Neuroendocrine Prostate Research Summary Research on the prostatic neuroendocrine cell and neuroendocrine differentiation in prostate cancer began at URMC in the early 1980's when the field was in its infancy. Up to that time, only a few scattered case reports and a handful of more in depth studies had been published since the time that prostatic neuroendocrine cells were first described by Pretl in 1944. Our group was the first to describe the presence of several peptides in these cells including somatostatin, bombesin-like peptides, calcitonin and related peptides (calcitonin gene-related peptide and katacalcin), and parathyroid hormone-related peptide. The first detailed ultrastructural analysis of prostatic neuroendocrine cells and classification of the neurosecretory granule morphology was performed at the URMC. The foundations for a guinea pig model for prostatic neuroendocrine cells were developed here. We also performed quantitative analysis of serotonin and calcitonin in prostatic tissues. An isoform of the calcitonin receptor was localized to neuroendocrine cells and further characterized. More recently, the clinical significance of serum chromogranin levels in patients with prostatic carcinoma was evaluated. Peer Reviewed Articles Wu C, Huang J. Phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway is essential for neuroendocrine differentiation of prostate cancer. J Biol Chem. 2007 Feb 9;282(6):3571-83. Huang J, Yao JL, di Sant'Agnese PA, Yang Q, Bourne PA, Na Y. Immunohistochemical characterization of neuroendocrine cells in prostate cancer. Prostate. 2006 Sep 15;66(13):1399-406. Yao JL, Madeb R, Bourne P, Lei J, Yang X, Tickoo S, Liu Z, Tan D, Cheng L, Hatem F, Huang J, Anthony di Sant'Agnese P. Small cell carcinoma of the prostate: an immunohistochemical study. Am J Surg Pathol. 2006 Jun;30(6):705-12. Wu C, Zhang L, Bourne PA, Reeder JE, di Sant'Agnese PA, Yao JL, Na Y, Huang J. Protein tyrosine phosphatase PTP1B is involved in neuroendocrine differentiation of prostate cancer. Prostate. 2006 Aug 1;66(11):1125-35. Huang J, Yao JL, Zhang L, Bourne PA, Quinn AM, di Sant'Agnese PA, Reeder JE. Differential expression of interleukin-8 and its receptors in the neuroendocrine and non-neuroendocrine compartments of prostate cancer. Am J Pathol. 2005 Jun;166(6):1807-15. Xie S, Lin HK, Ni J, Yang L, Wang L, di Sant'Agnese PA, Chang C. Regulation of interleukin-6-mediated PI3K activation and neuroendocrine differentiation by androgen signaling in prostate cancer LNCaP cells. Prostate. 2004 Jun 15;60(1):61-7. Abrahamsson PA, Dizeyi N, Alm P, di Sant'Agnese PA, Deftos LI, Aumuller G: Calcitonin and calcitonin gene-related peptide in the human prostate gland. Prostate 44(3):181-6, 2000. Wu, MI, di Sant' Agnese PA, Deftos LJ, Cockett ATK, and Gershagen S: Characterization of the cell specific expression of parathyroid hormone-related protein in normal and neoplastic prostate tissue. Urology 51:110-20, 1998. Deftos LJ, Nakada,S, Burton DW, di Sant'Agnese PA, Cockett ATK, and Abrahamsson P-A: Immunoassay and immunohistology studies of chromogranin A as a neuroendocrine marker in patients with carcinoma of the prostate. Urology 48:58-62, 1996. Iwamura M, Gershagen S, Lapets O, Moynes R, Abrahamsson P-A, Cockett ATK, Deftos L, and di Sant'Agnese PA: Immunohistochemical localization of parathyroid hormone-related protein in prostatic intraepithelial neoplasia. Human Pathology 26:797-801, 1995. Iwamura M, di Sant'Agnese PA, Wu G, Benning C, Cockett ATK., and Gershagen S: Overexpression of human epidermal growth factor receptor and c-erbB-2 by neuroendocrine cells in normal prostatic tissue. Urology 43:838-843, 1994. Iwamura M, Wu G, Abrahamsson P-A, di Sant'Agnese PA, Cockett ATK, and Deftos L: Parathyroid hormone-related protein is expressed by prostatic neuroendocrine cells. Urology 43:667-673, 1994. Cockett ATK, di Sant' Agnese PA, Gopinath P, Schoen SR, and Abrahamsson P-A: Relationship of neuroendocrine cells of prostate and serotonin to benign prostatic hyperplasia. Urology 42:512-519, 1993. Nakada S, di Sant' Agnese PA, Moynes R, Hiipakka R, Liao S, Cockett ATK, and Abrahamsson P-A: The androgen receptor status of neuroendocrine cells in human benign and malignant tissue. Cancer Research 53:1967-1970, 1993. Iwamura M, di Sant' Agnese PA, Wu G, Benning CM, Cockett ATK, Deftos LJ, and Abrahamsson P-A: Immunohistochemical localization of parathyroid hormone-related protein in human prostate cancer. Cancer Research 53:1724-1726, 1993. Davis NS, di Sant' Agnese PA, Ewing JF, and Mooney RA: The neuroendocrine prostate I: Characterization and quantitation of calcitonin in the human gland. Journal of Urology 142:884-8, 1989. di Sant' Agnese PA and de Mesy Jensen, KL: Myelinoid bodies in endocrine-paracrine (neuroendocrine, APUD) cells of the prostatourethral region. Journal of Submicroscopic Cytology-Pathology 21:557-564, 1989. di Sant' Agnese PA, de Mesy Jensen KL, and Ackroyd RK: Calcitonin, katacalcin and calcitonin gene-related peptide in the human prostate: An immunocytochemical and immunoelectron microscopic study. Archives of Pathology and Laboratory Medicine 133:790-796, 1989. di Sant' Agnese PA, Davis NS, Chen M., and de Mesy Jensen KL: Age related changes in the neuroendocrine (endocrine-paracrine) cell population and the serotonin content of the guinea pig prostate. Laboratory Investigation 57:729-736, 1987. di Sant' Agnese PA and de Mesy Jensen KL: Endocrine-paracrine (APUD) cells of the human female urethra and paraurethral ducts. The Journal of Urology 137:1250-1254, 1987. di Sant' Agnese PA and de Mesy Jensen KL: Neuroendocrine Differentiation in Prostatic Carcinoma. Human Pathology 18:849-856, 1987. Note: Also Abstracted in 1989 Yearbook of Pathology and Clinical Pathology. Wu G, Burzon D, di Sant' Agnese PA, Schoen S, Deftos L, Gershagen S, and Cockett ATK: Calcitonin receptor and mRNA expression in the human prostate. Urology 47(3):376-381, 1996. di Sant'Agnese PA: Calcitonin-like and bombesin-like immunoreactive endocrine-paracrine cells of the human prostate. Archives of Pathology and Laboratory Medicine 110:412-415, 1986. di Sant' Agnese PA, de Mesy Jensen KL, Churukian CJ, and Agarwal MM: Human prostatic endocrine-paracrine (APUD) cells - distributional analysis with a comparison of serotonin and neuron-specific enolase immunoreactivity and silver stains. Archives of Pathology and Laboratory Medicine 109:607-612, 1985. di Sant' Agnese PA and de Mesy Jensen KL: Endocrine-paracrine cells of the prostate and prostatic urethra - An ultrastructural study. Human Pathology 15:1034-1041, 1984. di Sant'Agnese PA and de Mesy Jensen KL: Somatostatin and/or somatostatin-like immunoreactive endocrine - paracrine cells in the human prostate gland. Archives of Pathology and Laboratory Medicine 108:693-696, 1984. Reviews, Editorials, Position Papers Huang J, Yao JL, and di Sant'Agnese PA. Neuroendocrine Differentiation in Prostate Cancer. In: Prostate Cancer: Principles and Practice, edited by Roger Kirby, Alan Partin, Mark Feneley and J. Kellogg Parsons. Chapter 27, pp. 143-50. Taylor and Francis Medical Books, Abdington, UK (2006). Huang J, di Sant'Agnese PA: Neuroendocrine differentiation in prostate cancer: An overview. In Advances in Oncology: The Expanding Role of Octreotide. Ed. SWJ Lamberts. BioScientifica Ltd, Bristol, 2002. di Sant'Agnese PA: Neuroendocrine differentiation in Prostate Carcinoma: An update on Recent Developments. Annals of Oncology 12 (Suppl 2):S135-S140, 2001. di Sant'Agnese PA: Divergent Neuroendocrine Differentiation in Prostatic Cancer. Semininars in Diagnostic Pathology:17(2):149-61, 2000. Bartsch G, Klocker H, Ackermann R, di Sant'Agnese PA, et al: Translational Research areas and New Treatment Modalities in Prostate Cancer in Murphy G, Khoury S, Parton A, Denis L, editors (2nd WHO/UICC International Consultation on Prostate Cancer). Health publication Ltd., 2000. Griffiths K, Cockett ATK, Coffey D, di Sant' Agnese PA, Krieg M, Lee C, McKeehan W, Neal DE, Partin A, and Schalken J: Regulation of prostatic growth. In: 4th International Consultation on Benign Prostatic Hyperplasia (BPH). (Proceedings) Denis L, Griffiths K, Shoury S, Cockett ATK, McConnell J, Chatelain C, Murphy G, Yoshida O. Eds. Health Publication Ltd., 1998. Cockett ATK and di Sant' Agnese PA: Prognostic Significance of Neuroendocrine differentiation in clinically localized prostatic carcinoma. The Prostate. 8:37-42 [Suppl.], 1998. di Sant'Agnese PA: Neuroendocrine differentiation in prostatic carcinoma: An update. The Prostate 8:74-9 [Suppl.], 1998. di Sant'Agnese PA: Neuroendocrine cells of the prostate and neuroendocrine differentiation in prostatic carcinoma: A review of morphologic aspects. Urology. 51:121-24, 1998. di Sant'Agnese PA: The identification and pathologic significance of neuroendocrine differentiation in human prostatic carcinoma. Pathology of the Prostate. Vol. 34, Major Problems in Pathology, Chapter 20:352-63. C. Foster, D. Bostwick. W.B. Saunders Publishers, 1998. Algaba F, Böcking A, Bono A, Bostwick D, Busch, C, di Sant'Agnese PA, et al: Prognostic markers in acinar prostate cancer. First International Consultation in Prostate Cancer Proceedings. G. Murphy et al, Editors. Scientific Communication International Ltd. Publishers, 415-23, 1997. Griffiths K, Coffey D, Cockett A, di Sant'Agnese PA, et al. Regulation of Prostatic growth. In: Third International Consultation on Benign Prostatic Hyperplasia. Cockett A, Khoury S, Azo Y, et al (Eds). Scientific Communication International Ltd., 1996. di Sant'Agnese, PA: Neuroendocrine differentiation in the precursors of prostate cancer. In: Precursors of Prostatic Adenocarcinoma: Recent Findings and New Concepts. European Urology 30:185-190, 1996. di Sant'Agnese, PA: Endocrine aspects of the prostate. Bloodworths Endocrine Pathology, 3rd Edition. Lechago, J. and Gould, VE (Eds) Williams & Wilkins, Baltimore (1996). di Sant'Agnese PA: Neuroendocrine differentiation in prostate cancer. In: Comprehensive Textbook of Genitourinary Oncology. Vogelzang N., Shipley W., Scardino P. (Ed), Williams & Wilkins, Baltimore, 1996. di Sant'Agnese PA: Neuroendocrine differentiation in the precursors of prostate cancer. In: Precursors of Prostatic Adenocarcinoma: Recent Findings and New Concepts. Montironi R and Schulman C (Eds). Karger, Basel Switzerland, 1996. (Reprinted as a book chapter from peer review article European Urology 30:185-190, 1996). von Eschenbach A, Brawer M, di Sant' Agnese PA, Humphrey P, Mahran H, Murphy G, Sebo,T, and Veltri R: Exploration of new pathologic factors in prostate cancer in terms of potential for prognostic significance and future applications. Cancer 78(2):372-375, 1996. di Sant' Agnese PA and Cockett ATK: Neuroendocrine differentiation in prostatic malignancy. Cancer 78:357-61, 1996. di Sant'Agnese PA: Neuroendocrine differentiation in prostatic carcinoma: Recent findings and new concepts. Cancer (Supplement) 75:1850-1859, 1995. de Mesy Jensen K, and di Sant'Agnese PA: A review of the ultrastructure of human prostatic and urethral endocrine-paracrine cells and neuroendocrine differentiation in prostatic carcinoma. In: Ultrastructure of Male Urogenital glands (pp.139-161). Riva A, Riva F, Mott P (Eds). Kluwer Academic Publishers. Boston, 1994. di Sant'Agnese PA and Cockett ATK: The prostatic endocrine-paracrine (neuroendocrine) regulatory system and neuroendocrine differentiation in prostatic carcinoma: A review and future directions in basic research. Journal of Urology 152:1927-1931, 1994. di Sant'Agnese PA: Neuroendocrine differentiation in prostatic adenocarcinoma does not represent true Paneth cell differentiation. Human Pathology 25:115-116, 1994. Abrahamsson P-A and di Sant'Agnese PA: Neuroendocrine cells in the human prostate gland. Journal of Andrology 14: 307-309, 1993. di Sant'Agnese PA: Neuroendocrine differentiation in carcinoma of the prostate: Diagnostic, prognostic, and therapeutic implications. Cancer (supplement) 70:254-268, 1992. di Sant'Agnese PA: Neuroendocrine differentiation in prostatic carcinoma. Human Pathology 23:287-296, 1992. di Sant'Agnese PA: Endocrine-paracrine (APUD;Neuroendocrine) cells in the normal and pathologic prostate. Bulletin de l'Association des Anatomistes 75: 63-67, 1991. di Sant'Agnese PA: The prostatic endocrine-paracrine cell and neuroendocrine differentiation in prostatic carcinoma. Progress in Reproductive and Urinary Tract Pathology, Vol. II, Damjanov I, Cohen AH, Mills SE, Young RH (Eds.), Field and Wood:87, 1991. di Sant'Agnese PA: Neuroendocrine differentiation and prostatic carcinoma: The concept "comes of age". (Peer Reviewed Editorial) Archives of Pathology and Laboratory Medicine 112:1097-1099, 1988. di Sant' Agnese PA and de Mesy Jensen KL: Prostatic endocrine-paracrine cell: Recent findings and possible relationship to nodular prostatic hyperplasia and prostatic neoplasia. Progress in Surgical Pathology, Vol. VIII:125, 1988.