Skip to main content
SpringerLink
Log in

Epidermal growth factor-related peptides and the epidermal growth factor receptor in normal and malignant prostate

  • Published:
World Journal of Urology Aims and scope Submit manuscript

Summary

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGFα) are two closely related peptides that interact with cell-surface epidermal growth factor receptors (EGFR) to induce receptor tyrosine phosphorylation and activation of intracellular signal-transduction pathways. EGF appears to be the predominant EGF-related growth factor in the normal prostate and in benign prostatic hyperplasia (BPH). Evidence indicates that EGF and TGFα are important for maintainence of the structural and functional integrity of the benign prostatic epithelium. The EGF-related peptides are primarily localized to the secretory epithelium of the benign prostate, and their production and secretion is augmented by the presence of circulating androgens. EGFR are located in the basal/neuroendocrine (NE) compartment of the benign prostate and exhibit relatively androgen-independent expression. The EGF-related peptides and EGFR are also present in neoplastic prostatic tissues. There is currently no direct evidence to implicate EGFR activation in the pathogenesis of BPH. However, the EGF-related peptides appear to play a functional role in the growth of prostatic carcinoma cells, with TGFα being the predominant growth factor. Numerous investigators have demonstrated the functional significance of a TGFα/EGFR-mediated autocrine growth pathway in cultured prostatic carcinoma cells. Studies of cultured prostate cancer cells, but not normal epithelial cells, demonstrate constitutive activation of EGFR. Androgen-independent cancer cells exhibit more EGFR expression and phosphorylation than do androgen-responsive prostate cancer cells. Most studies indicate that EGFR do not play a functional role in androgen-stimulated growth of prostate cancer cells. Several studies have correlated EGFR expression with increased nuclear size and tumor dedifferentiation. Future studies should focus on determining both the prognostic significance of EGFR expression and whether manipulation of EGFR-mediated growth can be exploited for therapeutic benefit in human prostate cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Aaronson S (1992) Growth factors and cancer. Science 254:1146–1153

    Google Scholar 

  2. Ching K, Ramsey E, Pettigrew N, D'Cunha R, Jason M, Dodd J (1993) Expression of mRNA for EGF, TGFα and their receptor in human prostate tissue and cell lines. Mol Cell Biochem 126:151–158

    Google Scholar 

  3. Connolly J, Rose D (1990) Production of epidermal growth factor and TGFα by the androgen-responsive LNCaP human prostate cancer cell line. Prostate 16:209–218

    Google Scholar 

  4. Connolly J, Rose D (1991) Autocrine regulation of DU145 human prostate cancer cell growth by EGF-related peptides. Prostate 19:173–180

    Google Scholar 

  5. Davies P, Eaton C (1989) Binding of EGF by human normal, hypertrophic and carcinomatous prostate. Prostate 14:123–132

    Google Scholar 

  6. Derynck R (1992) The physiology of TGF alpha. Adv Cancer Res 58:27–52

    Google Scholar 

  7. Elson S, Browne C, Thornburn G (1984) Identification of EGF-like activity in human male reproductive tissues and fluids. J Clin Endocrinol Metab 58:589–594

    Google Scholar 

  8. Fantl W, Escobedo J, Martin G, Turck C, Rosario M del, McCormick F, Williams L (1992) Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signalling pathways. Cell 69:413–423

    Google Scholar 

  9. Fong C, Sherwood E, Sutkowski D, Abu-Jawdeh G, Yokoo H, Bauer K, Kozlowski J, Lee C (1991) Reconstituted basement membrane promotes morphological and functional differentiation of primary human prostatic epithelial cells. Prostate 19:221–235

    Google Scholar 

  10. Fong C, Sherwood E, Braun E, Berg L, Lee C, Kozlowski J (1992) Regulation of prostatic carcinoma cell proliferation and secretory activity by extracellular matrix and stromal secretions. Prostate 21:121–131

    Google Scholar 

  11. Fong C, Sherwood E, Mendelsohn J, Lee C, Kozlowski J (1992) Epidermal growth factor monoclonal antibody inhibits constitutive receptor phosphorylation, reduces autonomous growth and sensitizes androgen-independent prostatic carcinoma cells to tumor necrosis factor α. Cancer Res 52:5887–5892

    Google Scholar 

  12. Fowler J, Lau J, Ghosh L, Mills S, Mounzer A (1988) EGF and prostatic carcinoma: an immunohistochemical study. J Urol 139:857–861

    Google Scholar 

  13. Fuse H, Sakamoto M, Okumura M, Matayama T (1992) EGF contents in seminal plasma as a marker of prostatic function. Arch Androl 29:79–85

    Google Scholar 

  14. Gray A, Dull T, Ullrich A (1983) Nucleotide sequence of EGF cDNA predicts a 128,000 molecular weight protein precursor. Nature 303:722–725

    Google Scholar 

  15. Grayhack JT, Kozlowski JM (1991) Benign prostatic hyperplasia. In: Gillenwater J, Grayhack J, Howards S, Duckett J (eds) Adult and pediatric urology. Yearbook, Chicago, pp 1211–1276

    Google Scholar 

  16. Goustin A, Leof A, Shipley G, Moses H (1986) Growth factors and cancer. Cancer Res 46:1105–1129

    Google Scholar 

  17. Harper M, Goddard L, Glynne-Jones E, Wilson D, Price-Thomas M, Peeling W, Griffiths K (1993) An immunocytochemical analysis of TGFα expression in benign and malignant prostate tumors. Prostate 23:9–23

    Google Scholar 

  18. Henttu M, Vihko P (1993) Growth factor regulation of gene expression in the human prostate cancer cell line LNCaP. Cancer Res 53:1051–1058

    Google Scholar 

  19. Hiramatsu M, Kashimata M, Minami N, Sato A, Muragama M, Minami N (1988) Androgenic regulation of EGF in the mouse ventral prostate. Biochem Int 17:311–317

    Google Scholar 

  20. Hofer D, Sherwood E, Bromberg W, Mendelsohn J, Lee C, Kozlowski J (1991) Autonomous growth of androgen-independent prostatic carcinoma cells: role of TGFα. Cancer Res 51:2780–2785

    CAS  PubMed  Google Scholar 

  21. Ibrahim G, Kerns B, MacDonald J, Ibrahim S, Kinney R, Humphrey P, Robertson C (1993) Differential immunoreactivity of EGFR in benign, dysplastic and malignant prostate tissue. J Urol 149:170–173

    Google Scholar 

  22. Iwamura M, Sant'agnese P di, Wu G, Benning C, Cockett A, Gershagen S (1994) Overexpression of human EGFR and c-erbB2 by neuroepithelial cells in normal prostatic tissues. Urology 43:838–843

    Google Scholar 

  23. Jacobs S, Story M (1988) Exocrine secretion of EGF by the rat prostate: effect of adrenergic agents, cholinergic agents and vasoactive intestinal polypeptide. Prostate 13:79–87

    Google Scholar 

  24. Jarrard D, Blitz B, Smith R, Patai B, Rukstalis D (1994) Effect of EGF on prostate cancer cell line PC3 growth and invasion. Prostate 24:46–53

    Google Scholar 

  25. Jones E, Harper M (1992) Studies on the proliferation, secretory activities and EGFR expression in BPH explant cultures. Prostate 20:133–149

    Google Scholar 

  26. Koenders P, Beex L, Kienhuis C, Kloppenborg P, Benraad T (1992) EGFR and prognosis in human breast cancer: a prospective study. Breast Cancer Res Treat 23:134–145

    Google Scholar 

  27. Kozlowski JM, Grayhack JT (1991) Carcinoma of the prostate. In: Gillenwater J, Grayhack J, Howards S, Duckett J (eds) Adult and pediatric urology. Yearbook, Chicago, pp 1277–1393

    Google Scholar 

  28. Lee C, Sensibar J, Dudek S, Hiipakka R, Liao S (1990) Prostatic ductal system in rats: regional variation in morphological and functional activities. Biol Reprod 43:1079–1086

    Google Scholar 

  29. Leevers S, Patterson H, Marshall C (1994) Requirement of ras for raf activation is overcome by targeting raf to the plasma membrane. Nature 369:411–414

    Google Scholar 

  30. Levine A, Ren M, Huber G, Kirschenbaum A (1992) The effect of androgen, estrogen and growth factors on the proliferation of cultured fibroblasts from fetal and adult human prostates. Endocrinology 130:2413–2419

    Google Scholar 

  31. Liu A, Davis R, Flores C, Menan M, Seethalakskim L (1992) Epidermal growth factor receptor binding and effects on the sex accessory organs of sexually mature male mice. J Urol 148:427–431

    Google Scholar 

  32. Liu X, Wiley S, Meikle A (1993) Androgens regulate proliferation of human prostate cancer cells in culture by increasing TGF and EGFR. J Clin Endocrinol Metab 77:1472–1478

    Google Scholar 

  33. Lloyd S, McClinton S, Brown I, Miller I, Kirk D, Eremin D, Moffat L, Leake R (1990) EGFR, nuclear proliferation antigen and IL-2 receptor expression in prostatic cancer. J Clin Lab Immunol 32:55–58

    Google Scholar 

  34. MacDonald A, Habib F (1992) Divergent responses to EGF in hormone sensitive and insensitive human prostate cancer cell lines. Br J Cancer 65:177–182

    Google Scholar 

  35. MacDonald A, Chisholm G, Habib F (1990) Production and response of a human prostate cancer cell line to transforming growth factor-like molecules. Br J Cancer 62:579–584

    Google Scholar 

  36. Masui H, Kawamoto T, Sato J, Wolf B, Sato G, Mendelsohn J (1984) Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 44:1002–1007

    Google Scholar 

  37. Maygarden S, Strom S, Ware J (1992) Localization of EGFR by immunohistochemical methods in human prostatic carcinoma, prostatic intraepithelial neoplasia and benign hyperplasia. Arch Pathol Lab Med 116:269–273

    Google Scholar 

  38. Montone K, Tomaszewski J (1993) In situ hybridization for EGFR external domain transcripts in prostatic adenocarcinoma. J Clin Lab Anal 7:188–195

    Google Scholar 

  39. Moodie S, Willumsen B, Weber W, Wolfman A (1993) Complexes of ras-GTP with raf-1 and mitogen-activated protein kinase. Science 260:1658–1661

    Google Scholar 

  40. Morris G, Dodd J (1990) EGFR mRNA levels in human prostate tumors and cell lines. J Urol 143:1272–1274

    Google Scholar 

  41. Myers R, Kudlow J, Grizzle W (1993) Expression of TGFα, EGF and EGFR in adenocarcinoma of the prostate and BPH. Mod Pathol 6:733–737

    Google Scholar 

  42. Nicholson S, Halcrow P, Sainsbury J, Angus B, Chambers P, Farndon J, Harris A (1988) EGFR status associated with failure of primary endocrine therapy in elderly postmenopausal patients with breast cancer. Br J Cancer 58:810–814

    Google Scholar 

  43. Nishi N, Matuo Y, Nakamoto T, Wada F (1988) Proliferation of epithelial cells derived from rat dorsolateral prostate in serum-free primary cell culture and their response to androgen. In Vitro Cell Dev Biol 24:778–786

    Google Scholar 

  44. Nishi N, Shimizu C, Okutsu Y, Kogawa Y, Takasuya H, Suno M, Wada F (1991) Rat prostatic growth factors: purification and characterization of high and low molecular weight EGFs from rat dorsolateral prostate. Biochim Biophys Acta 1095:268–275

    Google Scholar 

  45. Normanno N, Ciardello F, Brandt R, Saloman D (1994) EGF-related peptides in the pathogenesis of breast cancer. Breast Cancer Res Treat 29:11–27

    Google Scholar 

  46. Pawson T, Gish G (1992) SH2 and SH3 domains: from structure to function. Cell 71:359–362

    Google Scholar 

  47. Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I, Grignani F, Pawson T, Pelicci P (1992) A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 70:93–104

    Google Scholar 

  48. Reddy K, Mangold G, Tandon A, Yoneda T, Mundy G, Zilberstein A, Osborne C (1992) Inhibition of breast cancer cell growth in vitro by a tyrosine kinase inhibitor. Cancer Res 52:3636–3641

    Google Scholar 

  49. Rozackis-Adcock M, Fernley R, Wade J, Pawson T, Bowtell D (1993) The SH2 and SH3 domains of mammalian Grb2 couple the EGFR to the ras activator Sos-1. Science 363:83–85

    Google Scholar 

  50. St Arnaud R, Poyet P, Walker P, Labrie F (1988) Androgens modulate EGFR levels in the rat ventral prostate. Mol Cell Endocrinol 56:21–27

    Google Scholar 

  51. Saloman D, Kim N, Saeki T, Ciardello F (1990) Transforming growth factor alpha: an oncodevelopmental growth factor. Cancer Cells 2:389–397

    Google Scholar 

  52. Scott J, Urden M, Quiroga M, Sanchez-Pescodor R, Fong N, Selby M, Ruther W, Bell G (1983) Structure of mouse submaxillary messenger RNA encoding EGF and seven related proteins. Science 221:236–240

    Google Scholar 

  53. Seynaeve C, Stetler-Stevenson M, Sebers S, Kaur G, Sausville E, Worland P (1993) Cell cycle arrest and growth inhibition by the protein tyrosine kinase antagonist UCN-01 in human breast carcinoma cells. Cancer Res 53:2081–2086

    Google Scholar 

  54. Sherwood E, Berg L, McEwan R, Pasciak R, Kozlowski J, Lee C (1989) Two-dimensional protein profiles of cultured epithelial and stromal cells from hyperplastic human prostate. J Cell Biochem 40:201–214

    Google Scholar 

  55. Sherwood E, Berg L, Mitchell N, McNeal J, Kozlowski J, Lee C (1990) Differential cytokeratin expression in normal, hyperplastic and malignant epithelial cells from human prostate. J Urol 143:167–171

    Google Scholar 

  56. Sherwood E, Theyer G, Steiner G, Berg L, Kozlowski J, Lee C (1991) Differential expression of specific cytokeratin polypeptides in the basal and luminal epithelia of the human prostate. Prostate 18:303–314

    Google Scholar 

  57. Reference deleted

  58. Sutkowski D, Fong C, Sensibar J, Rademaker A, Sherwood E, Kozlowski J, Lee C (1992) Interaction of EGF and TGFβ in human prostate epithelial cells in culture. Prostate 21:133–145

    Google Scholar 

  59. Taylor T, Ramsdell J (1993) TGF alpha and its receptor are expressed in the epithelium of the rat prostate gland. Endocrinology 133:1306–1311

    Google Scholar 

  60. Tillotson J, Rose D (1991) Endogenous secretion of EGF peptides stimulates growth of DU145 prostate cancer cells. Cancer Lett 60:109–112

    Google Scholar 

  61. Ullrich A, Coussens L, Hayflick Y, Liberman T, Schlessinger J, Downsward J, Mayer E, Whittle N, Waterfield M, Seeburg P (1984) Human EGF cDNA sequences and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309:418–425

    CAS  PubMed  Google Scholar 

  62. Wilding G, Valverius E, Knabbe C, Gelmann E (1989) Role of TGF in human prostate cancer cell growth. Prostate 15:1–12

    Google Scholar 

  63. Wong S, Winchell L, McCune B, Earp H, Teixido J, Massaque J, Herman B, Lee D (1989) The TGF alpha precursor expressed on the cell surface binds to the domains: elements that control interactions of cytoplasmic signalling proteins. Science 252:668–678

    Google Scholar 

  64. Wu H, Kawamata H, Kawai K, Lee C, Oyasu R (1993) Immunohistochemical localization of EGF and TGFα in the male rat accessory sex organs. J Urol 150:990–993

    Google Scholar 

  65. Yang Y, Chisholm G, Habib F (1993) EGF and TGF concentrations in BPH and cancer of the prostate: their relationship with tissue androgen levels. Br J Cancer 67:152–155

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Section of Hematology/Oncology and the Ben May Institute, University of Chicago Medical Center, 5841 South Maryland Avenue, 60637, Chicago, IL, USA

    E. R. Sherwood

  2. Department of Urology, Northwestern University Medical School, 303 East Chicago Avenue, 60611, Chicago, IL, USA

    C. Lee

Authors
  1. E. R. Sherwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sherwood, E.R., Lee, C. Epidermal growth factor-related peptides and the epidermal growth factor receptor in normal and malignant prostate. World J Urol 13, 290–296 (1995). https://doi.org/10.1007/BF00185972

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00185972

Keywords

Search

Navigation