Neuroendocrine differentiation in prostate cancer

American Journal of Translational Research

Volumn 1, Issue 2, 2009, Pages 148-162

  Sun, Yin ^a   Niu, Junyang ^b   Huang, Jiaoti ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b ANHUI PROVINCIAL HOSPITAL   (China)

Author keywords

Hormonal therapy; Neuroendocrine; Prostate cancer

Indexed keywords

ANDROGEN; ANDROGEN RECEPTOR; ANTINEOPLASTIC AGENT; BOMBESIN; CHROMOGRANIN; CYTOKERATIN; GELATINASE B; INTERLEUKIN 6; INTERLEUKIN 8; MATRIX METALLOPROTEINASE 17; NEUROTENSIN; PROTEIN BCL 2; PROTEIN C FOS; SILIBININ; SURVIVIN; SYNAPTOPHYSIN; TRANSCRIPTION FACTOR ELK 1; VASCULOTROPIN;

ANDROGEN DEPRIVATION THERAPY; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER GRADING; CANCER INVASION; CANCER RESISTANCE; CARCINOID; CELL CYCLE ARREST; CELL DIFFERENTIATION; CELL FUNCTION; CELL PROLIFERATION; CELL STIMULATION; CELL STRUCTURE; CELL SURVIVAL; DIFFERENTIAL DIAGNOSIS; DRUG RECEPTOR BINDING; HUMAN; METASTASIS; NEUROSECRETORY CELL; NONHUMAN; PHARMACOLOGICAL BLOCKING; PROSTATE ADENOCARCINOMA; PROSTATE CANCER; PROSTATE EPITHELIUM; PROTEIN FUNCTION; REVIEW; SMALL CELL CARCINOMA; TREATMENT RESPONSE; TUMOR VASCULARIZATION;

EID: 77953404414     PISSN: None     EISSN: 19438141     Source Type: Journal    
DOI: None     Document Type: Review

References (148)

1. Isaacs JT and Coffey DS. Etiology and disease process of benign prostatic hyperplasia. Prostate Suppl 1989; 2: 33-50.
2. Bonkhoff H, Stein U and Remberger K. Multidirectional differentiation in the normal, hyperplastic, and neoplastic human prostate: simultaneous demonstration of cell-specific epithelial markers. Hum Pathol 1994; 25: 42-46.
3. Bonkhoff H and Remberger K. Differentiation pathways and histogenetic aspects of normal and abnormal prostatic growth: a stem cell model. Prostate 1996; 28: 98-106.
4. Qiu Y, Robinson D, Pretlow TG and Kung HJ. Etk/Bmx, a tyrosine kinase with a pleckstrin-homology domain, is an effector of phosphatidylinositol 3'-kinase and is involved in interleukin 6-induced neuroendocrine differentiation of prostate cancer cells. Proc Natl Acad Sci U S A 1998; 95: 3644-3649.
5. van Leenders G, Dijkman H, Hulsbergen-van de Kaa C, Ruiter D and Schalken J. Demonstration of intermediate cells during human prostate epithelial differentiation in situ and in vitro using triple-staining confocal scanning microscopy. Lab Invest 2000; 80: 1251-1258.
6. Hudson DL, O'Hare M, Watt FM and Masters JR. Proliferative heterogeneity in the human prostate: evidence for epithelial stem cells. Lab Invest 2000; 80: 1243-1250.
7. 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. Arch Pathol Lab Med 1985; 109: 607-612.
8. Santamaria L, Martin R, Martin JJ and Alonso L. Stereologic estimation of the number of neuroendocrine cells in normal human prostate detected by immunohistochemistry. Appl Immunohistochem Mol Morphol 2002; 10: 275-281.
9. Huang J and diSant'Agnese P. Neuroendocrine differentiation in prostate cancer: An overview. In: Lamberts S, editors. Advances in Oncology:The Expanding Role of Octreotide. Bristol:Bioscientifica Ltd: 2002. p. 243-262.
10. Abdul M, Anezinis PE, Logothetis CJ and Hoosein NM. Growth inhibition of human prostatic carcinoma cell lines by serotonin antagonists. Anticancer Res 1994; 14: 1215-1220.
11. Markwalder R and Reubi JC. Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. Cancer Res 1999; 59: 1152-1159.
12. Reubi JC, Wenger S, Schmuckli-Maurer J, Schaer JC and Gugger M. Bombesin receptor subtypes in human cancers: detection with the universal radioligand (125)I-D-TYR(6), beta-ALA(11), PHE(13), NLE(14) bombesin(6-14). Clin Cancer Res 2002; 8: 1139-1146.
13. Seethalakshmi L, Mitra SP, Dobner PR, Menon M and Carraway RE. Neurotensin receptor expression in prostate cancer cell line and growth effect of NT at physiological concentrations. Prostate 1997; 31: 183-192.
14. Dizeyi N, Konrad L, Bjartell A, Wu H, Gadaleanu V, Hansson J, Helboe L and Abrahamsson PA. Localization and mRNA expression of somatostatin receptor subtypes in human prostatic tissue and prostate cancer cell lines. Urol Oncol 2002; 7: 91-98.
15. Halmos G, Schally AV, Sun B, Davis R, Bostwick DG and Plonowski A. High expression of somatostatin receptors and messenger ribonucleic acid for its receptor subtypes in organ-confined and locally advanced human prostate cancers. J Clin Endocrinol Metab 2000; 85: 2564-2571.
16. Hansson J, Bjartell A, Gadaleanu V, Dizeyi N and Abrahamsson PA. Expression of somatostatin receptor subtypes 2 and 4 in human benign prostatic hyperplasia and prostatic cancer. Prostate 2002; 53: 50-59.
17. Petit T, Davidson KK, Lawrence RA, von Hoff DD and Izbicka E. Neuropeptide receptor status in human tumor cell lines. Anticancer Drugs 2001; 12: 133-136.
18. Magni P and Motta M. Expression of neuropeptide Y receptors in human prostate cancer cells. Ann Oncol 2001; 12 Suppl 2: S27-29.
19. Wu G, Burzon DT, di Sant'Agnese PA, Schoen S, Deftos LJ, Gershagen S and Cockett AT. Calcitonin receptor mRNA expression in the human prostate. Urology 1996; 47: 376-381.
20. Erasmus CE, Verhagen WI, Wauters CA and van Lindert EJ. Brain metastasis from prostate small cell carcinoma: not to be neglected. Can J Neurol Sci 2002; 29: 375-377.
21. Kawai S, Hiroshima K, Tsukamoto Y, Tobe T, Suzuki H, Ito H, Ohwada H and Ito H. Small cell carcinoma of the prostate expressing prostate-specific antigen and showing syndrome of inappropriate secretion of antidiuretic hormone: an autopsy case report. Pathol Int 2003; 53: 892-896.
22. Tanaka M, Suzuki Y, Takaoka K, Suzuki N, Murakami S, Matsuzaki O and Shimazaki J. Progression of prostate cancer to neuroendocrine cell tumor. Int J Urol 2001; 8: 431-436; discussion 437.
23. Miyoshi Y, Uemura H, Kitami K, Satomi Y, Kubota Y and Hosaka M. Neuroendocrine differentiated small cell carcinoma presenting as recurrent prostate cancer after androgen deprivation therapy. BJU Int 2001; 88: 982-983.
24. Yao JL, Madeb R, Bourne P, Lei J, Yang X, Tickoo S, Liu Z, Tan D, Cheng L, Hatem F, Huang J and Anthony di Sant'Agnese P. Small cell carcinoma of the prostate: an immunohistochemical study. Am J Surg Pathol 2006; 30: 705-712.
25. Papandreou CN, Daliani DD, Thall PF, Tu SM, Wang X, Reyes A, Troncoso P and Logothetis CJ. Results of a phase II study with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate. J Clin Oncol 2002; 20: 3072-3080.
26. Helpap B. Morphology and therapeutic strategies for neuroendocrine tumors of the genitourinary tract. Cancer 2002; 95: 1415-1420.
27. Ghannoum JE, DeLellis RA and Shin SJ. Primary carcinoid tumor of the prostate with concurrent adenocarcinoma: a case report. Int J Surg Pathol 2004; 12: 167-170.
28. Abrahamsson PA, Wadstrom LB, Alumets J, Falkmer S and Grimelius L. Peptide-hormone-and serotonin-immunoreactive tumour cells in carcinoma of the prostate. Pathol Res Pract 1987; 182: 298-307.
29. Bostwick DG, Dousa MK, Crawford BG and Wollan PC. Neuroendocrine differentiation in prostatic intraepithelial neoplasia and adenocarcinoma. Am J Surg Pathol 1994; 18: 1240-1246.
30. Bostwick DG, Qian J, Pacelli A, Zincke H, Blute M, Bergstralh EJ, Slezak JM and Cheng L. Neuroendocrine expression in node positive prostate cancer: correlation with systemic progression and patient survival. J Urol 2002; 168: 1204-1211.
31. Puccetti L, Supuran CT, Fasolo PP, Conti E, Sebastiani G, Lacquaniti S, Mandras R, Milazzo MG, Dogliani N, De Giuli P and Fasolis G. Skewing towards neuroendocrine phenotype in high grade or high stage androgen-responsive primary prostate cancer. Eur Urol 2005; 48: 215-221; Discussion 221-213.
32. Ahlgren G, Pedersen K, Lundberg S, Aus G, Hugosson J and Abrahamsson PA. Regressive changes and neuroendocrine differentiation in prostate cancer after neoadjuvant hormonal treatment. Prostate 2000; 42: 274-279.
33. Jiborn T, Bjartell A and Abrahamsson PA. Neuroendocrine differentiation in prostatic carcinoma during hormonal treatment. Urology 1998; 51: 585-589.
34. Berruti A, Dogliotti L, Mosca A, Bellina M, Mari M, Torta M, Tarabuzzi R, Bollito E, Fontana D and Angeli A. Circulating neuroendocrine markers in patients with prostate carcinoma. Cancer 2000; 88: 2590-2597.
35. Theodoropoulos VE, Tsigka A, Mihalopoulou A, Tsoukala V, Lazaris AC, Patsouris E and Ghikonti I. Evaluation of neuroendocrine staining and androgen receptor expression in incidental prostatic adenocarcinoma: prognostic implications. Urology 2005; 66: 897-902.
36. Ischia R, Hobisch A, Bauer R, Weiss U, Gasser RW, Horninger W, Bartsch G, Jr., Fuchs D, Bartsch G, Winkler H, Klocker H, Fischer-Colbrie R and Culig Z. Elevated levels of serum secretoneurin in patients with therapy resistant carcinoma of the prostate. J Urol 2000; 163: 1161-1164; discussion 1164-1165.
37. Krijnen JL, Bogdanowicz JF, Seldenrijk CA, Mulder PG and van der Kwast TH. The prognostic value of neuroendocrine differentiation in adenocarcinoma of the prostate in relation to progression of disease after endocrine therapy. J Urol 1997; 158: 171-174.
38. Berruti A, Dogliotti L, Mosca A, Gorzegno G, Bollito E, Mari M, Tarabuzzi R, Poggio M, Torta M, Fontana D and Angeli A. Potential clinical value of circulating chromogranin A in patients with prostate carcinoma. Ann Oncol 2001; 12 Suppl 2: S153-157.
39. Taplin ME, George DJ, Halabi S, Sanford B, Febbo PG, Hennessy KT, Mihos CG, Vogelzang NJ, Small EJ and Kantoff PW. Prognostic significance of plasma chromogranin a levels in patients with hormone-refractory prostate cancer treated in Cancer and Leukemia Group B 9480 study. Urology 2005; 66: 386-391.
40. Berruti A, Mosca A, Tucci M, Terrone C, Torta M, Tarabuzzi R, Russo L, Cracco C, Bollito E, Scarpa RM, Angeli A and Dogliotti L. Independent prognostic role of circulating chromogranin A in prostate cancer patients with hormone-refractory disease. Endocr Relat Cancer 2005; 12: 109-117.
41. Sciarra A, Monti S, Gentile V, Mariotti G, Cardi A, Voria G, Lucera R and Di Silverio F. Variation in chromogranin A serum levels during intermittent versus continuous androgen deprivation therapy for prostate adenocarcinoma. Prostate 2003; 55: 168-179.
42. Kamiya N, Akakura K, Suzuki H, Isshiki S, Komiya A, Ueda T and Ito H. Pretreatment serum level of neuron specific enolase (NSE) as a prognostic factor in metastatic prostate cancer patients treated with endocrine therapy. Eur Urol 2003; 44: 309-314; discussion 314.
43. Angelsen A, Syversen U, Stridsberg M, Haugen OA, Mjolnerod OK and Waldum HL. Use of neuroendocrine serum markers in the follow-up of patients with cancer of the prostate. Prostate 1997; 31: 110-117.
44. Lilleby W, Paus E, Skovlund E and Fossa SD. Prognostic value of neuroendocrine serum markers and PSA in irradiated patients with pN0 localized prostate cancer. Prostate 2001; 46: 126-133.
45. Yashi M, Muraishi O, Kobayashi Y, Tokue A and Nanjo H. Elevated serum progastrin-releasing peptide (31-98) in metastatic and androgen-independent prostate cancer patients. Prostate 2002; 51: 84-97.
46. Yashi M, Nukui A, Kurokawa S, Ochi M, Ishikawa S, Goto K, Kobayashi Y, Muraishi O and Tokue A. Elevated serum progastrin-releasing peptide (31-98) level is a predictor of short response duration after hormonal therapy in metastatic prostate cancer. Prostate 2003; 56: 305-312.
47. Nagakawa O, Furuya Y, Fujiuchi Y and Fuse H. Serum pro-gastrin-releasing peptide (31-98) in benign prostatic hyperplasia and prostatic carcinoma. Urology 2002; 60: 527-530.
48. Sim SJ, Glassman AB, Ro JY, Lee JJ, Logothetis CJ and Liu FJ. Serum calcitonin in small cell carcinoma of the prostate. Ann Clin Lab Sci 1996; 26: 487-495.
49. Singh D, Febbo PG, Ross K, Jackson DG, Manola J, Ladd C, Tamayo P, Renshaw AA, D'Amico AV, Richie JP, Lander ES, Loda M, Kantoff PW, Golub TR and Sellers WR. Gene expression correlates of clinical prostate cancer behavior. Cancer Cell 2002; 1: 203-209.
50. Moody TW, Chan D, Fahrenkrug J and Jensen RT. Neuropeptides as autocrine growth factors in cancer cells. Curr Pharm Des 2003; 9: 495-509.
51. Sehgal I, Powers S, Huntley B, Powis G, Pittelkow M and Maihle NJ. Neurotensin is an autocrine trophic factor stimulated by androgen withdrawal in human prostate cancer. Proc Natl Acad Sci U S A 1994; 91: 4673-4677.
52. Papandreou CN, Usmani B, Geng Y, Bogenrieder T, Freeman R, Wilk S, Finstad CL, Reuter VE, Powell CT, Scheinberg D, Magill C, Scher HI, Albino AP and Nanus DM. Neutral endopeptidase 24.11 loss in metastatic human prostate cancer contributes to androgen-independent progression. Nat Med 1998; 4: 50-57.
53. Jongsma J, Oomen MH, Noordzij MA, Van Weerden WM, Martens GJ, van der Kwast TH, Schroder FH and van Steenbrugge GJ. Kinetics of neuroendocrine differentiation in an androgen-dependent human prostate xenograft model. Am J Pathol 1999; 154: 543-551.
54. Jongsma J, Oomen MH, Noordzij MA, Van Weerden WM, Martens GJ, van der Kwast TH, Schroder FH and van Steenbrugge GJ. Androgen deprivation of the PC-310 correction of prohormone convertase-310 human prostate cancer model system induces neuroendocrine differentiation. Cancer Res 2000; 60: 741-748.
55. Jongsma J, Oomen MH, Noordzij MA, Van Weerden WM, Martens GJ, van der Kwast TH, Schroder FH and van Steenbrugge GJ. Different profiles of neuroendocrine cell differentiation evolve in the PC-310 human prostate cancer model during long-term androgen deprivation. Prostate 2002; 50: 203-215.
56. Huss WJ, Gregory CW and Smith GJ. Neuroendocrine cell differentiation in the CWR22 human prostate cancer xenograft: association with tumor cell proliferation prior to recurrence. Prostate 2004; 60: 91-97.
57. Masumori N, Tsuchiya K, Tu WH, Lee C, Kasper S, Tsukamoto T, Shappell SB and Matusik RJ. An allograft model of androgen independent prostatic neuroendocrine carcinoma derived from a large probasin promoter-T antigen transgenic mouse line. J Urol 2004; 171: 439-442.
58. Kaplan-Lefko PJ, Chen TM, Ittmann MM, Barrios RJ, Ayala GE, Huss WJ, Maddison LA, Foster BA and Greenberg NM. Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. Prostate 2003; 55: 219-237.
59. Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao J, Thomas GV, Li G, Roy-Burman P, Nelson PS, Liu X and Wu H. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 2003; 4: 209-221.
60. Liao CP, Zhong C, Saribekyan G, Bading J, Park R, Conti PS, Moats R, Berns A, Shi W, Zhou Z, Nikitin AY and Roy-Burman P. Mouse models of prostate adenocarcinoma with the capacity to monitor spontaneous carcinogenesis by bioluminescence or fluorescence. Cancer Res 2007; 67: 7525-7533.
61. Huang J, Yao JL, di Sant'Agnese PA, Yang Q, Bourne PA and Na Y. Immunohistochemical characterization of neuroendocrine cells in prostate cancer. Prostate 2006; 66: 1399-1406.
62. Bonkhoff H, Wernert N, Dhom G and Remberger K. Relation of endocrine-paracrine cells to cell proliferation in normal, hyperplastic, and neoplastic human prostate. Prostate 1991; 19: 91-98.
63. Bonkhoff H, Stein U and Remberger K. Endocrine-paracrine cell types in the prostate and prostatic adenocarcinoma are postmitotic cells. Hum Pathol 1995; 26: 167-170.
64. van Bokhoven A, Varella-Garcia M, Korch C, Johannes WU, Smith EE, Miller HL, Nordeen SK, Miller GJ and Lucia MS. Molecular characterization of human prostate carcinoma cell lines. Prostate 2003; 57: 205-225.
65. Vashchenko N and Abrahamsson PA. Neuroendocrine differentiation in prostate cancer: implications for new treatment modalities. Eur Urol 2005; 47: 147-155.
66. di Sant'Agnese PA. Neuroendocrine differentiation in human prostatic carcinoma. Hum Pathol 1992; 23: 287-296.
67. Xing N, Qian J, Bostwick D, Bergstralh E and Young CY. Neuroendocrine cells in human prostate over-express the anti-apoptosis protein survivin. Prostate 2001; 48: 7-15.
68. Bonkhoff H. Neuroendocrine cells in benign and malignant prostate tissue: morphogenesis, proliferation, and androgen receptor status. Prostate Suppl 1998; 8: 18-22.
69. Burchardt T, Burchardt M, Chen MW, Cao Y, de la Taille A, Shabsigh A, Hayek O, Dorai T and Buttyan R. Transdifferentiation of prostate cancer cells to a neuroendocrine cell phenotype in vitro and in vivo. J Urol 1999; 162: 1800-1805.
70. Roudier MP, True LD, Higano CS, Vesselle H, Ellis W, Lange P and Vessella RL. Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone. Hum Pathol 2003; 34: 646-653.
71. Cheville JC, Tindall D, Boelter C, Jenkins R, Lohse CM, Pankratz VS, Sebo TJ, Davis B and Blute ML. Metastatic prostate carcinoma to bone: clinical and pathologic features associated with cancer-specific survival. Cancer 2002; 95: 1028-1036.
72. Sauer CG, Roemer A and Grobholz R. Genetic analysis of neuroendocrine tumor cells in prostatic carcinoma. Prostate 2006; 66: 227-234.
73. Hansel DE, Nakayama M, Luo J, Abukhdeir AM, Park BH, Bieberich CJ, Hicks JL, Eisenberger M, Nelson WG, Mostwin JL and De Marzo AM. Shared TP53 gene mutation in morphologically and phenotypically distinct concurrent primary small cell neuroendocrine carcinoma and adenocarcinoma of the prostate. Prostate 2009;
74. Jin RJ, Wang Y, Masumori N, Ishii K, Tsukamoto T, Shappell SB, Hayward SW, Kasper S and Matusik RJ. NE-10 neuroendocrine cancer promotes the LNCaP xenograft growth in castrated mice. Cancer Res 2004; 64: 5489-5495.
75. Uchida K, Masumori N, Takahashi A, Itoh N, Kato K, Matusik RJ and Tsukamoto T. Murine androgen-independent neuroendocrine carcinoma promotes metastasis of human prostate cancer cell line LNCaP. Prostate 2006; 66: 536-545.
76. Jongsma J, Oomen MH, Noordzij MA, Romijn JC, van Der Kwast TH, Schroder FH and van Steenbrugge GJ. Androgen-independent growth is induced by neuropeptides in human prostate cancer cell lines. Prostate 2000; 42: 34-44.
77. Hoosein NM, Logothetis CJ and Chung LW. Differential effects of peptide hormones bombesin, vasoactive intestinal polypeptide and somatostatin analog RC-160 on the invasive capacity of human prostatic carcinoma cells. J Urol 1993; 149: 1209-1213.
78. Aprikian AG, Tremblay L, Han K and Chevalier S. Bombesin stimulates the motility of human prostate-carcinoma cells through tyrosine phosphorylation of focal adhesion kinase and of integrin-associated proteins. Int J Cancer 1997; 72: 498-504.
79. Allard P, Beaulieu P, Aprikian A and Chevalier S. Bombesin modulates the association of Src with a nuclear 110-kd protein expressed in dividing prostate cells. J Androl 2000; 21: 367-375.
80. Sumitomo M, Shen R, Goldberg JS, Dai J, Navarro D and Nanus DM. Neutral endopeptidase promotes phorbol ester-induced apoptosis in prostate cancer cells by inhibiting neuropeptide-induced protein kinase C delta degradation. Cancer Res 2000; 60: 6590-6596.
81. Lee LF, Guan J, Qiu Y and Kung HJ. Neuropeptide-induced androgen independence in prostate cancer cells: roles of nonreceptor tyrosine kinases Etk/Bmx, Src, and focal adhesion kinase. Mol Cell Biol 2001; 21: 8385-8397.
82. Xiao D, Qu X and Weber HC. GRP receptor-mediated immediate early gene expression and transcription factor Elk-1 activation in prostate cancer cells. Regul Pept 2002; 109: 141-148.
83. Yang JC, Ok JH, Busby JE, Borowsky AD, Kung HJ and Evans CP. Aberrant activation of androgen receptor in a new neuropeptide-autocrine model of androgen-insensitive prostate cancer. Cancer Res 2009; 69: 151-160.
84. Sehgal I and Thompson TC. Novel regulation of type IV collagenase (matrix metalloproteinase-9 and -2) activities by transforming growth factor-beta1 in human prostate cancer cell lines. Mol Biol Cell 1999; 10: 407-416.
85. Nagakawa O, Murakami K, Yamaura T, Fujiuchi Y, Murata J, Fuse H and Saiki I. Expression of membrane-type 1 matrix metalloproteinase (MT1-MMP) on prostate cancer cell lines. Cancer Lett 2000; 155: 173-179.
86. Ishimaru H, Kageyama Y, Hayashi T, Nemoto T, Eishi Y and Kihara K. Expression of matrix metalloproteinase-9 and bombesin/gastrin-releasing peptide in human prostate cancers and their lymph node metastases. Acta Oncol 2002; 41: 289-296.
87. Festuccia C, Guerra F, D'Ascenzo S, Giunciuglio D, Albini A and Bologna M. In vitro regulation of pericellular proteolysis in prostatic tumor cells treated with bombesin. Int J Cancer 1998; 75: 418-431.
88. Ritchie CK, Thomas KG, Andrews LR, Tindall DJ and Fitzpatrick LA. Effects of the calciotrophic peptides calcitonin and parathyroid hormone on prostate cancer growth and chemotaxis. Prostate 1997; 30: 183-187.
89. Wasilenko WJ, Cooper J, Palad AJ, Somers KD, Blackmore PF, Rhim JS, Wright GL, Jr. and Schellhammer PF. Calcium signaling in prostate cancer cells: evidence for multiple receptors and enhanced sensitivity to bombesin/GRP. Prostate 1997; 30: 167-173.
90. Dizeyi N, Bjartell A, Nilsson E, Hansson J, Gadaleanu V, Cross N and Abrahamsson PA. Expression of serotonin receptors and role of serotonin in human prostate cancer tissue and cell lines. Prostate 2004; 59: 328-336.
91. Lee LF, Louie MC, Desai SJ, Yang J, Chen HW, Evans CP and Kung HJ. Interleukin-8 confers androgen-independent growth and migration of LNCaP: differential effects of tyrosine kinases Src and FAK. Oncogene 2004; 23: 2197-2205.
92. Huang J, Yao JL, Zhang L, Bourne PA, Quinn AM, di Sant'Agnese PA and Reeder JE. Differential expression of interleukin-8 and its receptors in the neuroendocrine and non-neuroendocrine compartments of prostate cancer. Am J Pathol 2005; 166: 1807-1815.
93. Xue Y, Verhofstad A, Lange W, Smedts F, Debruyne F, de la Rosette J and Schalken J. Prostatic neuroendocrine cells have a unique keratin expression pattern and do not express Bcl-2: cell kinetic features of neuroendocrine cells in the human prostate. Am J Pathol 1997; 151: 1759-1765.
94. Segal NH, Cohen RJ, Haffejee Z and Savage N. BCL-2 proto-oncogene expression in prostate cancer and its relationship to the prostatic neuroendocrine cell. Arch Pathol Lab Med 1994; 118: 616-618.
95. Salido M, Vilches J and Lopez A. Neuropeptides bombesin and calcitonin induce resistance to etoposide induced apoptosis in prostate cancer cell lines. Histol Histopathol 2000; 15: 729-738.
96. Salido M, Vilches J and Roomans GM. Changes in elemental concentrations in LNCaP cells are associated with a protective effect of neuropeptides on etoposide-induced apoptosis. Cell Biol Int 2004; 28: 397-402.
97. Vilches J, Salido M, Fernandez-Segura E and Roomans GM. Neuropeptides, apoptosis and ion changes in prostate cancer. Methods of study and recent developments. Histol Histopathol 2004; 19: 951-961.
98. Bonkhoff H, Fixemer T, Hunsicker I and Remberger K. Simultaneous detection of DNA fragmentation (apoptosis), cell proliferation (MIB-1), and phenotype markers in routinely processed tissue sections. Virchows Arch 1999; 434: 71-73.
99. Fixemer T, Remberger K and Bonkhoff H. Apoptosis resistance of neuroendocrine phenotypes in prostatic adenocarcinoma. Prostate 2002; 53: 118-123.
100. Vanoverberghe K, Vanden Abeele F, Mariot P, Lepage G, Roudbaraki M, Bonnal JL, Mauroy B, Shuba Y, Skryma R and Prevarskaya N. Ca2+ homeostasis and apoptotic resistance of neuroendocrine-differentiated prostate cancer cells. Cell Death Differ 2004; 11: 321-330.
101. Harper ME, Glynne-Jones E, Goddard L, Thurston VJ and Griffiths K. Vascular endothelial growth factor (VEGF) expression in prostatic tumours and its relationship to neuroendocrine cells. Br J Cancer 1996; 74: 910-916.
102. Chevalier S, Defoy I, Lacoste J, Hamel L, Guy L, Begin LR and Aprikian AG. Vascular endothelial growth factor and signaling in the prostate: more than angiogenesis. Mol Cell Endocrinol 2002; 189: 169-179.
103. Collado B, Gutierrez-Canas I, Rodriguez-Henche N, Prieto JC and Carmena MJ. Vasoactive intestinal peptide increases vascular endothelial growth factor expression and neuroendocrine differentiation in human prostate cancer LNCaP cells. Regul Pept 2004; 119: 69-75.
104. Mazzucchelli R, Lopez-Beltran A, Scarpelli M and Montironi R. Predictive factors in prostate needle biopsy. Pathologica 2002; 94: 331-337.
105. Grobholz R, Bohrer MH, Siegsmund M, Junemann KP, Bleyl U and Woenckhaus M. Correlation between neovascularisation and neuroendocrine differentiation in prostatic carcinoma. Pathol Res Pract 2000; 196: 277-284.
106. Borre M, Nerstrom B and Overgaard J. Association between immunohistochemical expression of vascular endothelial growth factor (VEGF), VEGF-expressing neuroendo-crine-differentiated tumor cells, and outcome in prostate cancer patients subjected to watchful waiting. Clin Cancer Res 2000; 6: 1882-1890.
107. Levine L, Lucci JA, 3rd, Pazdrak B, Cheng JZ, Guo YS, Townsend CM, Jr. and Hellmich MR. Bombesin stimulates nuclear factor kappa B activation and expression of proangiogenic factors in prostate cancer cells. Cancer Res 2003; 63: 3495-3502.
108. Chigurupati S, Kulkarni T, Thomas S and Shah G. Calcitonin stimulates multiple stages of angiogenesis by directly acting on endothelial cells. Cancer Res 2005; 65: 8519-8529.
109. Busby JE, Shih SJ, Yang JC, Kung HJ and Evans CP. Angiogenesis is not mediated by prostate cancer neuropeptides. Angiogenesis 2003; 6: 289-293.
110. Ismail AH, Altaweel W, Chevalier S, Kassouf W and Aprikian AG. Expression of vascular endothelial growth factor-A in human lymph node metastases of prostate cancer. Can J Urol 2004; 11: 2146-2150.
111. Wright ME, Tsai MJ and Aebersold R. Androgen receptor represses the neuroendocrine transdifferentiation process in prostate cancer cells. Mol Endocrinol 2003; 17: 1726-1737.
112. Xie S, Lin HK, Ni J, Yang L, Wang L, di Sant'Agnese PA and Chang C. Regulation of interleukin-6-mediated PI3K activation and neuroendocrine differentiation by androgen signaling in prostate cancer LNCaP cells. Prostate 2004; 60: 61-67.
113. Foster BA, Evangelou A, Gingrich JR, Kaplan PJ, DeMayo F and Greenberg NM. Enforced expression of FGF-7 promotes epithelial hyperplasia whereas a dominant negative FGFR2iiib promotes the emergence of neuroendocrine phenotype in prostate glands of transgenic mice. Differentiation 2002; 70: 624-632.
114. Wilson EM, Oh Y, Hwa V and Rosenfeld RG. Interaction of IGF-binding protein-related protein 1 with a novel protein, neuroendocrine differentiation factor, results in neuroendocrine differentiation of prostate cancer cells. J Clin Endocrinol Metab 2001; 86: 4504-4511.
115. Meyer-Siegler K. COX-2 specific inhibitor, NS-398, increases macrophage migration inhibitory factor expression and induces neuroendocrine differentiation in C4-2b prostate cancer cells. Mol Med 2001; 7: 850-860.
116. Diaz M, Abdul M and Hoosein N. Modulation of neuroendocrine differentiation in prostate cancer by interleukin-1 and -2. Prostate Suppl 1998; 8: 32-36.
117. Albrecht M, Doroszewicz J, Gillen S, Gomes I, Wilhelm B, Stief T and Aumuller G. Proliferation of prostate cancer cells and activity of neutral endopeptidase is regulated by bombesin and IL-1beta with IL-1beta acting as a modulator of cellular differentiation. Prostate 2004; 58: 82-94.
118. Untergasser G, Plas E, Pfister G, Heinrich E and Berger P. Interferon-gamma induces neuroendocrine-like differentiation of human prostate basal-epithelial cells. Prostate 2005; 64: 419-429.
119. Cox ME, Deeble PD, Lakhani S and Parsons SJ. Acquisition of neuroendocrine characteristics by prostate tumor cells is reversible: implications for prostate cancer progression. Cancer Res 1999; 59: 3821-3830.
120. Cox ME, Deeble PD, Bissonette EA and Parsons SJ. Activated 3',5'-cyclic AMP-dependent protein kinase is sufficient to induce neuroendocrine-like differentiation of the LNCaP prostate tumor cell line. J Biol Chem 2000; 275: 13812-13818.
121. Deeble PD, Cox ME, Frierson HF, Jr., Sikes RA, Palmer JB, Davidson RJ, Casarez EV, Amorino GP and Parsons SJ. Androgen-independent growth and tumorigenesis of prostate cancer cells are enhanced by the presence of PKA-differentiated neuroendocrine cells. Cancer Res 2007; 67: 3663-3672.
122. Shimizu T, Ohta Y, Ozawa H, Matsushima H and Takeda K. Papaverine combined with prostaglandin E2 synergistically induces neuron-like morphological changes and decrease of malignancy in human prostatic cancer LNCaP cells. Anticancer Res 2000; 20: 761-767.
123. Mariot P, Vanoverberghe K, Lalevee N, Rossier MF and Prevarskaya N. Overexpression of an alpha 1H (Cav3.2) T-type calcium channel during neuroendocrine differentiation of human prostate cancer cells. J Biol Chem 2002; 277: 10824-10833.
124. Hu Y, Wang T, Stormo GD and Gordon JI. RNA interference of achaete-scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites. Proc Natl Acad Sci U S A 2004; 101: 5559-5564.
125. Deng X, Liu L, Huang J, Cheng L, Keller E, Parsons S and Hu C. Ionizing radiation induces prostate cancer neuroendocrine differentiation through interplay of CREB and ATF2: Implications for disease progression. Cancer Research 2008; in press:
126. Zi X and Agarwal R. Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc Natl Acad Sci U S A 1999; 96: 7490-7495.
127. Tyagi A, Agarwal C and Agarwal R. Inhibition of retinoblastoma protein (Rb) phosphorylation at serine sites and an increase in Rb-E2F complex formation by silibinin in androgen-dependent human prostate carcinoma LNCaP cells: role in prostate cancer prevention. Mol Cancer Ther 2002; 1: 525-532.
128. Yang X, Chen MW, Terry S, Vacherot F, Chopin DK, Bemis DL, Kitajewski J, Benson MC, Guo Y and Buttyan R. A human- and male-specific protocadherin that acts through the wnt signaling pathway to induce neuroendocrine transdifferentiation of prostate cancer cells. Cancer Res 2005; 65: 5263-5271.
129. Kim J, Adam RM and Freeman MR. Activation of the Erk mitogen-activated protein kinase pathway stimulates neuroendocrine differentiation in LNCaP cells independently of cell cycle withdrawal and STAT3 phosphorylation. Cancer Res 2002; 62: 1549-1554.
130. Zhang XQ, Kondrikov D, Yuan TC, Lin FF, Hansen J and Lin MF. Receptor protein tyrosine phosphatase alpha signaling is involved in androgen depletion-induced neuroendocrine differentiation of androgen-sensitive LNCaP human prostate cancer cells. Oncogene 2003; 22: 6704-6716.
131. Zelivianski S, Verni M, Moore C, Kondrikov D, Taylor R and Lin MF. Multipathways for transdifferentiation of human prostate cancer cells into neuroendocrine-like phenotype. Biochim Biophys Acta 2001; 1539: 28-43.
132. Wu C, Zhang L, Bourne PA, Reeder JE, di Sant'Agnese PA, Yao JL, Na Y and Huang J. Protein tyrosine phosphatase PTP1B is involved in neuroendocrine differentiation of prostate cancer. Prostate 2006; 66: 1125-1135.
133. Collado B, Sanchez MG, Diaz-Laviada I, Prieto JC and Carmena MJ. Vasoactive intestinal peptide (VIP) induces c-fos expression in LNCaP prostate cancer cells through a mechanism that involves Ca2+ signalling. Implications in angiogenesis and neuroendocrine differentiation. Biochim Biophys Acta 2005; 1744: 224-233.
134. Chung TD, Yu JJ, Kong TA, Spiotto MT and Lin JM. Interleukin-6 activates phosphatidyl-inositol-3 kinase, which inhibits apoptosis in human prostate cancer cell lines. Prostate 2000; 42: 1-7.
135. Qiu Y, Ravi L and Kung HJ. Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells. Nature 1998; 393: 83-85.
136. Spiotto MT and Chung TD. STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells. Prostate 2000; 42: 186-195.
137. Mori S, Murakami-Mori K and Bonavida B. Interleukin-6 induces G1 arrest through induction of p27(Kip1), a cyclin-dependent kinase inhibitor, and neuron-like morphology in LNCaP prostate tumor cells. Biochem Biophys Res Commun 1999; 257: 609-614.
138. Wang Q, Horiatis D and Pinski J. Interleukin-6 inhibits the growth of prostate cancer xenografts in mice by the process of neuroendocrine differentiation. Int J Cancer 2004; 111: 508-513.
139. Hobisch A, Ramoner R, Fuchs D, Godoy-Tundidor S, Bartsch G, Klocker H and Culig Z. Prostate cancer cells (LNCaP) generated after long-term interleukin 6 (IL-6) treatment express IL-6 and acquire an IL-6 partially resistant phenotype. Clin Cancer Res 2001; 7: 2941-2948.
140. Steiner H, Godoy-Tundidor S, Rogatsch H, Berger AP, Fuchs D, Comuzzi B, Bartsch G, Hobisch A and Culig Z. Accelerated in vivo growth of prostate tumors that up-regulate interleukin-6 is associated with reduced retinoblastoma protein expression and activation of the mitogen-activated protein kinase pathway. Am J Pathol 2003; 162: 655-663.
141. Mori R, Xiong S, Wang Q, Tarabolous C, Shimada H, Panteris E, Danenberg KD, Danenberg PV and Pinski JK. Gene profiling and pathway analysis of neuroendocrine transdifferentiated prostate cancer cells. Prostate 2008;
142. Isaacs JT. Prostate stem cells and benign prostatic hyperplasia. Prostate 2008; 68: 1025-1034.
143. Chen Y, Robles AI, Martinez LA, Liu F, Gimenez-Conti IB and Conti CJ. Expression of G1 cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors in androgen-induced prostate proliferation in castrated rats. Cell Growth Differ 1996; 7: 1571-1578.
144. Tsihlias J, Zhang W, Bhattacharya N, Flanagan M, Klotz L and Slingerland J. Involvement of p27Kip1 in G1 arrest by high dose 5 alpha-dihydrotestosterone in LNCaP human prostate cancer cells. Oncogene 2000; 19: 670-679.
145. Waltregny D, Leav I, Signoretti S, Soung P, Lin D, Merk F, Adams JY, Bhattacharya N, Cirenei N and Loda M. Androgen-driven prostate epithelial cell proliferation and differentiation in vivo involve the regulation of p27. Mol Endocrinol 2001; 15: 765-782.
146. Niu Y, Altuwaijri S, Lai KP, Wu CT, Ricke WA, Messing EM, Yao J, Yeh S and Chang C. Androgen receptor is a tumor suppressor and proliferator in prostate cancer. Proc Natl Acad Sci U S A 2008; 105: 12182-12187.
147. Gao J, Arnold JT and Isaacs JT. Conversion from a paracrine to an autocrine mechanism of androgen-stimulated growth during malignant transformation of prostatic epithelial cells. Cancer Res 2001; 61: 5038-5044.
148. Buchanan G, Greenberg NM, Scher HI, Harris JM, Marshall VR and Tilley WD. Collocation of androgen receptor gene mutations in prostate cancer. Clin Cancer Res 2001; 7: 1273-1281.