Open Journal of Urology, 2012, 2, 173-182 Published Online October 2012 (
Neuroendocrine Differentiation in the Progression of
Prostate Cancer: An Update on Recent Developments
Valérie Perrot
Laboratory M.E.R.C.I.-EA 3829, Institute of Research and Biomedical Innovation (IRIB), University of Rouen, Rouen, France
Received July 31, 2012; revised August 30, 2012; accepted September 10, 2012
Neuroendocrine (NE) differentiation, either benign or malignant, is the hallmark of prostate cancer (PCa). Clusters of
malignant NE cells are found in most prostate cancer cases. NE differentiation is among the non-mutually exclusive
theories proposed to explain the progression to androgen independence of PCa. NE differentiation is usually associated
with an increased aggressivity and invasiveness of prostate tumors and a poor prognosis. This review aims to present an
overview of current knowledge on neuroendocrine differentiation in PCa to improve our understanding of tumour pro-
gression and androgen independence. The NE component represents an important therapeutic axis. Development of new
generation of drugs that selectively target NE-like cells may lead to the development of new therapeutic modalities for
advanced and hormone-refractory PCa.
Keywords: Prostate Cancer; Hormonal Therapy; Neuroendocrine; Neuroendocrine Differentiation; Neuropeptides;
Chromogranin A; Tumorigenesis; Adenocarcinoma
1. Introduction
Prostate cancer (PCa) is a leading cause of cancer-related
deaths among men in the Western countries. Its incidence
is increasing annually worldwide due to better and earlier
detection and also because of general aging of the
world’s population [1]. PCa tumours are heterogenous,
most men harbour slow-growing tumours while others
have neoplasms rapidly progressing to metastatic disease
[2]. When PCa metastasizes, the patient 5-year survival
rate drops to near 30% from virtually 100% when disease
remains localized (confined to primary site) or regional
(spread to regional lymphnodes) [3]. PCa depends on
androgens in the early stages. Therefore, androgen abla-
tion is the most common therapy, aiming to deprive the
androgen-receptive cells of their growth stimulus. Al-
though most patients respond initially to this treatment,
the tumour eventually recurs and enters an androgen-ind-
ependent stage for which treatment options are few and
generally ineffective [4].
A lot of progress has been made in understanding the
mechanisms which drive the development and the pro-
gression of PCa, and in particular factors leading to the
development of androgen independence (Figure 1). In
this regard, evidence has emerged that androgen-resistant
Androgen ablation therapy of prostatic cells
poptosis inactivationNeuroendocrine differentiation Aberrant activation of AR
PTEN inactivation
Bcl-2 overexpression
Genetic mutations of AR
Amplification or overexpression of
AR and its coactivators
Activation by non-steroids (EGF,
IGF-I, IL-6)
Increase of intracrine androgens
(adrenal androgens, estradiol,
Increase of NE-like cells
Transdifferentiation of prostatic
epithelial cells
Stem cells
Production of neuropeptides and growth
factors (autocrine/paracrine transmissions)
Tumour cells proliferation and survival
Figure 1. Molecular mechanisms of the transition from androgen-dependence to androgen-independence of PCa. AR: An-
drogen receptor; EGF: Epidermal Growth Factor; IGF-I: Insulin-like Growth Factor-I; IL-6: Interleukin-6.
opyright © 2012 SciRes. OJU
PCa are often associated with tumour enrichment in neuro-
endocrine (NE) cells. In the past years a growing body of
literature showed increased interest in the NE differentia-
tion phenomenon that occurs in PCa. In contrast, less
information is available on the specific role that NE cells
play in the pathophysiology and prognosis of PCa. This
review aims to present an overview of the current know-
ledge on NE cells and differentiation in PCa to improve
our understanding of tumour progression and androgen
independence. Better knowledge of PCa initiation and
progression will help for developing new strategies for
tumour prevention and treatment.
2. Neuroendocrine Cells of the Normal
Prostate: Origin, Localisation and
Normal prostatic tissue is composed of stromal and
epithelial compartments. The stroma not only acts as a
supporting tissue, but also participates to the endocrine
and paracrine microenvironment that controls prostatic
epithelium growth and differentiation.
Three types of epithelial cells are found in adult pro-
static gland: secretory, basal and neuroendocrine (NE).
Luminal secretory cells are the most abundant and re-
quire androgens for growth and survival. They synthesize
and secrete products of the seminal plasma, including
prostatic-specific antigen (PSA). Basal cells are the prin-
cipal epithelial proliferating cell type and are androgen-
insensitive. They give rise to pluripotent cells, which are
responsive to androgens, and can differentiate into basal
cells, differentiated luminal cells, and possibly also NE
cells. NE cells are ubiquitously present throughout the
body and constitute a minor epithelial cell population
widely distributed in normal prostatic acini and ducts.
NE cells do not express the proliferation associated Ki 67
and MIB-1 antigens [5]. These post-mitotic cells are
highly specialized cells, which share structural, func-
tional and metabolic properties with neurons [6]. NE
cells do not express androgen receptors [7,8], suggesting
that they are androgen-insensitive [9].
The origin of NE cells in normal prostate is still under
debate. The fact that NE cells do not express cytokeratin,
a basal cell layer marker, suggests that they originate
differently from other prostatic epithelial cells. NE cells
may be derived either from undifferentiated basal cells of
the prostatic epithelium [10] or represent an independent
cell lineage derived from a neurogenic origin [11]. Fur-
ther investigations will be necessary to clearly establish
the origin of NE prostatic cells.
Histological studies revealed that in normal prostate
gland, NE cells exhibit two distinct morphologies: 1)
open cells with extensions at their apex that connect with
the lumen, and 2) closed cells with dendritic-like proc-
esses that extend between adjacent cells and do not have
contact with the lumen [12]. Both subpopulations of NE
cells participate to a communication network, in particu-
lar with the prostatic stroma, through their various secre-
tory products.
In normal prostate, NE cells regulate prostatic growth,
differentiation and secretion in an androgen-independent
manner. NE cells contain neurosecretory granules rich in
various peptide hormones and biogenic amines such as
calcitonin [13], parathyroid hormone-related protein
(PTHrP) [14], NE markers like chromogranins (CgA,
CgB) [15] and neuron-specific enolase (NSE), serotonin
[16], bombesin [17] and somatostatin [18] (Table 1).
The majority of these products can be either released
into the blood stream or act locally. Relatively high lev-
els of peptides are also found in the seminal fluid, sug-
gesting that they may regulate sperm function. Therefore,
the secretory products of NE cells affect target cells by
endocrine but also paracrine and/or autocrine transmis-
sions in an androgen-independent fashion due to the lack
of androgen receptor.
The prostatic epithelium contains cells expressing a
continuum of biological properties, differentiation mark-
ers, and variable degrees of androgen-dependence. It is
assumed that the prostatic epithelium is under hormonal
control of androgens for growth and survival. Conse-
quently, androgen deprivation, which is the most com-
mon PCa therapy, elicits massive loss (up to 90%) of
prostatic epithelial cells and their androgen-dependent
precursors [19], and a concomitant increase of androgen-
independent cells, such as NE and basal cells.
3. Neuroendocrine Differentiation,
Hormone-Independence and Tumour
Progression in Pca
Androgens play an important role in the development of
normal prostate as well as in the carcinogenesis of PCa
through the activation and signaling of the nuclear andro-
gen receptor (AR). During prostatic tumorigenesis, a pro-
gresssion from normal prostate to prostatic intraepithelial
neoplasia (PIN) to adenocarcinoma, and finally to small-
cell carcinoma of the prostate is observed. It is generally
admitted that NE differentiation is part of the oncogenic
A focal NE differentiation is present in almost all con-
ventional prostate adenocarcinoma occurring in 30% -
100% of the cases [20,21]. In addition, NE differentiation
can be found in highly aggressive small cell neuroendo-
crine prostate carcinoma, which are rare variants (0.5% -
2%), as well as in certain carcinoid and carcinoid-like
tumours. NE cells are also observed in PIN and in me-
tastatic PCa [22]. At all stages and grades of PCa, scat-
tered NE tumour cells, singly or in dispersed clusters, are
observed in the vicinity of non-endocrine dividing cells.
Copyright © 2012 SciRes. OJU
Table 1. General characteristics, functional roles, products
and receptors of normal NE and NE tumour cells in pros-
General characteristics
Normal NE cell Tumour NE cell
Androgen-receptor negative Androgen-receptor negative
Non/low-proliferating activity Non/low-proliferating activity
PSA-negative PSA-negative
Bcl-2-negative Bcl-2-positive
AMACR-negative AMACR-positive
Intermediate and basal cell markers Luminal secretory cell markers
(Cytokeratin-5) (Cytokeratin-18)
Non-aggressive Highly aggressive
Functional roles
Regulation of cell growth and differentiation
Regulation of homeostasis
Regulation of prostatic secretion
Bombesin/gastrin releasing peptide (GRP)
Calcitonin, calcitonin gene-related peptide
Cholecystokinin (CKK)
Chromogranins (CgA, CgB)
Gastrin-releasing peptide
-human chorionic gonadotropin (HCG)
Neuron-specific enolase (NSE)
Neuropeptide Y
Parathyroid hormone-related protein (PTHrP)
Proadrenomedullin N-terminal peptide
Thyroid stimulating hormone (TSH)-like peptide
Vascular endothelial growth factor (VEGF)
Vasoactive intestinal peptide (VIP)
Bombesin/GRP (GRPR)
Calcitonin (hCTR-2)
Gastrin releasing peptide (GRPR)
Neuropeptide Y
Serotonin (5HTR1A, B)
Somatostatin (SSTR1-5)
Vasoactive intestinal peptide
PTHrP receptor
A recent report, from Hirano et al., [23] described dif-
ferences in NE cell distribution in PCa. In low grade PCa,
morphological features of NE differentiation can be ob-
served in CgA-positive areas or occasionally in single
CgA cells. In moderately differentiated PCa, NE cells are
mostly organized in clusters of focal agglomerates, where-
as in high grade PCa, diffuse areas of NE differentiation
morphologically similar to surrounding carcinoma cells
can be observed.
The origin of NE tumour cells in PCa
The origin of NE cells in prostate tumoral lesions and
the underlying molecular mechanisms of enrichment
remain controversial. As proposed by Bonkhoff et al. [5,
24], NE tumour cells can arise from the intermediate
stem cells, under pathological conditions such as andro-
gen deprivation, contributing to increase NE cell popula-
tion beyond to normal. Alternatively, PCa cells can un-
dergo a “transdifferentiation” process to become NE-like
cells, which express NE markers and acquire a NE phe-
notype. They begin synthesizing their own growth fac-
tors, becoming more autonomous and less dependent on
the tissue microenvironmental control. These cells still
retain some epithelial characteristics [25], in particular
cytokeratin K8/18 [26] and prostatic acid phosphatase
[27] luminal cell markers, suggesting that they originate
from cancerous luminal epithelial cells. Thus, the in-
crease of NE tumour cells as a result of malignant trans-
formation of epithelial/basal cells is a common charac-
teristic of PCa progression. Further investigations will,
however, be necessary to clearly establish the origin of
NE tumour cells in prostate adenocarcinoma.
Despite controversies regarding their origin, it is be-
coming increasingly clear that NE tumour cells are dis-
tinct from NE cells in normal prostate (Table 1). Ac-
cording to histological studies, NE tumour cells are mor-
phologically similar to the surrounding carcinoma cells
[28]. Moreover, a recent study deciphered some genetic
features of NE tumour cells and concluded to their rela-
tionship with carcinoma cells [29]. They also differ from
normal NE cells in the overexpression of proteins, such
as anti-apoptotic protein B cell lymphoma protein 2 (Bcl-
2) [30] as well as-methylacyl-CoA racemase (AMACR),
an enzyme involved in the β-oxidation of fatty acids [27].
Additionally, NE tumour cells are posi- tive for cyto-
keratin 18, a luminal cell-type cytokeratin, whereas nor-
mal NE cells rather express cytokeratin 5, a basal cell
marker [25,26].
Mechanisms of androgen deprivation therapy-induced
NE differentiation
Primary androgen deprivation therapy is convention-
ally used as a treatment for PCa. The response is usually
transient and half of cancers progress to a hormone in-
dependent status over a period of 16 to 18 months, for
which there is no successful therapy [31].
Copyright © 2012 SciRes. OJU
One major feature regarding prostatic cancer cells is
their ability following androgen deprivation to undergo a
transdifferentiation process, in which they acquire char-
acteristics of NE cells and express NE markers, thus be-
coming NE-like cells. As they grow independently of
androgen, these subpopulations of NE-like cells give rise
to clones that have growth advantage, due to the loss of
checks and balances, over their counterparts that retain
androgen dependence. They may additionally acquire
other alterations at both genetic and epigenetic levels that
could contribute to the progression to androgen inde-
pendence. Thus, through the course of androgen depriva-
tion therapy, NE-like cells gradually substitute the func-
tion of stromal cells and allow continued proliferation of
cancer cells, contributing to progression and aggressive-
ness of PCa.
A growing body of literature confirms that NE differ-
entiation is more abundant in PCa after androgen with-
drawal, indicating that NE component of PCa is resistant
to hormone therapy [32]. Moreover, the increase in NE
differentiation also appears to be related to the duration
of treatment, including hormone deprivation therapy or
chemotherapy [33]. Indeed, a long-term androgen depri-
vation therapy can induce downstream signaling path-
ways that drive the acquisition of a NE aggressive phe-
notype. Acquisition of NE characteristics could also oc-
cur in response to the influence of prostatic environment,
and in particular the synergistic functional network be-
tween epithelial and NE prostatic system that may pro-
mote internal cell abnormalities, thus triggering the in-
duction, and maintenance of NE differentiation.
These observations initially made using clinical sam-
ples have been confirmed and the underlying molecular
mechanisms of androgen depletion-induced NE differen-
tiation studied in vitro and in animal models of PCa. In
an effort to reproduce NE differentiation of prostatic epi-
thelial cells in vitro, a number of human PCa cell lines
(i.e. LNCaP, DU145, PC3, PC-82, LAPC-4) as well as
stable clones of NE-like PCa cells and co-cultures of
prostatic cells which summarize tumour characteristics in
vivo have now been established. Several studies revealed
that androgen deprivation induced NE transdifferentia-
tion of both androgen-sensitive and androgen-insensitive
PCa cell lines which acquire NE phenotype and express
NE markers and peptides [34]. Androgen depletion in-
duced NE differentiation through the increase of intra-
cellular cyclic AMP (cAMP) levels that in turn induce
the activation of protein kinase A (PKA) [35]. Conflict-
ing results, however, have reported the involvement of
Erk/Mitogen-Activated Protein Kinase (MAPK) pathway
in cAMP/PKA-mediated NE differentiation.
The use of these androgen-sensitive and androgen-in-
sensitive PCa cell lines has led to interesting data and,
could still provide insights into molecular mechanisms of
NE differentiation, in addition to identifying novel thera-
peutic targets. Transdifferentiation processes of these
PCa cell lines by various stimuli are, however, transient
and cells can fully revert to their original phenotype in
the absence of inducers, thus making them different from
terminally differentiated human PCa NE cells. A better
characterization of expression profiles of NE markers
and tumorigenic activity of these different PCa cell lines
is still needed.
In this regards, stable clones of NE-like PCa cells have
been established to elucidate the molecular mechanisms
of NE differentiation and its role in PCa progression.
These NE-like LNCaP subclone cells obtained by pro-
longed culturing in androgen-reduced medium, termi-
nally transdifferentiate into NE-like cells and grow to
become independent cell lines which exhibit a high tu-
morigenicity compared to LNCaP parental cells [36,37].
Importantly, they cannot be reverted to LNCaP phenol-
type and they maintain the expression of various NE
markers. Therefore, LNCaP subclone cells resemble to
NE-like PCa cells found in adenocarcinomas and may
have a better clinical relevance than PCa cell lines pre-
viously mentioned.
In addition, co-culture models have been developed in
order to reconstitute the complex interplay existing be-
tween prostatic epithelial, stromal and extracellular ma-
trix (ECM) components of the prostate gland [38]. Ef-
forts need to be pursued to develop these cell culture
models that are taking into account dynamic cellular in-
teractions within the prostatic microenvironment which
may influence or promote internal cell abnormalities in
the progression towards the acquisition of NE phenotype
and the hormone-independent PCa cell growth.
Studies on in vivo animal models of PCa (human tu-
mour xenografts and transgenic mice (TRAMP and
LADY mice)) validate in vitro observations, supporting
the importance of NE differentiation in PCa. In these
animal models, tumour progression is associated with the
acquisition of NE characteristics by cancer cells. More-
over, NE differentiation has been reported to markedly
increase after castration in xenograft models of human
PCa and to precede the emergence of tumour cell prolif-
eration and progression to androgen independence [39].
Data from in vitro and in vivo studies collectively sup-
port the notion that androgen deprivation induces trans-
differentiation of androgen-sensitive adenocarcinoma
cells to become NE-like cells in PCa lesions. It remains
however to determine whether those transdifferentiated
NE-like cells exhibit similar biochemical properties as
that of NE-like PCa cells.
In addition to be induced by androgen deprivation
conditions, transdifferentiation of prostatic cells in NE-
like phenotype can also be initiated by various cues such
as cyclic AMP (cAMP), epinephrine, genistein, VIP, cal-
Copyright © 2012 SciRes. OJU
citonin, growth factors and cytokines as well as through
the activation of various intracellular signaling pathways,
including signal transducer and activator of transcription
(STAT-3), MAPKs, cAMP/PKA and phosphatidylinosi-
tol 3-kinase (PI3K) [40]. The diversity of the pathways
that may promote NE cell transdifferentiation could ex-
plain at least in part PCa heterogeneity. It remains yet to
determine if NE differentiation induced by agents other
than androgen depletion also occurs through inhibition of
AR signalling. A better knowledge of these alternative
signalling pathways will help to determine what drives
acquisition of the NE process and may also allow the
identification of new therapeutic targets in order to block
or prevent PCa progression.
Paracrine to autocrine shift in tumour cell regulation
during malignant transformation of epithelial cells
NE tumour cells do not express androgen receptors [7,
8]; they sustain their function in the androgen-deprived
environment by establishing autocrine and paracrine
networks to stimulate androgen-independent growth of
prostate carcinoma cells. These cells produce a wide
range of neuropeptides and neurotransmitters involved in
the interactions between the different compartments of
the prostate. An ever growing list of prostatic NE cell
products have been identified and cell surface receptors
for some of these NE products have been identified in
non-NE tumour cells [25,41].
The ability of non steroids like growth factors (insu-
lin-like growth factor I (IGF-I), keratinocyte growth fac-
tor (KGF)) and cytokines (interleulin 6 (IL-6)) to mimic
the effect of androgens through the mitogen-activated
protein kinase (MAPK) signaling pathway [25] contrib-
utes to the adaptation of NE tumour cells to an andro-
gen-depleted environment, thus increasing their malig-
nant potential. Therefore, the autocrine transmission may
become more important in androgen-independent tu-
mours and contribute to CaP progression. Furthermore,
during the evolution from normal to malignant cancer
cells, the shift to autocrine transmission may also be as-
sociated with the acquired regulation of genes involved
in proliferation and survival that are not normally ex-
pressed in normal prostate epithelial cells.
Cell-cell interactions are extremely important in main-
taining homeostasis between epithelial and stromal com-
partments of the prostate. Through the course of andro-
gen deprivation therapy, prostatic epithelial cell growth
and differentiation can be induced by paracrine growth
factors such as epidermal growth factor (EGF), fibroblast
growth factor (FGF), KGF, nerve growth factor (NGF)
and IGF-I [42,43] that will diffuse from stromal to
epithelial compartments, leading to the activation of AR
target genes in a ligand-independent manner. Growth
factors produced by prostatic epithelial cells can also act
in an autocrine manner to stimulate this process.
Aside from these observations, there is considerable
evidence indicating that during the transformation pro-
cess of prostatic epithelial cells some factors are shifted
from paracrine to autocrine regulation, as documented
for neurotropins. Classically, NGF, neurotropin-3 and
brain-derived growth factor are involved in the NE regu-
lation of prostatic function. NGF is produced by stromal
cells and is not a survival factor for epithelial cells in the
normal prostate. Interestingly, reports indicate that in
PCa, NGF can be secreted by malignant prostatic epithet-
lial cells and regulate an acquired survival pathway
through an autocrine mechanism [44].
Therefore, identification of other growth and survival
factors produced by NE tumour cells and a better
knowledge of the molecular mechanisms underlying this
acquired expression is critical to understand what causes
NE cells to become malignant and to effectively treat the
Role of NE tumour cells in PCa
NE tumour cell population is highly aggressive and
exhibit tumorigenic activity. Several studies reported that
the proportion of NE tumour cells is increased in high
grade and high stage tumours [16,45], and in particular in
androgen-deprived and androgen-independent tumours.
In most cases, NE differentiation is correlated with a
poor prognosis [46].
Tumour enrichment in NE-like cells and the conse-
quent increase in neurosecretory products can contribute
to the androgen-independent proliferation of PCa through
their mitogenic effects on adjacent cancer cells, thus in-
creasing malignancy and reducing responsiveness of can-
cer cells to androgen ablation therapy. Secretory products
of NE-like cells have been shown to increase the prolif-
eration index (Ki-67-positive cells) of neighboring can-
cer cells through paracrine mechanisms [5]. Some of the
peptide products of NE cells in the prostate, like bombe-
sin, calcitonin and PTHrP, can affect prostate adenocar-
cinoma cell proliferation in vitro [9,47].
Moreover, neurosecretory factors produced by NE-like
cells may also act by enhancing the sensitivity of prosta-
tic cancer cells to lower circulating androgen levels,
consequently allowing PCa to escape androgen ablation
therapy. NE-like cells may regulate adjacent tumour cells
by paracrine mechanisms, highlighting the strong po-
tential of neurosecretory products [48].
The balance between cell proliferation and cell death
is also disrupted in NE tumour cells. The malignant po-
tential associated with NE differentiation is strongly in-
creased by the fact that NE tumour cells are resistant to
apoptotic cell death [49,50]. This phenomenon may al-
low prostatic NE tumour cells to escape radiation and
chemotherapy. The apoptosis resistance of NE cells may
be partially explained by the overexpression of survival
proteins, such as survivin and clusterin. Survivin is a
Copyright © 2012 SciRes. OJU
member of the inhibitor of apoptosis (IAP) family with
direct inhibitory action on caspase-3 and caspase-7 activ-
ity. Its expression is observed during fetal development
but not in normal, terminally differentiated adult human
tissues [51]. Additionally, survivin overexpression has
been reported in various adenocarcinomas including PCa.
Interestingly, increased expression of survivin seems to
be associated with PCa progression after radical prost-
atectomy [52]. Clusterin is a glycoprotein, involved in
diverse biologic processes including transport of lipo-
proteins, modulation of cell-cell interactions, cell death
and tissue remodeling [53].
In addition, overexpression of the anti-apoptotic Bcl-2
protein by NE tumour cells may also protect them from
apoptotic stimuli, and thereby increase their resistance to
androgen deprivation therapy and their ability to progress
towards hormone-refractory prostate cancers (HRPC)
[49]. Therefore, enhancing the pro-apoptotic potential of
PCa malignant cells through targeting key players in-
volved in apoptosis resistance is one strategy to treat an-
drogen-independent PCa.
Furthermore, NE tumour cells may also block the apo-
ptotic process of prostatic cells in their vicinity through
their neurosecretory products, contributing to andro-
gen-independent proliferation of PCa cells and cancer
progression. Bombesin and calcitonin have been reported
to decrease apoptosis of PCa cells in vitro [54].
Several reports indicated that NE tumour cells might
also promote neovascularisation of PCa. They may mod-
ulate angiogenesis through secreted angiogenic factors
such as vascular endothelial growth factor (VEGF), pla-
telet-derived growth factor (PDGF) and basic fibroblast
growth factor (FGF), and thus influence prostatic cell
growth and differentiation. This idea is supported by the
fact that benign prostatic tissue contains low level of
VEGF, whereas VEGF staining intensity correlates with
Gleason grade. Complete androgen blockade for three
months before surgery, decreased VEGF level and vas-
cularisation, except in areas where cells are NE-like [55].
In radical prostatectomy samples, there is a correlation
between NE differentiation and neovascularisation and
both correlate with tumour grade and tumour stage.
Increasing knowledge of the role of NE-like cells
throughout the course of prostatic carcinogenesis and
tumour progression will pave the way to the development
of new therapeutic modalities for advanced and hor-
mone-refractory PCa.
4. Pronostic Significance of NE
Differentiation in PCa
Discrepancies in reported incidence (30% - 100%) of NE
differentiation in PCa mainly occur from the limited
number of NE cell biomarkers used to score NE features.
Classically, NE differentiation can be assessed by im-
munoreactivity for neuroendocrine markers or bioactive
hormones (somatostatin, 5-HT), measurement of serum
levels of NE markers or electron microscopy (neurose-
cretory granules).
Among the different NE markers, most of the attention
has been given to the detection of CgA and NSE in PCa
clinical specimens. CgA belongs to the granin family of
acidic secretory glycoproteins that is found in secretory
granules of the regulated pathway of a wide variety of
endocrine cells and neuron, including NE tumour cells.
Classically, CgA serves as a generic marker of the NE
cell population. So far, detection of CgA in neoplastic
tissue remains one of the most reliable methods to assess
NE differentiation [25]. CgA is considered as one of the
PCa progression marker after radical prostatectomy [56].
The use of CgA as a prognostic factor in androgen-sen-
sitive PCa is still controversial.
Despite the fact that PSA is commonly used as a mark-
er for the early detection of PCa as well as monitoring
the therapeutic response and tumour recurrence, it is not
enough specific and sensitive. A growing body of litera-
ture suggests that, independently of PSA, serum CgA is a
significant predictor of poor prognosis in patients with
advanced and hormone-refractory prostate cancers [22].
Consistent with histological findings, levels of CgA are
increased in PCa patients and correlate with tumour stage.
A microarray study on PCa revealed that CgA gene is
among the 5 genes strongly correlated with the Gleason
score, which can predict the outcome following radical
prostatectomy [56]. Therefore, serum measurements of
NE markers in conjunction with PSA could help screen
In addition to CgA, other serum markers such as CgB,
secretoneurin, a proteolytic product of secretogranin II
(also known as CgC), gastrin-releasing peptide/ProGRP
and NSE, may serve as additional prognostic and/or di-
agnostic markers [57,58]. Serum calcitonin level has
been reported to be a more specific marker for prostatic
small cell carcinoma [59].
The possibility to treat NE differentiation in androgen-
independent PCa is related to the development of specific
and sensitive markers, clinically detectable in patients
with PCa. Further investigations will be necessary to
strengthen the prognostic significance of NE tissue mark-
er in PCa.
5. Neuroendocrine-Targeted Therapy
One of the most troubling aspects of PCa progression is
the conversion from an androgen-dependent to independ-
ent state, which at present defies any effective treatment.
Different therapeutic approaches, including surgery, ra-
diation therapy, and androgen deprivation therapy, have
become the gold standard treatment for hormone-dep-
endent PCa. Until 2010, chemotherapy and in particular
Copyright © 2012 SciRes. OJU
taxane-based chemotherapy (paclitaxel, docetaxel) which
is of limited benefit represented the main therapeutic
option in the occurrence of hormone-refractory PCa.
Novel chemotherapeutics and targeted agents for patients
with metastatic hormone-refractory PCa stages have been
very recently introduced into clinical practice and include
abiraterone acetate (a new androgen biosynthesis inhibi-
tor), cabazitaxel (a novel microtubule inhibitor), MDV-
3100 (a novel androgen-receptor antagonist), the radio-
isotope alpharadin (radium-223), sipuleucel-T (an immu-
notherapeutic agent) and denosumab (a bone-targeting
agent) [60].
Other novel approaches currently being tested in early
clinical trials for advanced PCa include immunological
therapies (PCa vaccines, PCa antibodies), angiogenesis
inhibitors (targeting VEGF, PDGF, PDGF receptor), epi-
genetic therapy (histone deacetylase (HDAC) inhibitors),
pro-apoptotic agents (Bcl-2, survivin modulators), and
interference in growth-factor-mediated pathways (mam-
malian target of rapamycin (mTOR)) [61].
It is now widely accepted that NE differentiation
which occurs in prostatic adenocarcinomas is associated
with PCa progression and aggressiveness. NE-like cells
increase concomitantly with the duration of androgen de-
pletion, thus blocking NE function and/or differentiation
will most likely prolong the therapeutic window of an-
drogen deprivation therapy. The NE axis appears to be an
important therapeutic target for drug development in ad-
vanced PCa. Pharmaceutical agents (somatostatin ana-
logs, bombesin antagonists, serotonin antagonists, mTOR
inhibitor, pro-apoptotic agents) able to block the tumour-
promoting action of NE-like cells products are under
NE differentiation is the hallmark of PCa with possible
prognostic significance and consequences on therapy
response. Detection of focal NE differentiation, using
CgA marker, may help to identify patients who are more
prone to endocrine therapy failure. In organ-confined di-
sease, assessment of NE differentiation could identify
patients that would benefit from more aggressive therapy.
Intermittent androgen deprivation or antiandrogen mono-
therapy could be used to slow down marked NE differen-
tiation, in conjunction or not with NE targeted therapy, to
delay the progression towards hormone-independent PCa,
while maintaining clinical benefit [62].
The NE axis remains an important therapeutic pathway
for drug development in advanced PCa. Development of
new generation of drugs that selectively target NE-like
cells may help targeting populations of PCa that may be
resistant or becoming resistant to traditional therapies.
6. Conclusions
In the past years, much progress has been made towards
better understanding the development and progression of
PCa as well as the factors which drive the development
of androgen independence. NE differentiation is among
the non-mutually exclusive theories proposed to explain
the progression to androgen independence of PCa. Al-
though, NE differentiation has been demonstrated in a
variety of carcinomas arising in different tissues, making
it of oncological interest, very little is known about the
role of NE differentiation in PCa pathophysiology.
Recent progress in terms of PCa research highlighted
the role of NE differentiation in prostatic carcinomas.
Through the course of androgen deprivation therapy,
NE-like cells gradually substitute the function of stromal
cells and allow the continued proliferation of cancer cells,
contributing to the progression and the aggressiveness of
PCa. This subset of androgen-independent cancer cells is
also associated with a poor prognosis. Interest in under-
standing the neuroendocrine differentiation in PCa has
increased with the identification of several neuroendo-
crine factors regulating the homeostasis of prostate by
autocrine and/or paracrine mechanisms. There is now an
ever-growing list of factors that are secreted by these
prostatic NE tumour cells which regulate their prolifera-
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
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
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