancer in untreated and androgen-ablated patients. Prostate 45: 72–79
Pepper MS, Ferrara N, Orci L and Montesano R (1992) Potential synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun 189: 824–831
Quinn TP, Peters KG, deVries C, Ferrara N and Williams LT (1993) Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci USA 90: 7533–7537
Scott WW, Menon M and Walsh PC (1980) Hormonal therapy of prostate cancer. Cancer 45: 1929–1936
Seghezzi G, Patel S, Ren CJ, Gualandris A, Pintucci G, Robbins ES, Shapiro RL, Galloway AC, Rifkin DB and Mignatti P (1998) 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 141: 1659–1673
Senger DR, Galli SJ, Peruzzi CA, Harvey VS and Dvorak HF (1983) Tumour cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219: 983–985
Siegal JA, Yu E and Brawer MK (1995) Topography of neovascularity in human prostate carcinoma. Cancer 75: 2545–2551
Song Z, Powell WC, Kasahara N, van Bokhoven A, Miller GJ and Roy-Burman P (2000) The effect of fibroblast growth factor 8, isoform b, on the biology of prostate carcinoma cells and their interaction with stromal cells. Cancer Res 60: 6730–6736
Strohmeyer D, Rossing C, Bauerfeind A, Kaufmann O, Schlechte H, Bartsch G and Loening S (2000) Vascular endothelial growth factor and its correlation with angiogenesis and p53 expression in prostate cancer. Prostate 45 ( 3): 216–224
Takahashi Y, Kitadai Y, Bucana CD, Cleary KR and Ellis LM (1995) Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 55: 3964–3968
Tanaka A, Miyamoto K, Minamino N, Takeda M, Sato B, Matsuo H and Matsumoto K (1992) Cloning and characterization of an androgen-induced growth factor essential for the androgen-independent growth of mouse mammary carcinoma cells. Proc Natl Acad Sci USA 89: 8928–8932
Tanaka A, Furuya A, Yamasaki M, Hanai N, Kuriki K, Kamiakito T, Kobayashi Y, Yoshida H, Koike M and Fukayama M (1998) High frequency of fibroblast growth factor (FGF) 8 expression in clinical prostate cancers and breast tissues, immunohistochemically demonstrated by a newly established neutralising monoclonal antibody against FGF 8. Cancer Res 58: 2053–2056
Tennant MK, Thrasher JB, Twomey PA, Drivdahl RH, Birnbaun RS and Plymate SR (1996) 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 81: 3774–3782
Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D and Bohlen P (1992) Identification of the KDR tyrosine kinase as a receptor for vascular endothelial growth factor. Biochem Biophys Res Commun 187: 1579–1586
Toi M, Inada K, Suzuki H and Tominaga T (1995) Tumour angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res Treat 36: 193–204
Weidner N, Carroll PR, Flax J, Blumenfeld W and Folkman J (1993) Tumour angiogenesis correlates with metastasis in invasive prostate cancer. Am J Pathol 143: 401
Zhang L, Scott PAE, Turley H, Leek R, Lewis CE, Gatter KC, Harris AL, Mackenzie IZ, Rees MCP and Bicknell R (1998) 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 185: 402–408
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
West, A., O'Donnell, M., Charlton, R. et al. Correlation of vascular endothelial growth factor expression with fibroblast growth factor-8 expression and clinico-pathologic parameters in human prostate cancer. Br J Cancer 85, 576–583 (2001). https://doi.org/10.1054/bjoc.2001.1971
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2001.1971
Keywords
This article is cited by
-
Bone microenvironment signaling of cancer stem cells as a therapeutic target in metastatic prostate cancer
Cell Biology and Toxicology (2020)
-
Does true Gleason pattern 3 merit its cancer descriptor?
Nature Reviews Urology (2016)
-
Vascular morphology differentiates prostate cancer mortality risk among men with higher Gleason grade
Cancer Causes & Control (2016)
-
Role of active surveillance and focal therapy in low- and intermediate-risk prostate cancers
World Journal of Urology (2015)
-
Active Surveillance for Low-Risk Prostate Cancer
Current Urology Reports (2015)