Abstract
Microvessel density (MVD) has been associated with progression of prostate cancer. Although basic fibroblast growth factor (bFGF) is a known endothelial mitogen, the prognostic role of bFGF and its receptor FGFR-1 in prostate cancer has been controversial. The aim of our study was to examine the tissue distribution and prognostic significance of bFGF, FGFR-1, and microvascular proliferation. Sections from 104 radical prostatectomy specimens were examined by factor VIII/Ki-67 staining for proliferating capillary index (PCI) and MVD, and tissue microarray sections were immunostained for bFGF and FGFR-1. Increased PCI (median 0.49%) was related to strong stromal expression of bFGF (P=0.003) but was without prognostic impact. Strong bFGF staining was associated with well-differentiated tumors, no capsular penetration, low serum-prostate-specific antigen (s-PSA), low tumor cell proliferation, and increased time to biochemical failure (P=0.007), and was of independent prognostic importance in multivariate survival analysis. bFGF expression in vessels was associated with low MVD (P=0.0003). In contrast, strong tumor cell FGFR-1 expression was related to high preoperative s-PSA. Thus, increased stromal and vessel bFGF was associated with less aggressive tumors. Our findings indicate a complex relationship between bFGF/FGFR-1 expression and prognosis of prostate cancer. Vascular proliferation revealed no prognostic impact in this study.
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Bono AV, Celato N, Cova V, Salvadore M, Chinetti S, Novario R (2002) Microvessel density in prostate carcinoma. Prostate Cancer Prostatic Dis 5:123–127
Brawer MK, Deering RE, Brown M, Preston SD, Bigler SA (1994) Predictors of pathologic stage in prostatic carcinoma. The role of neovascularity. Cancer 73:678–687
Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660
Cronauer MV, Hittmair A, Eder IE et al (1997) Basic fibroblast growth factor levels in cancer cells and in sera of patients suffering from proliferative disorders of the prostate. Prostate 31:223–233
Cronauer MV, Schulz WA, Seifert HH, Ackermann R, Burchardt M (2003) Fibroblast growth factors and their receptors in urological cancers: basic research and clinical implications. Eur Urol 43:309–319
Dell'era P, Nicoli S, Peri G, Nieddu M, Ennas MG, Presta M (2005) FGF2-induced upregulation of DNA polymerase-delta p12 subunit in endothelial cells. Oncogene 24:1117–1121
Deshmukh N, Scotson J, Dodson AR, Smith PH, Ke Y, Foster CS (1997) Differential expression of acidic and basic fibroblast growth factors in benign prostatic hyperplasia identified by immunohistochemistry. Br J Urol 80:869–874
Dorkin TJ, Robinson MC, Marsh C, Bjartell A, Neal DE, Leung HY (1999) 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, Leung HY (1999) aFGF immunoreactivity in prostate cancer and its co-localization with bFGF and FGF8. J Pathol 189:564–569
Eberhard A, Kahlert S, Goede V, Hemmerlein B, Plate KH, Augustin HG (2000) Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res 60:1388–1393
Feng S, Wang F, Matsubara A, Kan M, McKeehan WL (1997) Fibroblast growth factor receptor 2 limits and receptor 1 accelerates tumorigenicity of prostate epithelial cells. Cancer Res 57:5369–5378
Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186
Fox SB, Gatter KC, Bicknell R, Going JJ, Stanton P, Cooke TG, Harris AL (1993) Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer. Cancer Res 53:4161–4163
Freeman KW, Gangula RD, Welm BE, Ozen M, Foster BA, Rosen JM, Ittmann M, Greenberg NM, Spencer DM (2003) Conditional activation of fibroblast growth factor receptor (FGFR) 1, but not FGFR2, in prostate cancer cells leads to increased osteopontin induction, extracellular signal-regulated kinase activation, and in vivo proliferation. Cancer Res 63:6237–6243
Fregene TA, Khanuja PS, Noto AC, Gehani SK, Van Egmont EM, Luz DA, Pienta KJ (1993) Tumor-associated angiogenesis in prostate cancer. Anticancer Res 13:2377–2381
Gaudric A, N'Guyen T, Moenner M, Glacet-Bernard A, Barritault D (1992) Quantification of angiogenesis due to basic fibroblast growth factor in a modified rabbit corneal model. Ophthalmic Res 24:181–188
Giri D, Ropiquet F, Ittmann M (1999) Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. Clin Cancer Res 5:1063–1071
Giri D, Ittmann M (2000) Interleukin-1alpha is a paracrine inducer of FGF7, a key epithelial growth factor in benign prostatic hyperplasia. Am J Pathol 157:249–255
Giri D, Ittmann M (2001) Interleukin-8 is a paracrine inducer of fibroblast growth factor 2, a stromal and epithelial growth factor in benign prostatic hyperplasia. Am J Pathol 159:139–147
Gowardhan B, Douglas DA, Mathers ME, McKie AB, McCracken SR, Robson CN, Leung HY (2005) Evaluation of the fibroblast growth factor system as a potential target for therapy in human prostate cancer. Br J Cancer 92(2):320–327
Halvorsen OJ, Haukaas S, Hoisaeter PA, Akslen LA (2000) Independent prognostic importance of microvessel density in clinically localized prostate cancer. Anticancer Res 20:3791–3799
Halvorsen OJ, Haukaas S, Hoisaeter PA, Akslen LA (2001) Maximum Ki-67 staining in prostate cancer provides independent prognostic information after radical prostatectomy. Anticancer Res 21:4071–4076
Hlatky L, Hahnfeldt P, Folkman J (2002) Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn't tell us. J Natl Cancer Inst 94:883–893
Hoos A, Urist MJ, Stojadinovic A et al (2001) Validation of tissue microarrays for immunohistochemical profiling of cancer specimens using the example of human fibroblastic tumors. Am J Pathol 158:1245–1251
Ittman M, Mansukhani A (1997) Expression of fibroblast growth factors (FGFs) and FGF receptors in human prostate. J Urol 157:351–356
Jaye M, Schlessinger J, Dionne CA (1992) Fibroblast growth factor receptor tyrosine kinases: molecular analysis and signal transduction. Biochim Biophys Acta 1135:185–199
Johnson DE, Lu J, Chen H, Werner S, Williams LT (1991) The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain. Mol Cell Biol 11:4627–4634
Klein RD, Maliner-Jongewaard MS, Udayakumar TS, Boyd JL, Nagle RB, Bowden GT (1999) Promatrilysin expression is induced by fibroblast growth factors in the prostatic carcinoma cell line LNCaP but not in normal primary prostate epithelial cells. Prostate 41:215–223
Kloth S, Gerdes J, Wanke C, Minuth WW (1998) Basic fibroblast growth factor is a morphogenic modulator in kidney vessel development. Kidney Int 53:970–978
Kononen J, Bubendorf L, Kallioniemi A et al (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847
Kwabi-Addo B, Ropiquet F, Giri D, Ittmann M (2001) Alternative splicing of fibroblast growth factor receptors in human prostate cancer. Prostate 46:163–172
Lee SH, Schloss DJ, Swain JL (2000) Maintenance of vascular integrity in the embryo requires signaling through the fibroblast growth factor receptor. J Biol Chem 275:33679–33687
Nocito A, Bubendorf L, Maria Tinner E et al (2001) Microarrays of bladder cancer tissue are highly representative of proliferation index and histological grade. J Pathol 194:349–357
Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M (1996) Receptor specificity of the fibroblast growth factor family. J Biol Chem 271:15292–15297
Ozen M, Giri D, Ropiquet F, Mansukhani A, Ittmann M (2001) Role of fibroblast growth factor receptor signaling in prostate cancer cell survival. J Natl Cancer Inst 93:1783–1790
Powers CJ, McLeskey SW, Wellstein A (2000) Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 7:165–197
Ropiquet F, Giri D, Kwabi-Addo B, Mansukhani A, Ittmann M (2000) Increased expression of fibroblast growth factor 6 in human prostatic intraepithelial neoplasia and prostate cancer. Cancer Res 60:4245–4250
Russell PJ, Bennett S, Joshua A, Yu Y, Downing SR, Hill MA, Kingsley EA, Mason RS, Berry J (1999) Elevated expression of FGF-2 does not cause prostate cancer progression in LNCaP cells. Prostate 40:1–13
Sinowatz F, Schams D, Einspanier R, Arnold G, Pfeffer M, Temmim-Baker L, Amselgruber W, Plendl J (2000) Cellular localization of fibroblast growth factor 2 (FGF-2) in benign prostatic hyperplasia. Histol Histopathol 15:475–481
Straume O, Akslen LA (2002) Importance of vascular phenotype by basic fibroblast growth factor, and influence of the angiogenic factors basic fibroblast growth factor/fibroblast growth factor receptor-1 and ephrin-A1/EphA2 on melanoma progression. Am J Pathol 160:1009–1019
Straume O, Chappuis PO, Salvesen HB, Halvorsen OJ, Haukaas SA, Goffin JR, Begin LR, Foulkes WD, Akslen LA (2002) Prognostic importance of glomeruloid microvascular proliferation indicates an aggressive angiogenic phenotype in human cancers. Cancer Res 62:6808–6811
Strohmeyer D, Rossing C, Strauss F, Bauerfeind A, Kaufmann O, Loening S (2000) Tumor angiogenesis is associated with progression after radical prostatectomy in pT2/pT3 prostate cancer. Prostate 42:26–33
Strohmeyer D, Strauss F, Rossing C, Roberts C, Kaufmann O, Bartsch G, Effert P (2004) Expression of bFGF, VEGF and c-met and their correlation with microvessel density and progression in prostate carcinoma. Anticancer Res 24:1797–1804
Sugamoto T, Tanji N, Sato K, Fujita H, Nishio S, Sakanaka M, Yokoyama M (2001) The expression of basic fibroblast growth factor and vascular endothelial growth factor in prostatic adenocarcinoma: correlation with neovascularization. Anticancer Res 21:77–88
Udayakumar TS, Klein RD, Maliner MS, Nagle RB, Bowden GT (2001) Aberrant expression of fibroblast growth factor receptor-1 in prostate epithelial cells allows induction of promatrilysin expression by fibroblast growth factors. Int J Cancer 91:187–192
Valve EM, Nevalainen MT, Nurmi MJ, Laato MK, Martikainen PM, Harkonen PL (2001) Increased expression of FGF-8 isoforms and FGF receptors in human premalignant prostatic intraepithelial neoplasia lesions and prostate cancer. Lab Invest 81:815–826
Vartanian RK, Weidner N (1994) Correlation of intratumoral endothelial cell proliferation with microvessel density (tumor angiogenesis) and tumor cell proliferation in breast carcinoma. Am J Pathol 144:1188–1194
Vartanian RK, Weidner N (1995) Endothelial cell proliferation in prostatic carcinoma and prostatic hyperplasia: correlation with Gleason's score, microvessel density, and epithelial cell proliferation. Lab Invest 73:844–850
Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med 324:1–8
Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J (1993) Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143:401–409
Werner S, Duan DS, de Vries C, Peters KG, Johnson DE, Williams LT (1992) Differential splicing in the extracellular region of fibroblast growth factor receptor 1 generates receptor variants with different ligand-binding specificities. Mol Cell Biol 12:82–88
Acknowledgements
The authors would like to thank Dr. med. Oddbjørn Straume, Mrs. Karen Bøhm-Nilsen, Mrs. Gerd Lillian Hallseth, Mr. Bendik Nordanger, and Mrs. Grethe Waaler for excellent technical assistance.
The experiments comply with the current laws of the country (Norway) in which they were performed.
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Gravdal, K., Halvorsen, O.J., Haukaas, S.A. et al. Expression of bFGF/FGFR-1 and vascular proliferation related to clinicopathologic features and tumor progress in localized prostate cancer. Virchows Arch 448, 68–74 (2006). https://doi.org/10.1007/s00428-005-0075-3
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DOI: https://doi.org/10.1007/s00428-005-0075-3