sb">tive activity. As our knowledge of the neuroendocrine
factors develops, in the future our focus will be to deter-
mine how they interact with other prostate cell types that
reside in the dynamic prostatic microenvironment. Inves-
tigation of how NE factors and the resulting downstream
signaling pathways contribute to the initiation and the
progression of PCa should be pursued and will help iden-
tifying new therapeutic tools to block or prevent PCa
progression.
The NE axis remains an important therapeutic target
for drug development in advanced PCa. Development of
new generation of drugs directed against NE-like cells
may help targeting populations of PCa cells that may be
resistant to traditional therapies, thus helping setting up
individualized therapy which takes into account the het-
erogeneity of PCa.
Financial & Competing Interests Disclosure
Work performed in the laboratory of the author has been
supported by the University of Rouen. The author has no
other relevant affiliation or financial involvement with
any organization or entity with a financial interest in or
financial conflict with the subject matter or materials
discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of
this manuscript.
7. Acknowledgements
I thank Dr. Léna Diaw (NIH/NHLBI, USA) for critical
reading of the manuscript.
Copyright © 2012 SciRes. OJU
V. PERROT
180
REFERENCES
[1] W. A. Schulz, M. Burchardt and M. V. Cronauer, “Mo-
lecular Biology of Prostate Cancer,” Molecular Human
Reproduction, Vol. 9, 2003, pp. 437-448.
doi:10.1093/molehr/gag064
[2] D. E. Neal, H. Y. Leung, P. H. Powell, F. C. Hamdy and J.
L. Donovan, “Unanswered Questions in Screening for
Prostate Cancer,” European Journal of Cancer, Vol. 36,
No. 10, 2000, pp. 1316-1321.
doi:10.1016/S0959-8049(00)00104-0
[3] A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu and M. J.
Thun, “Cancer Statistics, 2009,” CA: A Cancer Journal
for Clinicians, Vol. 59, No 4, 2009, pp. 225-249.
doi:10.3322/caac.20006
[4] S. P. Balk, “Androgen Receptor as a Target in Androgen-
Independent Prostate Cancer,” Urology, Vol. 60, 2002, pp.
132-139. doi:10.1016/S0090-4295(02)01593-5
[5] H. Bonkhoff, U. Stein and K. Remberger, “Endocrine-
Paracrine Cell Types in the Prostate and Prostatic Ade-
nocarcinoma Are Postmitotic Cells,” Human Pathology,
Vol. 26, 1995, pp. 167-170.
doi:10.1016/0046-8177(95)90033-0
[6] P. A. di Sant’Agnese, “Neuroendocrine Cells of the Pros-
tate and Neuroendocrine Differentiation in Prostatic Car-
cinoma: A Review of Morphologic Aspects,” Urology,
Vol. 51, 1998, pp. 121-124.
doi:10.1016/S0090-4295(98)00064-8
[7] H. Bonkhoff, U. Stein and K. Remberger, “Androgen
Receptor Status in Endocrine-Paracrine Cell Types of the
Normal, Hyperplasia, and Neoplastic Human Prostate,”
Virchows Archiv A: Pathological Anatomy and Histology,
Vol. 423, 1993, pp. 291-294. doi:10.1007/BF01606893
[8] J. L. M. Krijnen, P. J. A. Janssen, J. A. de Winter
Ruizevel, H. Van Krimpen, F. H. Schröder and T. H. Van
der Kwast, “Do Neuroendocrine Cells in Human Prostate
Cancer Express Androgen Receptor?” Histochemistry,
Vol. 100, 1993, pp. 393-398. doi:10.1007/BF00268938
[9] S. Y. Nakada, P. A. di Sant’Agnese, R. A. Moynes, R. A.
Hiipakka, S. Liao, A. T. Cockett and P. A. Abrahamsson,
“The Androgen Receptor Status of neuroendocrine Cells
in Human Benign and Malignant Prostatic Tissue,” Can-
cer Research, Vol. 53, 1993, pp. 1967-1970.
[10] H. Bonkhoff and K. Remberger, “Differentiation Path-
ways and Histogenic Aspects of Normal and Abnormal
Prostatic Growth: A Stem Cell Model,” Prostate, Vol. 28,
1996, pp. 98-106.
doi:10.1002/(SICI)1097-0045(199602)28:2<98::AID-PR
OS4>3.0.CO;2-J
[11] G. Aumuller, M. Leonhardt, M. Janssen, L. Konrad, A.
Bjartell and P. A. Abrahamsson, “Neurogenic Origin of
Human Prostate Endocrine Cells,” Urology, Vol. 53,
1999, pp. 1041-1048.
doi:10.1016/S0090-4295(98)00631-1
[12] P. A. di Sant’Agnese, “Neuroendocrine Differentiation in
Human Prostatic Carcinoma,” Human Pathology, Vol. 23,
1992, pp. 287-296. doi:10.1016/0046-8177(92)90110-O
[13] C. K. Ritchie, G. Thomas, L. R. Andrews, D. J. Tindall
and L. A. Fitzpatrick, “Effects of the Calciotrophic Pep-
tides Calcitonin and Parathyroid Hormone on Prostate
Cancer Growth and Chemotaxis,” Prostate, Vol. 30, 1997,
pp. 183-187.
doi:10.1002/(SICI)1097-0045(19970215)30:3<183::AID-
PROS6>3.0.CO;2-N
[14] M. Iwamura, G. Wu, P. A. Abrahamsson, P. A. di Sant’
Agnese, A. T. K. Cockett and L. J. Deftos, “Parathyroid
Hormone-Related Protein Is Expressed by Prostatic Neu-
roendocrine Cells,” Urology, Vol. 43, 1994, pp. 667-674.
doi:10.1016/0090-4295(94)90182-1
[15] H. Bonkhoff, N. Wernert, G. Dhom and K. Remberger,
“Relation of Endocrine-Paracrine Cells to Proliferation in
Normal and Hyperplastic, Neoplastic Human Prostate,”
Prostate, Vol. 19, 1991, pp. 91-98.
doi:10.1002/pros.2990190202
[16] P. A. Abrahamsson, L. B. Wadstrom, J. Alumets, S.
Falkmer and L. Grimelius, “Peptide Hormone- and Sero-
tonin-Immunoreactive Cells in Normal and Hypersplastic
Prostate Glands,” Pathology Research and Practice, Vol.
185, 1989, pp. 373-380.
doi:10.1016/S0344-0338(89)80016-0
[17] A. G. Aprikian, K. Han, L. Guy, F. Landry, L. R. Begin
and S. Chevalier, “Neuroendocrine Differentiation and
Bombesin/Gastrin-Releasing Peptide Family of Neuro-
peptides in the Progress of Human Prostate Cancer,” The
Prostate: Supplement, Vol. 82, 1998, pp. 738-743.
[18] P. di Sant’Agnese and K. de Mesy Jensen, “Somatostatin
and Somatostatin-Like Immunoreactive Endocrine-Parac-
rine Cells in the Human Prostate Gland,” Archives of Pa-
thology & Laboratory Medicine, Vol. 108, 1984, pp. 693-
696.
[19] J. Hansson and P. A. Abrahamsson, “Neuroendocrine
Pathogenesis in Adenocarcinoma of the Prostate,” Annals
of Oncology, Vol. 12, No. 3, 2001, pp. 145-152.
doi:10.1093/annonc/12.suppl_2.S145
[20] P. A. di Sant’Agnese, “Neuroendocrine Differentiation in
Carcinoma of the Prostate Diagnostic, Prognostic, and
Therapeutic Implications,” Cancer, Vol. 70, 1992, pp.
254-268.
doi:10.1002/1097-0142(19920701)70:1+<254::AID-CNC
R2820701312>3.0.CO;2-E
[21] P. A. Abrahamsson, “Neuroendocrine Differentiation in
Prostatic Carcinoma,” Prostate, Vol. 39, No. 2, 1999, pp.
135-148.
doi:10.1002/(SICI)1097-0045(19990501)39:2<135::AID-
PROS9>3.0.CO;2-S
[22] A. Berruti, L. Dogliotti, A. Mosca, M. Bellina, M. Mari,
M. Torta, R. Tarabuzzi, E. Bollito, D. Fontana and A.
Angeli, “Circulating Neuroendocrine Markers in Patients
with Prostate Carcinoma,” Cancer, Vol. 88, 2000, pp.
2590-2597.
doi:10.1002/1097-0142(20000601)88:11<2590::AID-CN
CR23>3.0.CO;2-D
[23] D. Hirano, T. Jike, Y. Okada, S. Minei, Y. Takimoto and
N. Nemoto, “Immunohistochemical and Ultrastructural
Features of Neuroendocrine Differentiated Carcinomas of
the Prostate: An Immunoelectron Microscopic Study,”
Ultrastructural Pathology, Vol. 29, 2005, pp. 367-375.
doi:10.1080/019131290945718
Copyright © 2012 SciRes. OJU
V. PERROT 181
[24] H. Bonkhoff, “Neuroendocrine Cells in Benign and Ma-
lignant Prostate Tissue: Morphogenesis, Proliferation, and
Androgen Receptor Status,” Prostate, Supplement 8,
1998, pp. 18-22.
doi:10.1002/(SICI)1097-0045(1998)8+<18::AID-PROS4
>3.0.CO;2-C
[25] N. Vashchenko and P. A. Abrahamsson, “Neuroendocrine
Differentiation in Prostate Cancer: Implications for New
Treatment Modalities,” European Urology, Vol. 47, 2005,
pp. 147-155. doi:10.1016/j.eururo.2004.09.007
[26] A. van Bokhoven, M. Varella-Garcia, C. Korch, W. U.
Johannes, E. E. Smith, H. L. Miller and M. S. Lucia,
“Molecular Characterization of Human Prostate Carci-
noma Cell Lines,” Prostate, Vol. 57, 2003, pp. 205-225.
doi:10.1002/pros.10290
[27] J. Huang, J. L. Yao, P. A. di Sant’Agnese, Q. Yang, P. A.
Bourne and Y. Na, “Immunohistochemical Characteri-
zation of Neuroendocrine Cells in Prostate Cancer,” Pro-
state, Vol. 66, 2006, pp. 1399-1406.
doi:10.1002/pros.20434
[28] N. Xing, J. Qian, D. Bostwick, E. bergstralh and C. Y. F.
Young, “Neuroendocrine Cells in Human Prostate Over-
express the Anti-Apoptosis Protein Surviving,” Prostate,
Vol. 48, 2001, pp. 7-15. doi:10.1002/pros.1076
[29] C. G. Sauer, A. Roemer and R. Grobholz, “Genetic Ana-
lysis of Neuroendocrine Tumour Cells in Prostatic Car-
cinoma,” Prostate, Vol. 66, 2006, pp. 227-234.
doi:10.1002/pros.20338
[30] Y. Xue, A. Verhofstad, W. Lange, F. Smedts, F. De-
bruyne, J. de la Rosette and J. Schalken, “Prostatic Neu-
roendocrine Cells Have a Unique Keratin Expression Pat-
tern and Do Not Express Bcl-2: Cell Kinetic Features of
Neuroendocrine Cells in the Human Prostate,” American
Journal of Pathology, Vol. 151, 1997, pp. 1759-1765.
[31] P. A. di Sant’Agnese, “Neuroendocrine Differentiation in
Prostatic Carcinoma: An Update on Recent Developments,”
Annals of Oncology, Vol. 12, Supplement 2, 2001, pp.
135-140. doi:10.1093/annonc/12.suppl_2.S135
[32] A. H. R. Ismail, F. Landry, A. G. Aprikian and S. Cheva-
lier, “Androgen Ablation Promotes Neuroendocrine Cell
Differentiation in Dog and Human Prostate,” Prostate,
Vol. 51, 2002, pp. 117-125. doi:10.1002/pros.10066
[33] D. Hirano, Y. Okada, S. Minei, Y. Takimoto and N.
Nemoto, “Neuroendocrine Differentiation in Hormone
Refractory Prostate Cancer Following Androgen Depriva-
tion Therapy,” European Urology, Vol. 45, 2004, pp. 586-
592. doi:10.1016/j.eururo.2003.11.032
[34] T. C. Yuan, S. Veeramani and M. F. Lin, “Neuroendo-
crine-Like Prostate Cancer Cells: Neuroendocrine Trans-
differentiation of Prostate Adenocarcinoma Cells,” Endo-
crine-Related Cancer, Vol. 14, 2007, pp. 531-547.
doi:10.1677/ERC-07-0061
[35] P. D. Deeble, D. J. Murphy, S. J. Parsons and M. E. Cox,
“Interleukin-6- and Cyclic AMP-Mediated Signaling Po-
tentiates Neuroendocrine Differentiation of LNCaP Pros-
tate Tumor Cells,” Molecular and Cellular Biology, Vol.
21, 2001, pp. 8471-8482.
doi:10.1128/MCB.21.24.8471-8482.2001
[36] X. Q. Zhang, D. Kondrikov, T. C. Yuan, F. F. Lin, J.
Hansen and M. F. Lin, “Receptor Protein Tyrosine Pho-
sphatase Alpha Signaling Is Involved in Androgen Deple-
tion-Induced Neuroendocrine Differentiation of Andro-
gen-Sensitive LNCaP Human Prostate Cancer Cells,”
Oncogene, Vol. 22, 2003, pp. 6704-6716.
doi:10.1038/sj.onc.1206764
[37] T. C. Yuan, S. Veeramanin, F. F. Lin, D. Kondrikou, S.
Zelivianski, T. Igawa, D. Karan, S. K. Batra and M. F.
Lin, “Androgen Deprivation Induces Human Prostate
Epithelial Neuroendocrine Differentiation of Androgen-
Sensitive LNCaP Cells,” Endocrine-Related Cancer, Vol.
13, 2006, pp. 151-167. doi:10.1677/erc.1.01043
[38] J. T. Arnold and J. T. Isaacs, “Mechanisms Involved in
the Progression of Androgen-Independent Prostate Can-
cers: It Is Not Only the Cancer Cell’s Fault,” Endocrine-
Related Cancer, Vol. 9, 2002, pp. 61-73.
doi:10.1677/erc.0.0090061
[39] W. J. Huss, C. V. Gregory and G. J. Smith, “Neuroen-
docrine Cell Differentiation in the CWR33 Human Pros-
tate Cancer Xenograft: Association with Tumor Cell Pro-
liferation Prior to Recurrence,” Prostate, Vol. 60, 2004,
pp. 91-97. doi:10.1002/pros.20032
[40] E. C. Nelson, A. J. Cambio, J. C. Yang, J. H. Ok, P. N.
Lara Jr. and C. P. Evans, “Clinical Implications of Neuro-
endocrine Differentiation in Prostate Cancer,” Prostate
Cancer and Prostatic Diseases, Vol. 10, 2007, pp. 6-14.
doi:10.1038/sj.pcan.4500922
[41] J. Huang and P. A. di Sant’Agnese, “Neuroendocrine
Differentiation in Prostate Cancer: An Overview. Ad-
vances in Oncology. The Expanding Role of Octreotide,”
BioScientifica Ltd., Bristol, 2002.
[42] G. R. Cunha, S. W. Hayward, R. Dahiya and B. A. Foster,
“Smooth Muscle-Epithelial Interactions in Normal and
Neoplastic Prostatic Development,” Acta Anatomica, Vol.
155, 1996, pp. 63-72. doi:10.1159/000147791
[43] Y. C. Wong and Y. Z. Wang, “Growth Factors and
Epithelial-Stromal Interactions in Prostate Cancer Devel-
opment,” International Review of Cytology, Vol. 199,
2000, pp. 65-116. doi:10.1016/S0074-7696(00)99002-8
[44] A. T. Weeraratna, J. T. Arnold, D. J. George, A. DeMarzo
and J. T. Isaacs, “Rational Basis for Trk Inhibition Ther-
apy for Prostate Cancer,” Prostate, Vol. 45, 2000, pp.
140-148.
doi:10.1002/1097-0045(20001001)45:2<140::AID-PROS
8>3.0.CO;2-#
[45] M. H. Bohrer and J. Schmoll, “Immunohistochemical and
Morphometric Studies on Neuroendocrine Differentiation
of Prostate Adenocarcinomas,” Verhandlungen der Deut-
schen Gesellschaft für Pathologie, Vol. 77, 1993, pp.
107-110.
[46] S. Isshiki, K. Akakura, A. Komiya, H. Suzuki, N. Kamiya
and H. Ito, “Chromogranin A Concentration as a Serum
Marker to Predict Prognosis after Endocrine Therapy for
Prostate Cancer,” Journal of Urology, Vol. 167, 2002, pp.
512-515. doi:10.1016/S0022-5347(01)69075-X
[47] M. Iwamura, P. A. di Sant’Agnese, G. Wu, C. M.
Benning, A. T. Cockett, L. J. Deftos and P. A. Abrahams-
son, “Immunohistochemical Localization of Parathyroid
Hormone-Related Protein in Human Prostate Cancer,”
Copyright © 2012 SciRes. OJU
V. PERROT
Copyright © 2012 SciRes. OJU
182
Cancer Research, Vol. 53, 1993, pp. 1724-1726.
[48] R. J. Jin, W. Yongqing, N. Masumori, I. Kenichiro, T.
Tsukamoto, S. B. Shappell, S. W. Hayward, S. Kasper
and R. J. Matusik, “NE-10 Neuroendocrine Cancer Pro-
motes the LNCaP Xenograft Growth in Castrated Mice,”
Cancer Research, Vol. 64, 2004, pp. 5489-5495.
doi:10.1158/0008-5472.CAN-03-3117
[49] A. J. Raffo, H. Perlman, M. W. Chen, M. L. Day, J. S.
Streitman and R. Buttyan, “Overexpression of Bcl-2 Pro-
tects Prostate Cancer Cells from Apoptosis in Vitro and
Confers Resistance to Androgen Depletion in Vivo,” Can-
cer Research, Vol. 55, 1995, pp. 4438-4445.
[50] T. Fixemer, K. Remberger and H. Bonkhoff, “Apoptosis
Resistance of Neuroendocrine Phenotypes in Prostatic
Adenocarcinoma,” Prostate, Vol. 53, 2002, pp. 118-123.
doi:10.1002/pros.10133
[51] T. Yamamoto and N. Tanigawa, “The Role of Survivin as
a New Target of Diagnosis and Treatment in Human Can-
cer,” Medical Electron Microscopy, Vol. 34, 2001, pp.
207-212. doi:10.1007/s007950100017
[52] S. F. Shariat, Y. Lotan, H. Saboorian, S. M. Khoddam, C.
G. Roehrborn, K. M. Slawin and R. Ashfaq, “Survivin
Expression Is Associated with Features of Biologically
Aggressive Prostate Carcinoma,” Cancer, Vol. 100, 2004,
pp. 751-757. doi:10.1002/cncr.20039
[53] C. Koch-Brandt and C. Morgans, “Clusterin: A Role in
Cell Survival in the Face of Apoptosis?” Progress in Mo-
lecular and Subcellular Biology, Vol. 16, 1996, pp. 130-
149. doi:10.1007/978-3-642-79850-4_8
[54] J. Vilches, M. Salido, E. Fernandez-Segura and G. M.
Roomans, “Neuropeptides, Apoptosis and Ion Changes in
Prostate Cancer. Methods of Study and Recent Develop-
ments,” Histology and Histopathology, Vol. 19, 2004, pp.
951-961.
[55] R. Mazzucchelli, A. Lopez-Beltran, M. Scarpelli and R.
Montironi, “Predictive Factors in Prostate Needle Bi-
opsy,” Pathologica, Vol. 94, 2002, pp. 331-337.
doi:10.1007/s102420200060
[56] D. Singh, P. G. Febbo and K. Ross, “Gene Expression
Correlates of Clinical Prostate Cancer Behaviour,” Can-
cer Cell, Vol. 1, 2002, pp. 203-209.
doi:10.1016/S1535-6108(02)00030-2
[57] R. Ischia, A. Hobisch, R. Bauer, U. Weiss, R. W. Gasser,
W. Horninger, G. Bartsch Jr., D. Fuchs, G. Bartsch, H.
Winkler, H. locker, R. Fischer-Colbrie and Z. Culig,
“Elevated Levels of Serum Secretoneurin in Patients with
Therapy Resistant Carcinoma of the Prostate,” Journal of
Urology, Vol. 163, 2000, pp. 1161-1165.
doi:10.1016/S0022-5347(05)67714-2
[58] M. Yashi, A. Nukui, S. Kurokawa, M. Ochi, S. Ishikawa,
K. Goto, Y. Kobayashi, O. Muraishi and A. Tokue, “Ele-
vated Serum Progastrin-Releasing Peptide (31 - 98) Level
Is a Predictor of Short Response Duration after Hormonal
Therapy in Metastatic Prostate Cancer,” Prostate, Vol. 56,
2003, pp. 305-312. doi:10.1002/pros.10260
[59] S. J. Sim, A. B. Glassman, J. Y. Ro, J. J. Lee, C. J. Lo-
gothetis and F. J. Liu, “Serum Calcitonin in Small Cell
Carcinoma of the Prostate,” Annals of Clinical & Labo-
ratory Science, Vol. 26, 1996, pp. 487-495.
[60] V. Adamo, L. Noto, T. Franchina, G. Chiofalo, M. Pic-
ciotto, G. Toscano and N. Caristi, “Emerging Targeted
Therapies for Castration-Resistant Prostate Cancer,” Fron-
tiers in Endocrinology, Vol. 3, 2012, pp. 1-11.
[61] S. Detchokul and A. G. Frauman, “Recent Developments
in Prostate Cancer Biomarker Research: Therapeutic Im-
plications,” British Journal of Pharmacology, Vol. 71,
2011, pp. 157-174.
doi:10.1111/j.1365-2125.2010.03766.x
[62] W. P. Harris, E. A. Mostaghel, P. S. Nelson and B. Mont-
gomery, “Androgen Deprivation Therapy: Progress in
Understanding Mechanisms of Resistance and Optimizing
Androgen Depletion,” Nature Clinical Practice Urology,
Vol. 6, No. 2, 2009, pp. 76-85. doi:10.1038/ncpuro1296