Summary
Growth of the prostate is controlled by androgen. However, there is information indicating that androgen may not act directly, but may act indirectly through polypeptide growth factors, to control prostate growth. This review will focus on the involvement of members of the fibroblast growth factor (FGF) family in this process. The properties of FGFs and FGF-receptors are described that implicate these molecules in growth control. Information is provided that prostate stromal cells synthesize FGF2 and FGF7. FGF2 is a potent mitogen for stromal cells; whereas, FGF7 is exclusively a mitogen for epithelial cells. Transforming growth factor beta (TGFβ), also produced by prostate cells, inhibit cell growth. This suggests that prostate growth is controlled by autocrine and paracrine mechanisms. Evidence is presented that altered FGF expression accompanies benign prostatic hyperplasia and prostate cancer. A model is proposed whereby androgen regulates TGFβ, influencing FGF2 and FGF7 expression, and in turn regulating growth of the prostatic stroma and epithelium. An imbalance in the influence of these growth factors may contribute to prostate disease.
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Alarid ET, Rubin JS, Young P, Chedid M, Ron D, Aaronson SA, Cunha GR (1994) Keratinocyte growth factor functions in epithelial induction during seminal vesicle development. Proc Natl Acad Sci USA 91:1074–1078
Bacher M, Rausch U, Goebel H-W, Polzar B, Mannherz HG, Aumuller G (1993) Stromal and epithelial cells from rat ventral prostate during androgen deprivation and estrogen treatment-regulation of transcription. Exp Clin Endocrinol 101:78–86
Baird A, Bohlen P (1990) Fibroblast growth factor. In: Sporn MB, Roberts AB (eds) Peptide growth factors and their receptors, vol I. Springer, Berlin Heidelberg New York, pp 369–418
Baird A, Ling N (1987) Fibroblast growth factors are present in the extracellular matrix produced by endothelial cells in vitro: implications for a role of heparinase-like enzymes in the neovascular response. Biochem Biophys Res Commun 142:428–435
Bartsch G, Muller HR, Oberholzer M, Rohr HP (1979) Light microscopic stereological analysis of the normal human prostate and of benign prostatic hyperplasia. J Urol 122:487–491
Begun FP, Story MT, Hopp KA, Shapiro E, Lawson RK (1995) Regional concentration of basic fibroblast growth factor in normal and benign hyperplastic human prostates. J Urol 153:839–843
Bellot F, Crumley G, Kaplow JM, Schlessinger J, Jaye M, Dionne CA (1991) Ligand-induced transphosphorylation between different FGF receptors. EMBO J 10:2849–2854
Benharroch D, Birnbaum D (1990) Biology of the fibroblast growth factor gene family. Isr J Med Sci 26:212–219
Burgess WH, Maciag T (1989) The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem 58:575–606
Chellaiah AT, McEwen DG, Werner S, Xu J, Ornitz DM (1994) Fibroblast growth factor receptor (FGFR) 3. J Biol Chem 269: 11 620–11 627
Chung LWK (1993) Implications of stromal-epithelial interaction in human prostate cancer growth, progression and differentiation. Semin Cancer Biol 4:183–192
Chung LWK, Gleave ME, Hsieh J-T, Hong S-J, Zhau HE (1991) Reciprocal mesenchymal-epithelial interaction affecting prostate tumour growth and hormonal responsiveness. Cancer Surv 11:91–121
Chung LWK, Li W, Gleave ME, Hsieh J-T, Wu H-C, Sikes RA, Zhau HE, Bandy KMG, Logothetis CJ, Rubin JS, Eschenbach AC von (1992) Human prostate cancer model: roles of growth factors and extracellular matrices. J Cell Biochem 16H (Suppl):99–105
Clements DA, Wang J-K, Dionne CA, Goldfarb M (1993) Activation of fibroblast growth factor (FGF) receptors by recombinant human FGF-5. Oncogene 8:1311–1316
Crabb JW, Armes LG, Carr SA, Johnson CM, Roberts GD, Bordoli RS, McKeehan WL (1986) Complete primary structure of prostatropin, a prostate epithelial cell growth factor. Biochemistry 25:4988–4993
Cunha GR (1984) Androgenic effects upon prostatic epithelium via trophic influences from stroma. In: Kimball FA, Buhl AF, Carter DB (eds) New approaches to the study of benign prostatic hyperplasia. Alan R. Liss, New York, pp 81–102
Cunha GR, Chung LWK (1981) Stromal-epithelial interactions. I. Induction of prostatic phenotype in urothelium of testicular feminized (TFm/y) mice. J Steroid Biochem 14:1317–1321
Cunha GA, Hayashi N, Wong YC (1991) Regulation of differentiation and growth of normal adult and neoplastic epithelia by inductive mesenchyme. Cancer Surv 11:73–90
D'Amore PA (1990) Modes of FGF release in vivo and in vitro. Cancer Metastasis Rev 9:227–238
Dionne CA, Crumley G, Bellot F, Kaplow JM, Searfoss G, Ruta M, Burgess WH, Jaye M, Schlessinger J (1990) Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors. EMBO J 9:2685–2692
Finch PW, Rubin JS, Miki T, Ron D, Aaronson SA (1989) Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science 245:752–755
Gabrilove JL, Levine AC, Kirgchenbaum A, Droller M (1989) Effect of long-acting gonadotropin-releasing hormone analog (Leuprolide) therapy on prostate size and symptoms in 15 men with benign prostatic hyperplasia. J Clin Endocrinol Metab 69:629
Geller J, Sionit LR, Baird A, Kohls M, Connors KM, Hoffman RM (1994) In vivo and in vitro effects of androgen on fibroblast growth factor-2 concentrations in the human prostate. Prostate 25:206–209
Givol D, Yayon A (1992) Complexity of FGF receptors: genetic basis for structural diversity and functional specificity. FASEB J 6:3362–3369
Gleave ME, Hsieh JT, Eschenbach AC von, Chung LWK (1992) Prostate and bone fibroblasts induce human prostate cancer growth in vivo: implications for bidirectional tumorstromal cell interaction in prostate carcinoma growth and metastasis. J Urol 147:1151–1159
Gospodarowicz D (1990) Fibroblast growth factor and its involvement in developmental processes. Curr Top Dev Biol 24:57–93
Guimond S, Maccarana M, Olwin BB, Lindahl U, Rapraeger AC (1993) Activating and inhibitory heparin sequences for FGF-2 (basic FGF). Distinct requirements for FGF-1, FGF-2, and FGF-4. J Biol Chem 268:23906–23914
Hall JA, Harris MA, Intres R, Harris SE (1993) Acidic fibroblast growth factor gene 5′ non-coding exon and flanking region from hamster DDT1 cells: identification of the promoter region and transcriptional regulation by testosterone and aFGF protein. J Cell Biochem 51:116–127
Harris SE, Rong ZX, Hall JA, Harris MA, Norris J, Smith RG, Lubahn DB, Wilson EM, French FS (1992) Androgen regulation of growth factor and early growth response gene expression in hamster DDT1-MF2 and human prostate LNCAP cells. In: Li JJ, et al. (eds) Hormonal carcinogenesis. Springer, Berlin Heidelberg New York, pp 182–192
Hattori Y, Odagiri H, Nakatani H, Miyagawa K, Naito K, Sakamoto H, Katoh O, Yoshida T, Sugimura T, Terada M (1990) K-sam, an amplified gene in stomach cancer, is a member of the heparin-binding growth factor receptor genes. Proc Natl Acad Sci USA 87:5983–5987
Hebert JM, Basilico C, Goldfarb M, Haub O, Martin G (1990) Isolation of cDNAs encoding four mouse FGF family members and characterization of their expression patterns during embryogenesis. Dev Biol 138:454–463
Jacobs SC, Pikna D, Lawson RK (1979) Prostatic osteoblastic factor. Invest Urol 17:195–198
Jacobs SC, Story MT, Sasse J, Lawson RK (1988) Characterization of growth factors derived from the rat ventral prostate. J Urol 139:1106–1110
Jans DA (1994) Nuclear signaling pathways for polypeptide ligands and their membrane receptors? FASEB J 8:841–847
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, Williams LT (1993) Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res 60:1–41
Kasayama S, Sumitani S, Tanaka A, Yamanishi H, Nakamura N, Matsumoto K, Sato B (1991) Heparin inhibits autocrine stimulation but not fibroblast growth factor stimulation of cell proliferation of androgen-responsive Shionogi carcinoma 115. J Cell Physiol 148:260–266
Katz AE, Benson MC, Wise GW, Olsson CA, Bandyk MG, Sawczuk IS, Tomashefsky P, Buttyan R (1989) Gene activity during the early phase of androgen-stimulated rat prostate regrowth. Cancer Res 49:5889–5894
Klagsbrun M (1989) The fibroblast growth factor family: structural and biological properties. Prog Growth Factor Res 1:207–235
Kyprianou N, Isaacs JT (1988) Identification of a cellular receptor for transforming growth factor beta in rat ventral prostate and its negative regulation by androgens. Endocrinology 123:2124–2131
Kyprianou N, Isaacs JT (1989) Expression of transforming growth factor beta in the rat ventral prostate during castration-induced programmed cell death. Mol Endocrinol 3:1515–1522
Lahtonen R, Bolton NJ, Konturri M, Vihko R (1982) Nuclear androgen receptors in the epithelium and stroma of human benign prostatic hypertrophic glands. Prostate 4:129–139
Mannson P-E, Adams P, Kan M, McKeehan WL (1989) Heparin-binding growth factor gene expression and receptor characteristics in normal rat prostate and two transplantable rat prostate tumors. Cancer Res 49:2485–2494
McKeehan WL (1991) Growth factor receptors and prostate cell growth. Cancer Surv 11:165–175
McKeehan WL, Adams PS, Rosser MP (1984) Direct mitogenic effects of insulin, epidermal growth factor, glucocorticoid, cholera toxin, unknown pituitary factors, and possibly prolactin, but not androgen, on normal rat prostate epithelial cells in serum-free, primary cell culture. Cancer Res 44:1998–2010
McKeehan WL, Kan M, Hou J, Wang F, Adams P, Mansson P-E (1991) Heparin-binding (fibroblast) growth factor/receptor gene expression in the prostate. In: Karr JP, Coffey DS, Smith RG, Tindall DJ (eds) Molecular and cellular biology of prostate cancer. Plenum, New York, pp 115–126
McKeehan WL, Hou J, Adams P, Wang F, Yan G-C, Kan M (1993) Heparin-binding fibroblast growth factors and prostate cancer. In: Yang SS, Warner HR (eds) The underlying molecular, cellular, and immunological factors in cancer and aging. Plenum, New York, pp 203–213
McNeal JE (1984) Anatomy of the prostate and morphogenesis of BPH. In: Kimball FA, Buhl AF, Carter DB (eds) New approaches to the study of benign prostatic hyperplasia. Alan R. Liss, New York, pp 27–53
Miki T, Bottaro DP, Fleming TP, Smith CL, Burgess WH, Chan AM-L, Aaronson SA (1992) Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene. Proc Natl Acad Sci USA 89:246–250
Miyamoto M, Naruo K-I, Seko C, Matsumoto S, Kondo T, Kurokawa T (1993) Molecular cloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property. Mol Cell Biol 13:4251–4259
Mori H, Maki M, Oishi K, Jaye M, Igarashi K, Yoshida O, Hatanaka M (1990) Increased expression of genes for basic fibroblast growth factor and transforming growth factor type 2 in human benign prostatic hyperplasia. Prostate 16:71–80
Mydlo JH, Bulbul MA, Richon VM, Heston WDW, Fair WR (1988) Heparin-binding growth factor isolated from human prostate extracts. Prostate 12:243–255
Nakamoto T, Chang CS, Li AK, Chodak GW (1992) Basic fibroblast growth factor in human prostate cancer cells. Cancer Res 52:571–577
Nakanishi Y, Kihara K, Mizuno K, Masamune Y, Yoshitake Y, Nishikawa K (1992) Direct effect of basic fibroblast growth factor on gene transcription in a cell-free system. Proc Natl Acad Sci USA 89:5216–5220
Nishi N, Matuo Y, Kunitomi K, Takenaka I, Usami M, Kotake T, Wada F (1988) Comparative analysis of growth factors in normal and pathologic human prostate. Prostate 13:39–48
Noda M, Vogel R (1989) Fibroblast growth factor enhances type β1 transforming growth factor gene expression in osteoblast-like cells. J Cell Biol 109:2529–2535
Nonomura N, Lu J, Tanaka A, Yamanishi H, Sato B, Sonoda T, Matsumoto K (1990) Interaction of androgen-induced autocrine heparin-binding growth factor with fibroblast growth factor receptor on androgen-dependent Shionogi carcinoma 115 cells. Cancer Res 50:2316–2321
Ornitz DM, Yayon A, Flanagan JG, Svahn CM, Levi E, Leder P (1992) Heparin is required for cell-free binding of basic fibroblast growth factor to a soluble receptor and for mitogenesis in whole cells. Mol Cell Biol 12:240–247
Payson RA, Canatan H, Chotani MA, Wang WP, Harris SE, Myers RL, Chiu IM (1993) Cloning of two novel forms of human acidic fibroblast growth factor (aFGF) mRNA. Nucleic Acids Res 21:489–495
Peehl DM, Stamey TA (1986) Serum-free growth of adult human prostate epithelial cells. In Vito Cell Dev Biol 22:82–90
Peehl DM, Stamey TA, Rubin JS (1991) Fibroblast growth factors can replace epidermal growth factor for clonal proliferation of human prostate epithelial cells. J Urol 145:331A
Peters CA, Barrack ER (1987) Androgen receptor localization in the human prostate: demonstration of heterogeneity using a new method of steroid receptor autoradiography. J Steroid Biochem 27:533–541
Peters CA, Walsh PC (1987) The effect of nafarelin acetate, a luteinizing hormone-releasing hormone agonist, on benign prostatic hyperplasia. N Engl J Med 317:599–604
Roberts AB, Sporn MB (1990) The transforming growth factor-betas. In: Sporn MB, Roberts AB (eds) Handbook of experimental pharmacology, vol 95/1. Peptide growth factors and their receptors. Springer, Berlin Heidelberg New York, pp 419–472
Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, Maroteaux P, Le Merrer M, Munnich A (1994) Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371:252–254
Rubin JS, Osada H, Finch PW, Taylor WG, Rudikoff S, Aaronson SA (1989) Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci USA 86:802–806
Rusnati M, Coltrini D, Caccia P, Dell'era P, Zoppetti G, Oreste P, Valsasina B, Presta M (1994) Distinct role of 2-O-, N- and 6-O-sulfate groups of heparin in the formation of the ternary complex with basic fibroblast growth factor and soluble FGF receptor-1. Biochem Biophys Res Commun 203:450–458
Saito H, Kouhara H, Harada T, Miyake S, Sugiyama H, Kishimoto T, Sato B (1994) Mapping of a transcription element critical for expression of the fibroblast growth factor receptor 1 gene. Biochem Biophys Res Commun 198:1020–1026
Schroeder FH, Wasterhof M, Bosch RJLH, Kurth KH (1986) Benign prostatic hyperplasia treated by castration or the LH-RH analogue buserelin: a report on 6 cases. Eur Urol 12:318–321
Shain SA, Ke LD, Wong G, Karaganis AG (1992) Rat prostate cancer cell line-specific production and apparent secretion of heparin-binding growth factors. Cell Growth Differ 3:249–258
Shapiro E, Becich MJ, Hartanto V, Lepor H (1992) The relative proportion of stromal and epithelial hyperplasia is related to the development of symptomatic benign prostate hyperplasia. J Urol 147:1293–1297
Sherwood ER, Fong C-J, Lee C, Kozlowski JM (1992) Basic fibroblast growth factor: a potential mediator of stromal growth in the human prostate. Endocrinology 130:2955–2963
Steiner MS (1993) Role of peptide growth factors in the prostate: a review. Urology 42:99–110
Story MT (1991) Polypeptide modulators of prostatic growth and development. Cancer Surv 11:123–146
Story MT (1991) Fibroblast growth factor: implications in the etiology of benign prostatic hyperplasia. In: Karr JP, Coffey DS, Smith RG, Tindall DJ (eds) Molecular and cellular biology of prostate cancer. Plenum, New York, pp 81–90
Story MT (1994) Positive and negative modulators of prostate cell proliferation. Biomed Pharmacother 48 [Suppl 1]:355–415
Story MT, Esch F, Shimasaki S, Sasse J, Jacobs SC, Lawson RK (1987) Amino-terminal sequence of a large form of basic fibroblast growth factor isolated from human benign prostatic hyperplastic tissue. Biochem Biophys Res Commun 142:702–709
Story MT, Sasse J, Jacobs SC, Lawson RK (1987) Prostatic growth factor: purification and structural relationship to basic fibroblast growth factor. Biochemistry 26:3843–3849
Story MT, Livingston B, Baeten L, Swartz SJ, Jacobs SC, Begun FP, Lawson RK (1989) Cultured human prostate-derived fibroblasts produce a factor that stimulates their growth with properties indistinguishable from basic fibroblast growth factor. Prostate 15:355–365
Story MT, Hopp KA, Meier DA, Begun FP, Lawson RK (1993) Influence of transforming growth factor β1 and other growth factors on basic fibroblast growth factor level and proliferation of cultured human prostate-derived fibroblasts. Prostate 22:183–197
Story MT, Hopp KA, Molter M, Meier DA (1994) Characteristics of FGF-receptors expressed by stromal and epithelial cells cultured from normal and hyperplastic prostates. Growth Factors 10:269–280
Story MT, Hopp KA, Meier DA (1995) Regulation of basic fibroblast growth factor expression by transforming growth factor beta in cultured human prostate stromal cells. Prostate (in press)
Story MT, Hopp KA, Molter M (1995) Keratinocyte growth factor mRNA expression by cultured prostate stromal cells is down-regulated by transforming growth factor beta. J Urol 153:343A
Sugimura Y, Cunha GR, Hayword S, Hayashi N, Arima K, Kawamura J, Rubin JS, Aaronson SA, Mie T (1994) Keratinocyte growth factor (KGF) is a mediator of testosterone induced prostatic development. J Urol 151:381A
Sumitani S, Kasayama S, Sato B (1993) A role for heparan sulfate in androgen-induced deoxyribonucleic acid synthesis of mouse mammary carcinoma (Shionogi carcinoma 115)-derived SC-3 cells. Endocrinology 132:1199–1206
Tanaka A, Miyamoto K, Minamino N, Tekeda M, Sato B, Matsuo H, Matsumoto K (1992) Cloning and characterization of an androgen-induced growth factor essential for the androgen-dependent growth of mous mammary carcinoma cells. Proc Natl Acad Sci USA 89:8928–8932
Thompson TC (1990) Growth factors and oncogenes in prostate cancer. Cancer Cells 2:345–354
Ueno H, Gunn M, Dell K, Tseng A, Williams LT (1992) A truncated form of fibroblast growth factor receptor 1 inhibits signal transduction by multiple types of fibroblast growth factor receptor. J Biol Chem 267:1397–1406
Ueno H, Escobedo J, Williams LT (1993) Dominant-negative mutations of platelet-derived growth factor (PDGF) receptors. Inhibition of receptor function by ligand-dependent formation of heterodimers between PDGF alpha- and beta-receptors. J Biol Chem 268:22814–22819
Vainikka S, Partanen J, Bellosta P, Coulier F, Basilico C, Jaye M, Alitalo K (1992) Fibroblast growth factor receptor-4 shows novel features in genomic structure, ligand binding and signal transduction. EMBO J 11:4273–4280
Vlodavsky I, Bar-Shavit R, Ishai-Michaeli R, Bashkin P, Fuks Z (1991) Extracellular sequestration and release of fibroblast growth factor: a regulatory mechanism? Trends Biochem Sci 16:268–271
Ware JL (1993) Growth factors and their receptors as determinants in the proliferation and metastasis of human prostate cancer. Cancer Metastasis Rev 12:287–301
Werner S, Duan D-SR, Vries C de, 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
Werner S, Smola H, Liao X, Longaker MT, Krieg T, Hofschneider PH, Williams LT (1994) The function of KGF in morphogenesis of epithelium and reepithelialization of wounds. Science 266:819–822
Yan G, Fukabori Y, Nikolaropoulous S, Wang F, McKeehan WL (1992) Heparin-binding keratinocyte growth factor is a candidate stromal to epithelial cell andromedin. Mol Endocrinol 6:2123–2128
Yan G, Fukabori Y, McBride G, Nikolaropolous S, McKeehan WL (1993) Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy. Mol Cell Biol 13:4513–4522
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Story, M.T. Regulation of prostate growth by fibroblast growth factors. World J Urol 13, 297–305 (1995). https://doi.org/10.1007/BF00185973
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DOI: https://doi.org/10.1007/BF00185973