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NEUROENDOCRINE DIFFERENTIATION IN PROSTATE CANCER
A. SCIARRA
et al.
Neuroendocrine differentiation in human prostate tissue:
is it detectable and treatable?
A. SCIARRA, G. MARIOTTI, V. GENTILE, G. VORIA, A. PASTORE, S. MONTI and F. DI SILVERIO
Department of Urology ‘U. Bracci’, University La Sapienza, Rome, Italy
Accepted for publication 9 September 2002
INTRODUCTION
Until recently the available publications on
neuroendocrine (NE) differentiation in the
prostate were few compared with the
voluminous literature related to NE cells in
other organs, e.g. the gastrointestinal tract
and lung. This situation has begun to change,
with a marked increase in the number of
publications related to NE differentiation in
prostatic carcinoma. Nonetheless, research on
the prostatic NE system is still in its infancy.
Very little is known about the specific role that
these cells have in the prostate, or their
relationship to the pathogenesis, growth and
prognosis of prostatic diseases. In this review
we present some of the information that is
know about NE cells and differentiation in the
prostate. We then speculate on the potential
role of NE differentiation in prostate
carcinoma and how this differentiation may
be clinically analysed and treated.
PROSTATIC NE CELLS: ORIGIN AND
LOCATION
NE cells, in addition to basal and secretory
cells, represent the third epithelial cell type of
normal prostatic tissue [1]; all three cell types
share a common origin from pluripotent stem
cells. The stem-cell model, as defined by
Bonkhoff and Remburger [2], distinguishes
three compartments in the prostatic
epithelium: (i) the stem-cell compartment
which is androgen-independent and
unresponsive to androgen; (ii) the
proliferation compartment of androgenindependent but androgen-responsive cells;
and (iii) the differentiation compartment
derived from committed basal cells, giving rise
to androgen-independent NE cells, androgenresponsive basal cells and androgendependent secretory cells.
NE cells of the urethro-prostatic region were
first described by Pretl in 1944 [3]. They
represent a minor epithelial cell population
438
which is present in the normal, hyperplastic
and dysplastic prostate. NE cells are located in
all regions of the human prostate at birth, but
rapidly decrease in the peripheral prostate
after birth and then reappear at puberty [4].
After puberty, the number of NE cells seems
to increase until an apparently optimum
level is reached, which persists from 25 to
54 years old [5]. The relationship of age
beyond puberty to the number and
distribution of these endocrine-paracrine cells
has not been definitively assessed, but in the
guinea pig these cells in the peripheral
prostate increase markedly with adult age [6].
Studies on adult human prostates indicate
that NE cells are more frequent in the
periurethral ducts than in the peripheral parts
of the gland [7]. Others [8,9] also described
the presence of NE cells in the stroma of fetal
and infantile prostates.
There are two morphological types of
prostatic NE cells, i.e. open flask-shaped cells
with long slender extensions reaching the
lumen, and closed cells with no luminal
extension [10]. Both cell types have a complex
appearance with irregular dendrite-like
processes extending between adjacent
epithelial cells.
NE cells are further characterized by the
presence of cytoplasmic dense core granules,
and ultrastructural studies have shown
these constitutive NE cell organelles to be
markedly heterogeneous in size and form,
suggesting the existence of several cell
variants [10]. Abrahamsson et al. [1]
summarized the histological and cytological
patterns of NE cells in the prostate gland as:
‘Ideally, a NE cell is defined as a cell of
neuronal or epithelial type that fulfils all or
most of the following criteria: it contains
secretion granules; its secretion is essentially
directed towards the blood; the secretion
granules store peptide hormones and or
biogenic amines; it is often argynophil or even
argentaffin, and is immunoreactive to
antisera against neurone-specific enolase
©
(NSE) or chromogranin A or other so-called
NE markers’.
Immunocytochemical studies show that the
androgen receptor is not expressed in
prostatic NE cells, suggesting that they may
function independently of androgen
regulation [11].
PROSTATIC NE CELLS: FUNCTION
The function of NE cells in the prostate is
unknown, but it is hypothesized that they may
be involved in regulating the growth and
differentiation of the developing prostate,
and in regulating secretory processes in the
mature gland. This hypothesis is based on
three factors: (i) the morphology of the NE
cells; (ii) the known function of the NE
secretory products; and (iii) the analogy with
the known physiology of NE cells in the
peripheral system.
NE cells were defined by Pearse [12] as
‘APUD’ to refer to chemical characteristics
of ‘amine precursor uptake and
decarboxylation’, common to the cells of this
system. The NE prostate cells produce
serotonin, chromogranin A, chromogranin B,
secretogranin or chromogranin C, and a
thyroid-stimulating hormone-like peptide.
Other granules are present in smaller
subpopulations of NE cells, e.g. a calcitoningene family including calcitonin, katacalcin
and calcitonin gene-related peptide,
parathyroid hormone-related protein
(PTHrH), and ahCG-like peptide. Finally, some
peptides are inconsistently present in some
NE cells, e.g. bombesin, gastric-releasing
peptide or somatostatin. These regulatory
peptides may act through lumecrine,
endocrine, paracrine and autocrine
mechanisms. The rather long dendritic
processes of these cells suggest paracrine
regulation. The open cell type may be related
to lumecrine secretion, but more probably
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NEUROENDOCRINE DIFFERENTIATION IN PROSTATE CANCER
reflects sampling of the luminal contents to
relay regulatory signals to epithelial prostatic
cells, to maintain homeostasis of the exocrine
secretion.
TGF-a antibody; TGF-a has been reported to
be expressed in various NE tumours [19].
PROSTATIC NE CELLS: REGULATION
Some of these products have growth factor
activity, e.g. serotonin, calcitonin gene-related
peptide, bombesin), others have
neurosecretory inhibitory properties
(somatostatin) and others may be involved in
regulating secretory processes (serotonin,
chromogranins, bombesin, PTHrH) [13].
The most predominant product of prostatic
NE cells is chromogranin A, a member of a
family of acidic secretory proteins found in
the secretory granules of a wide variety of
endocrine cells and neurones. The function of
chromogranin A is still an open question [14];
it may have extracellular bioactivity and act as
an autocrine paracrine regulatory agent in
secretory processes. Moreover, chromogranin
A may modulate peptide hormone processing
because it has several dibasic sites, which
possibly serve as competitive substrates for
proteolytic enzymes [14].
Another secretory product commonly
associated with prostatic NE cells is serotonin,
a biogenic amine that mediates different
functions by binding to several receptor
subtypes [15]. Growth factor activity has been
attributed to serotonin, it may also be
involved in regulating morphogenesis, and it
has been shown to regulate the secretion of
peptide hormones from endocrine cells [16].
Serotonin may also serve as a
neurotransmitter and vasoactive agent; in the
male genital tract, neurotransmitters
including serotonin may be ‘permissive’ for
androgen action [17]. Finally, NSE is often
expressed by prostatic NE cells and is
sometimes referred to as a marker of NE
differentiation [14].
Expression of angiogenic factors such as
platelet-derived growth factor and basic
fibroblast growth factor has been shown in
NE tumours. Intense granular cytoplasmic
staining for vascular endothelial growth
factor (VEGF) was reported in a cluster of a
NE-like cells in prostate carcinoma, and a
similar distribution of VEGF and
chromogranin A-positive cells, suggesting coexpression in some cells [18]. Therefore NE
cells in the prostate might modulate
angiogenesis and thus influence prostate
growth and differentiation. A subpopulation
of NE cells was also intensely stained with
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2003 BJU INTERNATIONAL
Prostatic NE cells show no proliferative
activity; prostatic epithelial cells characterized
by chromogranin A consistently lack the
proliferation-associated Ki-67 and MIB-1
antigens [20]. Thus an important question is
how these prostatic NE cells are regulated.
NE cells in normal and neoplastic prostate are
devoid of androgen receptors, indicating that
they are androgen-insensitive, but they
express EGFR and c-erbB-2. Iwamura et al.
[21] described the expression of human EGFRs
in prostatic NE cells, suggesting that EGF is
significantly involved in the regulation of
these cells. The same authors also reported
the expression of PTHrP and its mRNA in
prostatic NE cells; EGF regulates the secretion
of PTHrP and PTHrP may be involved in the
regulation of EGFR on NE cells. In conclusion,
it seems that NE cells in the prostate gland are
directly modulated by some growth factors
(EGF, TGF-a) and not by hormones. Moreover,
epithelial secretory and basal prostate cells
probably influence NE cells by cross-signalling
at their junctions [21]. NE cell regulatory
pathways may also involve the cell's products
(neuropeptides, i.e. serotonin).
Diaz et al. [22] reported that expression of the
NE marker chromogranin A in the LNCaP and
DU-145 human prostate cancer cell lines
was up-regulated by interleukin-1b and
interleukin-6, and down-regulated by
interleukin-2. In particular, interleukin-6 may
influence prostate cell growth modulating NE
activity in the prostate gland. In the prostate,
interleukin-6 induces the formation of neurite
extensions, and morphological features
associated with NE differentiation and
enhanced expression of neuronal markers
[23]. Some authors also report that NE cells in
the prostate are innervated by autonomic
efferent nerves, suggesting the regulation of
these cells by the nervous system [10].
DETECTING NE DIFFERENTIATION AND
ACTIVITY IN THE PROSTATE
Serum levels of NE markers, particularly
chromogranin A, could reflect the NE activity
of prostate carcinoma and be used during the
follow-up evaluation of advanced prostate
carcinoma. There is co-expression of NE
markers and prostate markers such as PSA
in prostate carcinoma cells [24]. Serum
levels of chromogranin A, pancreastatin,
chromogranin B and C were evaluated and
compared as serum markers in the follow-up
of patients with prostate cancer [25].
Chromogranin A appears to be the best
marker of NE activity, but in some poorly
undifferentiated tumours, chromogranin B is
the major component and could be expressed
in poorly differentiated carcinomas that
almost completely lack chromogranin A and
C. According to Wu et al. [26], in about half of
patients with metastatic prostate cancer
increases in serum chromogranin A precede
that of PSA, suggesting that chromogranin A
is an early marker of prostate tumour
progression.
Increased serum levels of chromogranin A
were more consistent in patients with
androgen-insensitive prostate tumours [27]
and there was a significant correlation
between NE serum markers and distant
metastases, but not with locally progressive
disease [27]. Patients with tumours and who
had high plasma chromogranin A or NSE
levels were suggested to have a poorer
prognosis, which is less recognized by tumour
grading alone, than those not presenting with
this type of differentiation [27].
Angelsen et al. [25] reported a correlation
between the number of chromogranin Apositive NE cells and serum chromogranin A
levels in patients with prostate cancer. Serum
chromogranin A levels must be interpreted
cautiously in patients with impaired renal
function or in those receiving treatment for
peptic ulcer with drugs such as omeprazole,
as these particular situations can induce high
serum chromogranin A levels [28].
In contrast to chromogranin A, the utility of
measuring NSE in patients with advanced
prostate cancer is uncertain. The incidence of
high NSE levels in patients with prostate
cancer was lower than that of high
chromogranin A levels [28]. Cussenot et al.
[28] found that high NSE levels are more
frequent during hormonal escape, but they
have no prognostic value compared with
chromogranin A expression and have poor
concordance with immunohistochemical
data.
Ischia et al. [29] measured secretoneurin, a
product of proteolytic processing of
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A . S C I A R R A ET AL.
chromogranin C in patients with prostate
diseases. Mean secretoneurin serum levels
were significantly higher in patients with
hormone therapy-resistant prostate cancer
than in patients with prostatitis, BPH and
localized prostate cancer. There was a
statistically significant correlation between
secretoneurin and chromogranin A levels, but
not between secretoneurin and serum PSA
levels. However, the determination of NE
markers in serum may be not specific for
prostate activity and only the analysis of a
very large stratified population may
determine whether there is a significant
serum marker of NE activity in prostate
cancer.
Immunohistochemical staining for NE
products in prostate cancer has been used by
several authors (Fig. 1); di Sant'Agnese [30]
noted that the immunocytochemical
detection of serotonin, generic NE markers
and specific peptides in prostate tissue may
not be a very good indicator of ‘true’ NE
differentiation and activity in prostate
carcinoma. Perhaps the immunocytochemical
detection of these products indicates storage,
but not necessarily production and/or
secretion of the products. Indeed, high levels
of constitutive secretion of NE products may
result in minimal storage and minimal
immunostaining. In addition, the presence of
NE products may not be sufficient for activity,
as receptors for those products are needed to
effect their actions. A more specific method to
detect NE cell activity is to analyse the gene
expression of chromogranin A in prostate
tissue by semiquantitative RT-PCR [31]
(Fig. 2).
However, there is a problem about the type of
prostate tissue sample; evaluating prostate
biopsy specimens for NE differentiation may
not provide a complete analysis. The problem
of obtaining specimens which represent the
real extent of NE differentiation in the
prostate was shown by Cohen et al. [32].
A relatively new method proposed to detect
NE differentiation is total-body
somatostatin-receptor scintigraphy (SRS)
(Fig. 3). This method takes advantage of the
over-expression of type II somatostatin
receptors on the cell surface of most NE
tumours. Some authors showed that positive
SRS strongly predicts the presence of tumours
with NE differentiation [33]. SRS is
undertaken after an intravenous injection
with 111In-pentatreotide, a radioactive
440
FIG. 1.
Immunohistochemical
staining for chromogranin A
in a case of prostate cancer.
FIG. 2. Semiquantitative RT-PCR analysis to detect gene expression of chromogranin A (CgrA) in prostate
tissue. b-actin is used as the control (PC, prostate cancer; BPH, benign prostatic hyperplasia).
PC
M
1
2
PC
3
4
5
BPH
6
7
8
9
W
PSA
214 bp
a
CgrA
299 bp
b
b-actin
336 bp
c
somatostatin analogue. Planar images of the
body are taken in anterior and posterior
projections at 4 and 24 h after injection with
111
In-pentatreotide. The images are analysed
qualitatively and semi-quantitatively. With
this technique, the presence of NE
differentiation both at the primary (prostate)
and metastatic sites of tumours can be
detected. We described a case with prostate
cancer, showing high serum PSA levels (86 ng/
mL), and normal bone scintigraphy and CT
findings [34]. Histological sections from the
prostate biopsy were assessed for
chromogranin A expression by
immunohistochemistry and more than one
focus with extensive staining for
chromogranin A was detectable in the tumour
cells. High chromogranin A plasma levels
(126 ng/mL; normal <90) were detected by
radio-immunoassay. The patient underwent
an iliac bone marrow biopsy and the histology
showed tumour cell clusters positive for PSA
on immunohistochemical staining. Moreover,
the patient underwent SRS and an intense
focus of abnormal 111In-pentatreotide uptake
was detected in the left part of the prostate,
with other foci of lower intensity in the iliac
crest bilaterally at 4 h after injection. Six
months later a new conventional bone scan
was positive, and similar areas of abnormal
uptake were detected.
NE CELLS IN BPH
There are markedly fewer NE cells and NE
secretory products in mature nodules of BPH.
However, it was also noted that small,
presumably proliferating hyperplastic
nodules, and what appear to be growth foci in
somewhat larger nodules, contained
abundant NE cells [35]. Additional studies
showed a correlation between the
proliferating cell marker Ki-67 expression in
proximate non-NE prostate cells and the
number of NE cells in BPH tissue [36]. NE cells
may be important also in the homeostasis of
the glandular structure and in the first phase
of BPH development.
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2003 BJU INTERNATIONAL
NEUROENDOCRINE DIFFERENTIATION IN PROSTATE CANCER
FIG. 3. Total-body somatostatin receptor
scintigraphy using 111In-pentatreotide. The arrows
show an intense focus of abnormal 111In uptake (red
areas in the left of the prostate, central arrow in a)
and other foci of low intensity in the iliac crest
bilaterally (a) and in the sternum (b).
a
b
NE CELLS IN PROSTATIC INTRAEPITHELIAL
NEOPLASIA (PIN)
In 1994 Bostwick et al. [37] published a study
on PIN and NE differentiation; they used
whole-mount sections from radical
prostatectomy specimens which included PIN,
normal gland and prostate cancer. At least
one NE marker was positive in 88% of highgrade PIN. The number of NE cells in PIN was
intermediate between that in normal and
carcinomatous prostate.
Iwamura et al. [38] showed that in high-grade
PIN there is strong staining for antibodies to
PTHrP and only weak or negative staining in
normal and hyperplastic prostates. The Bcl-2
proto-oncogene, which is an anti-apoptotic
factor, is also preferentially expressed in foci
near NE differentiation [39]. NE
differentiation in high-grade PIN may
contribute to the development of this lesion
and, more importantly, may condition its
development into prostate carcinoma.
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2003 BJU INTERNATIONAL
NE CELLS IN PROSTATIC CARCINOMA
Three NE tumour phenotypes can be
distinguished: (i) small cell NE carcinoma,
accounting for 1–2% of prostatic malignancy;
(ii) carcinoid-like tumours, also rare and
poorly defined; and (iii) conventional prostatic
adenocarcinoma with focal NE differentiation
[10], which is very common.
Immunohistochemical studies show that
focal NE differentiation occurs in virtually all
common prostatic adenocarcinomas [10,24].
This differentiation takes the form of
individual cells or clusters of cells with NE
differentiation, scattered among a
predominant population of non-NE
malignant cells. Extensive and multifocal NE
features are detected in ª10% of all prostatic
malignancies [10,24]. These tumours tend to
be more aggressive and resistant to hormonal
therapy.
There is currently no convincing evidence that
neoplastic NE cells originate from
transformed NE cells of benign glands or
premalignant lesions. Immunohistochemical
data show that foci of NE in prostate
adenocarcinoma harbour a significant
number of amphicrine tumour cells
expressing both NE (chromogranin A) and
exocrine (PSA) markers [40]. The frequent
occurrence of intermediate differentiation
between exocrine and NE cell types strongly
supports the concept that NE tumour cells
derive from exocrine (PSA-positive) cell types
during tumour progression [40]. As well as
normal NE cells, malignant NE cells are unable
to proliferate.
The most frequent products are serotonin and
chromogranin A, but nearly all of the normal
products of prostatic NE cells have been
described in cells with NE differentiation in
prostatic carcinoma. Some of the regulatory
peptides produced by NE cells in the prostate
can affect prostate adenocarcinoma cell
proliferation in vitro, as documented for
bombesin, calcitonin and PTHrP [11,38]. An
increased proliferative activity of non-NE
tumour cells in the vicinity of NE foci is
probably related to these findings. NE cells
may also contribute to cancer progression
increasing the anti-apoptotic activity through
a hyperexpression of Bcl-2 [39]. Bcl-2
increases as prostate cancer becomes
androgen-independent and there is a
proportional relationship between the tissue
levels of bcl-2 and NSE in most prostate
cancers [39,41]. Furthermore, malignant NE
cells consistently lack the androgen receptor
[42]; their activity may represent an
independent cofactor unrelated to the
carcinogenic activity of androgens.
It has been suggested that patients with
prostate tumours presenting with high
chromogranin A levels have a poor prognosis
[43]. However, some studies showed no
prognostic differences in tumours with and
with no focal NE differentiation or in patients
with or without high serum chromogranin A
levels [32,44]. These studies did not stratify
their patients for tumour grade. Interestingly,
when only analysing patients with poorly
differentiated tumours, focal NE
differentiation is a more significant
independent prognostic factor [45].
Berruti et al. [46] analysed serum NSE and
chromogranin A levels in patients with BPH,
PIN, hormone-naïve prostate cancer and
hormone-refractory prostate cancer. High
chromogranin A levels were noted particularly
in 36% of patients with hormone-naïve
disease and in 45% with hormone-refractory
disease. There was no correlation between
PSA and chromogranin A levels. The
androgen-independent growth of prostate
cancer can be caused by different
mechanisms; one of these is receptor-specific
paracrine or autocrine growth modulation
of human prostatic cancer cells by
neuropeptides secreted by NE cells. The role of
NE cells and their secreted bioactive
neuropeptides in the progression of human
prostate cancer from an androgen-dependent
to an androgen-independent state is still
unclear. Why this induction takes place and
whether these cells have the potential to
induce androgen-independent cell growth
remains unknown.
NE DIFFERENTIATION AND HORMONE
THERAPY
If NE cells are androgen-independent it
would seem reasonable to suppose that: (i)
androgen receptor-negative NE cells would
increase in number despite hormonal
suppression, and (ii) tumours with NE
differentiation and androgen-receptor
negativity may be resistant to hormonal
manipulation.
Jongsma et al. [47] showed that the
proliferation of prostatic cancer cell lines
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A . S C I A R R A ET AL.
under conditions of androgen depletion can
be modulated by neuropeptides which are
known to be produced by NE cells, and the
androgen suppression or depletion can lead
to an induction of NE differentiation.
The NE component of prostate
adenocarcinoma is resistant to hormone
therapy; some studies showed that the
number of NE tumour cells [47] and
chromogranin A serum levels increase with
escape of human prostate tumour from
hormonal therapy [48,49]. Focal NE
differentiation may help to identify patients
who are more prone to endocrine therapy
failure.
Ahlgren et al. [50] assessed the extent of NE
differentiation in prostate cancer after
3 months of hormonal treatment. Radical
prostatectomy specimens from patients
randomized to 3-month neoadjuvant LHRH
analogue treatment or to surgery alone were
available for the analysis. Both the number of
chromogranin A-positive cells and the
proportion of NE-positive tumours were
significantly greater (P < 0.003) in the
neoadjuvant than in the control group. NE
differentiation did not correlate with the
decrease in serum PSA after hormonal
therapy.
Currently we are analysing [31] serum
concentrations and prostate gene expression
(by RT-PCR) of chromogranin A and PSA in
patients with prostatic cancer and BPH. In the
latter, tissue samples for the analysis were
obtained from radical prostatectomy. These
patients will be progressively stratified on the
basis of Gleason score and neoadjuvant
LHRH-analogue therapy (3 or 6 months). In a
few cases we found that in prostate cancers
treated with LHRH analogue the serum
chromogranin A levels were significantly
(P < 0.01) higher than in the untreated group.
On the contrary, serum PSA levels were higher
in untreated than in treated patients.
Chromogranin A and PSA mRNA were
expressed in all prostate tissue samples
analysed (both BPH and prostate cancer) with
highest levels in prostate cancer tissue
(P < 0.01). Considering treated and untreated
prostate cancer cases separately,
chromogranin A mRNA levels of treated cases
were significantly higher (P < 0.05) than
those of untreated prostate cancers. On the
contrary, levels of PSA mRNA of untreated
cases were significantly higher than those of
treated cases.
442
FIG. 4. A possible treatment strategy for patients with prostate cancer in progression during hormonal
therapy, based on chromogranin A determination. High or normal chromogranin A values are referred to
serum levels and, if available, to mRNA expression on prostate tissue. CAB, complete androgen blockade.
How to treat?
We propose:
CAB
Biochemical and/or clinical progression
High chromogranin A and/or positive SRS
Normal chromogranin A and negative SRS
CAB + Long acting
somatostatin analogue
- antiandrogen withdrawal
- modification of antiandrogen
- oestrogens
Stratifying prostate cancer cases by Gleason
score, the highest serum and mRNA levels of
chromogranin A were in patients with a
Gleason score of >7 and the difference
between treated and untreated cases was
more significant if limited to the analysis of
these tumours. These results, if confirmed
on larger and stratified populations, suggest
that hormone therapy in prostate cancer
induces different effects on PSA and
chromogranin A.
The hypotheses that must be considered are:
(i) chromogranin A may represent a useful
marker to detect progression in poorly
differentiated prostate cancer; (ii)
chromogranin A may help in the analysis of
androgen-independent growth and
progression in prostate cancer; (iii) if
chromogranin A mRNA expression reflects NE
activity in the prostate, continuous androgensuppression therapy seems to produce a
hyperactivation of NE cells in the prostate.
This may be one of the mechanisms by which
prostate cancer progresses during hormonal
therapy in an androgen-independent tumour.
All these aspects would have significant
implications for treating prostate cancer that
is resistant to hormone therapy.
NE DIFFERENTIATION IN PROSTATIC
CARCINOMA: TREATMENT
Many approaches to treating prostatic cancer
rely on the responsiveness of this tissue to the
androgen-oestrogen axis. However, a
significant subset of prostate cancers involves
the NE cells of this gland. These observations
suggest an approach to therapy based on the
growth characteristics of NE cells and the
growth-regulating characteristics of NE
products, e.g. chromogranins, PTHrP and
other peptides. These approaches should be
based on the NE regulatory axis, rather than
(or in addition to) the gonadal regulatory axis.
Currently it is unknown how best to treat NE
prostate cells. As these cells are post-mitotic
and do not express androgen receptors,
chemotherapy/radiotherapy and antiandrogen therapy probably are of little
benefit; cytotoxic agents and radiation
therapy predominantly affect cycling cancer
cells.
Several of the peptides known to be expressed
by NE cells in prostate cancer are potent
candidates for drug therapy. NE carcinomas
and foci of NE differentiation in carcinoma
from various organ systems are known to
express somatostatin receptors, which inhibit
NE secretion and possibly NE growth [51].
Long-acting somatostatin analogues have
had some positive effects on prostatic
carcinoma [51,52]. This was initially thought
to be an indirect effect by the action of
somatostatin on central neurosecretory type
cells, but it has recently been shown that
there is also a more direct effect on prostate
carcinoma [51]. Somatostatin analogues may
inhibit NE tumour growth, directly interacting
with somatostatin receptors that are present
in both normal and malignant prostate cancer
tissue.
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2003 BJU INTERNATIONAL
NEUROENDOCRINE DIFFERENTIATION IN PROSTATE CANCER
Bombesin is a small peptide produced by
prostatic NE cells [10]. Because it is a potent
mitogen bombesin may be useful in treating
prostate cancer [42]. Bombesin antagonists
inhibited the growth of a human small-cell
carcinoma cell line both in vitro and in vivo
[53]. Bombesin receptors have been detected
on prostate carcinoma in vitro [54]. The
bombesin antagonist RC-3095 inhibited the
growth of Dunning R-3327 and AT-1 cells
[53], but the remission produced by RC-3095
was of short duration, probably because
of a down-regulation of the bombesin
receptor.
differentiation in prostate cancer could be
assessed. Our strategy is directed to patients
initially undergoing hormone therapy; if there
is tumour progression during complete
androgen blockade we select how to
modulate therapy on the basis of
chromogranin A serum levels and/or
chromogranin A mRNA expression (Fig. 4). In
cases with high chromogranin A levels or
positive findings on SRS, we combine
hormone therapy with a somatostatin
analogue. In cases with normal values for
chromogranin A we continue with hormone
therapy, modifying or suspending the antiandrogen used or adding oestrogens.
6
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Increasing evidence also indicates the
presence of specific receptors for serotonin in
prostate tissue. Moreover, some results
suggested effects of selective serotonin
receptor antagonists on the growth of human
prostate carcinoma cell lines. The serotonin
inhibitor pindobind inhibited the proliferation
of androgen-independent tumour cell lines in
a dose-dependent manner [55].
Further studies are needed to evaluate
potential new therapeutic approaches which
are directed against the NE component. It is
possible that in the future, antagonist peptide
growth factors, or antibodies to NE growth
factors or their receptors, may be of use in
treating prostate carcinoma with NE
differentiation.
CONCLUSIONS
ACKNOWLEDGEMENT
The study of the biology of NE prostate cells
might answer questions about disease
progression and hormone escape. The role of
PSA has been questioned particularly in a
subset of cases with hormone-refractory
disease. Measuring NE markers might
complement the PSA assay in selected cases
of poorly differentiated and/or androgenindependent prostate tumours. The
complementary information provided by NE
markers with PSA is supported further by the
absence of a correlation between
chromogranin A and PSA levels. In these cases
an increase in chromogranin A expression,
despite low PSA levels, may indicate
progression and a poor prognosis.
The authors acknowledge the support of the
Association of Basic Research in Urology
(ARBU) (President Prof. Franco Di Silverio).
To clearly assess the prognostic significance
of focal NE differentiation in prostate cancer,
the most important criteria are the selection
of cases on the basis of tumour Gleason score
and concomitant or previous hormone
therapies; moreover, the type, duration and
intermittence of hormone therapy may be
equally relevant.
3
The type of NE markers analysed is also
important; this analysis is initially expected to
be more accurate using radical prostatectomy
specimens than prostate biopsy specimens.
Different treatment strategies to affect NE
5
11
12
©
2003 BJU INTERNATIONAL
13
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Correspondence: F. Di Silverio, Department of
Urology, University La Sapienza, V. Policlinico
00161, Rome, Italy.
e-mail: [email protected]
Abbreviations: NE, neuroendocrine; NSE,
neurone-specific enolase; PTHrH, parathyroid
hormone-related protein; VEGF, vascular
endothelial growth factor; SRS,
somatostatin-receptor scintigraphy; PIN,
prostatic intraepithelial neoplasia.
445