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Regular Articles |
From the Department of Pathology*
and The James
Buchanan Brady Urological Institute,
The Johns
Hopkins University Medical Institutions, Baltimore, Maryland
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As indicated in the model shown in Figure 1
, the majority of prostatic epithelial
cells in the adult gland are androgen dependent for
survival.7
For example, castration of the male rat leads to
programmed cell death in the prostate with loss of up to 90% of the
total epithelial cells.7,8
The remaining epithelial cells
do not require androgen for survival and are thus considered androgen
independent. At least some of these surviving androgen-independent
epithelial cells remain androgen sensitive, because the subsequent
administration of exogenous androgens to the castrate animal results in
induction of proliferation and the regeneration of the prostate to the
normal size and morphology. By experimentally cycling serum androgen
levels, this process of involution and subsequent androgen-induced
regeneration can be repeated numerous times. Such results led
Isaacs and Coffey4
to postulate a stem cell model of
prostate organization whereby slowly proliferating androgen-independent
reserve stem cells give rise to a second population of more rapidly
cycling androgen-independent but androgen-responsive amplifying cells.
(This proposed amplifying population is analogous to the TP cells seen
in other organ systems and will be referred to as such in accordance
with those systems; see Figure 1
.) Although these TP cells may be
actively cycling, their capacity for self-renewal is greatly diminished
as compared with the reserve stem cells (Figure 1)
, which maintain
their numbers. Rather, by undergoing a limited number of population
doublings, these TP cells are postulated to amplify the number of
epithelial secretory cells derived from the stem cell compartment. The
TP cells respond to androgens by giving rise to more mature cells
(previously referred to as transit cells) with very limited
proliferative potential that subsequently undergo terminal
differentiation into androgen-dependent secretory cells.4
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,18
and Bcl-2,19
and they lack expression of the major prostatic secretory proteins,
such as prostate-specific antigen and prostate-specific acid
phosphatase in the human20
and prostatic binding protein in
the rat ventral prostate.21
The secretory compartment
generally consists of a luminal layer of columnar cells. The apical
aspect of the secretory cells projects into the lumen, and the basal
aspect rests on the basal cells.9-11
Secretory cells
express prostate-specific antigen and prostate-specific acid
phosphatase, high relative levels of AR,14,15,22
cytokeratins 8 and 18, and they lack expression of cytokeratins 5 and
14,13,23
glutathione
S-transferase-18
(usually), and
Bcl-219
(see Figure 1
).
Several lines of evidence suggest that prostate secretory cells arise
from maturation of cells derived from the basal cell compartment.
First, immunohistochemical and radiolabeling experiments show that the
bulk of the proliferating pool in the normal-appearing human prostate
is restricted to some of the basal cells.24,25
Second, cell
types with combined phenotypic characteristics intermediate between
those of basal cells and secretory cells are present in both the
developing and the adult prostate. For example, electron microscopic
studies of the human prostate show that there are scattered cells with
morphological features of both basal and secretory cells that reach
from the basement membrane to the lumen.26
In the rat
neonatal prostate grown in organ culture, the cells that make up the
initial solid epithelial buds co-express both the basal cell-specific
cytokeratins 5 and 14, as well as the cytokeratins 8 and 18. As the
prostate differentiates under androgenic stimulation, the ducts
canalize, basal and luminal cells become morphologically distinct, and
the cytokeratin pattern changes to reflect that in the
adult27
such that only basal cells express cytokeratins 5
and 14. In addition, double-labeling studies have shown that in
androgen-cycling experiments in rats and in the normal human prostate
and prostate cancer, individual cells are found that have cytokeratin
expression profiles of both basal and secretory cells.28,29
Indeed, it has been suggested that these latter cells may represent the
"amplifying compartment" or TP compartment in the prostate, as
outlined in Figure 1
.28-30
Finally, Bonkhoff et
al5
have also shown that the human prostate contains cells
that express both basal cell-specific keratin and prostate-specific
antigen, as well as other cells that express both prostate-specific
antigen and chromogranin A (a neuroendocrine cell marker). These
results imply the existence of cells that are intermediate in
differentiation between basal and secretory cells, and others that are
intermediate between basal and neuroendocrine cells. Thus, given that
prostate basal cells make up the bulk of proliferating cells and that
they appear capable of multiple lines of differentiation, prostatic
stem cells are most likely located in the basal
compartment.5,6
High-grade prostatic intraepithelial neoplasia (PIN) is the presumed precursor lesion to many, if not most, prostatic adenocarcinomas.31,32 As in precursor lesions of cancer of the colon and cervix, there is an overall increase in the proliferative fraction in PIN. Also, the compartmentalization of proliferating cells is altered such that the ratio of proliferating secretory-type cells to proliferating basal cells is greatly increased.24,25 The mechanisms for such altered proliferation in cancer precursor lesions are not understood. Although cell proliferation and differentiation are controlled in the prostate by circulating androgens, little is known regarding the molecular mechanisms by which these processes are coordinated in normal tissue and altered in prostatic neoplasia.
Progression through the cell cycle is controlled by the activated cyclin:cyclin-dependent kinase complexes.33 Members of the cip/kip family of cyclin-dependent kinase inhibitors, such as p27Kip1 and p21/waf1/cip1, bind to and inhibit the activity of the cyclin:cyclin-dependent kinase complexes resulting in a block in the progression through the cell cycle.33 p27Kip1 is widely expressed in mammalian tissues and has been implicated in cell cycle arrest.34,35 Increased levels of p27Kip1 appear to serve as a barrier for progression to S phase and may signal exit from the cell cycle.36,37 In vitro experiments have shown that p27Kip1 levels are high in quiescent cells, but that in response to mitogens, the levels fall and they remain low in proliferating cells. Withdrawal of mitogens results in re-expression of p27Kip1 to high levels.38 Although in the vast majority of tumor types that have been examined, the p27Kip1 gene is altered only very rarely, several different neoplasms, including those from the breast, lung, colon, stomach, and prostate show reduced p27Kip1 protein levels.37,39-47
In the prostate, down-regulation of p27Kip1 occurs in the vast majority of adenocarcinomas,39-41 and reduced levels positively correlate with Gleason grade.39-41 In addition, reduced levels may be useful as a predictor of prognosis independent of grade and stage.40,41 We have begun to test the hypothesis that p27Kip1 down-regulation renders cells capable of serving as the TP compartment in the prostate. In addition, we sought to determine the potential role of down-regulation of p27Kip1 protein expression in the development of prostatic neoplasia by examining expression in high-grade PIN. We propose that down-regulation of p27Kip1 in human prostate removes a block to cell cycle progression that renders cells capable of rapidly entering into the proliferative phase of the cell cycle on appropriate additional stimulation. In addition, we propose that critical alterations in the normal regulatory control of p27Kip1 levels occur early in prostatic carcinogenesis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Formalin-fixed, paraffin-embedded archival tissues containing primary prostatic carcinomas, high-grade PIN, and pelvic lymph node metastases were obtained from The Johns Hopkins Hospital (Baltimore, MD). All of these specimens were from radical prostatectomies and concomitant pelvic lymph node dissections performed between 1991 and 1998. The mean age of patients was 59.6 years (range, 47 to 71). Specimens were selected to represent a limited spectrum of Gleason scores ranging from 6 to 9, with a wide spectrum of pathological stages (N = 41). Pathological stage ranged from organ confined (pT2) to T(any)N1Mx, using the TNM system of the American Joint Committee on Cancer and the International Union Against Cancer. Control tissues consisting of tonsils, esophagus, colon, epidermis, and urinary bladder were obtained from the surgical pathology archives of The Johns Hopkins Hospital.
Monoclonal Antibodies and Immunohistochemistry
Mouse anti-human monoclonal antibodies were obtained as follows: anti-p27Kip1 (dilution, 1:800; Transduction Laboratories, Lexington, KY); 34ßE12 (1:50; Enzo Biochem, Inc., Farmingdale, NY), KI-67 (clone MIB-1, 1:100; Immunotech-Coulter, Miami, FL); proliferating cell nuclear antigen (PCNA, 1:250; Transduction Laboratories); and AR (clone AR-A441), which was generously provided by Dr. Dean P. Edwards (University of Colorado Health Sciences Center, Denver, CO). Immunohistochemistry was performed as described48 using diaminobenzidine (brown) as the chromagen with a light hematoxylin (blue) counterstain. All primary antibody incubations were carried out for 45 minutes at room temperature. For 34ßE12-cytokeratin staining, the sections were pretreated with protease type 27 (Sigma Chemical Co., St. Louis, MO) at 2 mg/ml for 20 minutes at 37°C before incubation with the primary antibodies. Because our pilot studies showed that large specimens that are slowly fixed over several hours retain strong p27Kip1 expression only in the outer aspect of the samples, which are promptly fixed, and because p27Kip1 protein levels are regulated by specific proteolysis,49,50 we used samples that were obtained immediately after surgical resection that were harvested fresh. All specimens consisted of portions of tumor and normal tissue that were immersed in 10% neutral buffered formalin immediately after surgical resection.
Semiquantitative Staining of p27Kip1 in Invasive Prostate Cancer
Semiquantitative grading of the tumors with respect to p27Kip1 immunohistochemical staining was carried out by estimation of the percentage of tumor cells in a representative section of carcinoma that were strongly positive for nuclear p27Kip1 immunoreactivity, as compared with surrounding normal-appearing prostatic acinar secretory cells.
Statistical Analysis
Statistical analysis was carried out on a Dell Pentium II personal computer using Stata 5.0 software for Windows 95.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In nonneoplastic normal-appearing prostate from all zones,
moderate to strong p27Kip1 staining was present in the vast
majority (range, 85 to 100%) of nuclei of secretory cells (Figure 2, B, C, E, F, and G
; Figure 3, A, E, and F
). Although cytoplasmic
staining was present in normal-appearing secretory cells, it was weak
or negative in the vast majority of these cells. Scattered
collections of small lymphocytes that showed strong positive
nuclear p27Kip1 immunoreactivity were invariably present,
serving as internal positive controls. In the basal cell
compartment, expression of p27Kip1 was much more variable
than in the secretory compartment (Figure 2B)
, such that there was a
spectrum of acinar profiles. In some acini, all basal cells were
negative or markedly reduced for p27Kip1, whereas in
others, there was a mixture of both strongly positive and
negative/markedly reduced cells, and in others all basal cells were
strongly positive. This
variability was examined systematically in basal cells in the various
zones of the prostate (as defined by McNeal),9-11
as well
as in nodular hyperplasia benign prostatic hyperplasia (BPH) tissue.
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. Areas of BPH
that were highly inflamed were excluded from these analyses. For these
comparisons, we assigned a given acinus to one of two groups. Acini in
the high-staining group contained strong staining in greater than 50%
of the identifiable basal cells, as compared with overlying secretory
cells, whereas acini in the low-staining group contained strong
staining in 
50% of basal cells. The results of these analyses
(analysis of variance using Bartlett's test of equal variances)
indicated significant differences among the groups of tissues analyzed
(Table 1
; F3,28 = 8.47;
P = 0.0004). Pairwise comparisons (Table 2)
showed that BPH tissue contained a
significantly higher percentage of low-staining acinar profiles than
normal-appearing peripheral zone and normal-appearing transition
zone. Although the central zone had a somewhat higher mean score of low
staining acinar profiles, the results as compared with the other
zones were not statistically significant.
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. As a result of the very weak staining for
AR in the basal cells in general, it was difficult to determine with
certainty whether there was a strict concordance between AR and
p27Kip1 in the basal compartment overall, although there
was clear concordance in many acini, in which both markers were
markedly decreased or negative as compared with adjacent overlying
secretory epithelium.
Prostatic ducts/acini are generally assumed to contain two cell layers,
although as previously noted, electron microscopic studies have shown
occasional layering of apparent basal cells in normal prostate. We also
noticed a third, intermediate, zone of cells that was present variably
in all zones of the normal prostate, was localized between the
basal-most cells and the luminal secretory cells, and was consistently
negative for p27Kip1 (Figure 2E
, large arrows). This third
layer of p27Kip1-negative cells was most easily recognized
in the periurethral gland region of the prostate, where it was often
accentuated. Figure 2F
shows the periurethral gland region with three
cellular zones where the basal-most cells and the luminal cells stain
positively, yet a distinct multilayered middle zone of cells negative
for p27Kip1 (Figure 2F
, inset) can be identified. To rule
out the possibility that the periurethral gland region does not simply
reflect benign bladder mucosa extending into prostatic acini, we
examined the expression of p27Kip1 in normal bladder
mucosa. By contrast to the periurethral region, benign urothelial
mucosa from the urinary bladder revealed an absence of a distinct zone
of cells that were negative for p27Kip1. Rather,
approximately 90% of the total nuclei in the bladder mucosa were
strongly positive for nuclear p27Kip1 staining, and
although negative cells predominated near the basal-most aspect, they
were also scattered throughout all layers of the mucosa.
The appearance of a potential third middle layer of cells was further
investigated in androgen-deprived human prostates, because these
typically show an increase in the number of layers that make up the
basal compartment.53,54
Figure 2, G and H
, is from a
patient who was treated with androgen blockade therapy before
prostatectomy; the basal compartment appears prominent, hyperchromatic,
and multilayered. Staining of an adjacent section with 34ßE12 for
basal cell-specific cytokeratins demonstrates that these cells are part
of the basal cell compartment (Figure 2H)
. We examined five prostates
from patients who were treated with androgen deprivation therapy before
radical prostatectomy, and all have shown this pattern of increased
numbers of p27Kip1-negative basal cells that often appear
as a third layer in the prostate epithelium. These cells may be
proliferation competent and poised for rapid growth after androgen
stimulation. Our results support the hypothesis that there is a
variable third layer of prostatic acinar cells that are defined by
p27Kip1 negativity, basal cell specific cytokeratin
expression, and prominence in periurethral and androgen-deprived
prostate tissue.
Because p27Kip1 levels are negatively correlated with
proliferation,36,55
we examined p27Kip1
expression levels in mitotic cells and in cells in the proliferative
phase of the cycle using the proliferation markers Ki-67 and PCNA. In
all cells with mitotic figures, generally only seen in PIN and invasive
cancer, p27Kip1 expression was negative (Figure 3C)
. As
noted previously in normal-appearing prostate epithelium, the majority
of the nonmitotic but proliferating cells were in the basal
compartment. In these proliferative cells, p27Kip1 was
generally low or absent, as determined by staining of adjacent
sections. There were no clear examples of cells that were strongly
p27Kip1 positive and positive for either of the
proliferation markers. In acini in which the majority of the basal
cells were negative for p27Kip1, the overall proliferative
fraction was elevated over those acini in which the basal cells were
uniformly positive for p27Kip1. At times, entire layers of
p27Kip1-negative basal cells were positive for PCNA (Figure 3, A and B)
. However, because not all p27Kip1-negative
cells were in the proliferative phase of the cell cycle, we conclude
that absence of p27Kip1 in prostate epithelial cells may be
necessary yet not sufficient for entrance into the proliferative phase
of the cell cycle.
To examine further the relationship between p27Kip1 negativity and proliferative status, we stained sections of oral mucosa, epidermis, esophagus, and colon. In each tissue, many of the cells in the basal zone or crypts were devoid of staining for p27Kip1. As the cells matured toward the surface of these epithelia, nuclear p27Kip1 expression increased and cell proliferation decreased. However, not all of the p27Kip1-negative cells were in the proliferative phase of the cycle as determined by PCNA and Ki-67 staining (data not shown). These results suggest that down-regulation of p27Kip1 may be necessary but not sufficient for progression to the proliferative phase of the cell cycle in human epithelial cells in vivo. In lymphoid tissue of the tonsils and lymph nodes, by contrast, we found an essentially 1:1 inverse relation between the staining for the proliferative marker Ki-67 and p27Kip1, as previously noted.56
Expression of p27Kip1 in High-Grade PIN and Invasive Prostate Carcinoma
In high-grade PIN there was a consistent down-regulation (11 of 11
cases) of p27Kip1 as compared with adjacent benign
prostatic epithelium. This down-regulation consisted of an increased
number of cells that were devoid of nuclear expression and a more
pronounced generalized decrease in overall nuclear p27Kip1
intensity. In each case, between 50 and 75% of high-grade PIN cells
showed markedly reduced or negative nuclear staining as compared with
adjacent and surrounding secretory cells. In most cases, there was an
increased amount of cytoplasmic staining in PIN versus the
normal-appearing epithelial secretory cells. Figure 3, D and E
,
demonstrates down-regulation of p27Kip1 in high-grade PIN
in a prostatic acinus that contains both benign epithelium and
high-grade PIN within the same structure.
In invasive carcinomas, there was down-regulation of
p27Kip1 as compared with adjacent normal-appearing
epithelium (Figure 3, C and F)
. Again, this consisted of both an
increase in the total number of negative nuclei and a generalized
decrease in intensity in the majority of tumor cells. As in high-grade
PIN, invasive tumor cells at times contained p27Kip1
cytoplasmic immunoreactivity (Figure 3C)
.
To determine whether there was a relation between p27Kip1
expression and tumor grade or pathological stage, specimens from 41
patients were analyzed. All
specimens contained an internal positive control of benign,
noninflamed, nonatrophic prostatic acinar secretory cells, and >85%
of these cells were strongly positive for nuclear p27Kip1.
No cases were completely devoid of tumor cell staining, and staining
for p27Kip1 in invasive prostatic carcinoma was
heterogeneous. Semiquantitative grading was performed by estimating the
percentage of tumor cells in the specimen that were strongly positive
for nuclear p27Kip1 expression. This method was used as
opposed to previous methods that counted the negative tumor cells at
high power, because there was extensive heterogeneity of tumor cell
staining for p27Kip1, which creates a bias depending on
which areas are selected for counting. In addition, it was relatively
simple to identify strongly positive tumor cells, and this facilitated
counting. The scoring ranged from 0 to 70% strongly positive tumor
cells. Specimens were divided into two groups in relation to staining
for p27Kip1 (Table 3)
; group 1 (n =
20) had 
10% of the tumor cells strongly positive for nuclear
p27Kip1, and group 2 (n = 21) had
<10% of tumor cells strongly positive. For pathological grade,
specimens were also divided into two groups, intermediate (Gleason
score 6; n = 11) and high (Gleason score 7;
n = 30). Among this cohort of patients (Table 3)
,
p27Kip1 staining proved to be a significant predictor of
high Gleason score (odds ratio, 7.7; SE = 6.75; z
= 2.36; P = 0.018; 95% confidence interval,
1.42–42.7) but not of pathological stage at radical prostatectomy
(odds ratio, 2.8; SE = 2.03; z = 1.48;
P = 0.15; 95% confidence interval, 0.62–11.59). This
data set is limited in number (n = 41) and,
therefore, may not reveal a potential weak association between
p27Kip1 expression and pathological stage. As a control for
this data set, however, linear regression analysis showed that Gleason
grade was highly predictive of pathological stage at radical
prostatectomy (n = 41; P <
0.0001; r2
= 0.40; slope = 0.85; SE =
0.17; 95% confidence interval, 0.51–1.19). Thus, we do expect that if
a strong relation between p27Kip1 and pathological stage at
radical prostatectomy were present, we would likely have uncovered it.
Lymph node metastases (n = 11), which were all
detected as microscopic lesions identified after radical prostatectomy
and concomitant pelvic lymph node dissection, all showed decreased
levels of p27Kip1 immunoreactivity as compared with
surrounding benign lymphoid cells (no normal prostate is present in the
lymph nodes for comparison) and as compared with staining of secretory
cells from a separate section from the patient's prostate.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the current study, we focused to a large extent on characterizing
expression of p27Kip1 in various zones of the
normal-appearing prostate, as well as epithelial BPH tissue, analyses
that have not been reported on in a systematic fashion thus far. We
found that in normal-appearing prostate tissues, p27Kip1
was expressed in >85% of nuclei of secretory cells, which have been
shown previously to have a very low proliferative rate
(<0.1%).24,25
By contrast, the basal cell compartment,
which contains the bulk of any of the proliferating cells in the
normal-appearing human prostate, was much more heterogeneous and
contained a significant number of p27Kip1-negative cells.
This implies the existence of at least two populations of basal cells,
one that is p27Kip1 negative and another that is
p27Kip1 positive. In addition, there was a distinct third
layer of cells that was present variably, which was localized between
the basal-most cells and the luminal cells. This layer of cells was
characterized by basal cell-specific cytokeratin expression and an
absence of p27Kip1 immunoreactivity. This layer was
accentuated in the periurethral regions of normal-appearing prostate
and in prostatic tissue treated with androgen deprivation therapy.
Based on these results, we hypothesize that the prostate contains a
variable middle compartment. This compartment is p27Kip1
negative (Figure 4)
. It functions as a
potential TP compartment with cells that are intermediate in phenotype
between the predominantly resting stem cells (p27Kip1
positive) in the basal compartment and the resting mature cells in
the secretory compartment. These cells are capable of a limited number
of proliferation events and are also capable of differentiating into
mature postmitotic cells. We are currently extending these studies to
include double-labeling experiments with p27Kip1 and
various cytokeratins to determine whether the cells that we have
identified as p27Kip1 negative, and the presumed TP
compartment, co-localize with cells previously found to have
intermediate patterns of cytokeratin expression.29
We are
also extending these studies to examination of the rat prostate, in
which our preliminary experiments (De Marzo et al, unpublished results)
indicate strong expression of p27Kip1 in the vast majority
of secretory epithelium of all lobes of the adult prostate and seminal
vesicle, except in actively proliferating cells, and in the majority of
the remaining resting epithelial cells of the ventral prostate after
castration-induced involution.
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By contrast to normal-appearing secretory epithelium, in all high-grade PIN lesions, primary invasive carcinomas and regional lymph node metastases, the expression of p27Kip1 was decreased as compared with adjacent nonneoplastic epithelial secretory cells and/or lymphoid cells. These findings are concordant with other recent studies,39-41 and they implicate a decrease in nuclear p27Kip1 expression as an essential early event in the development of prostatic neoplasia. Additionally, our studies showing increased numbers of secretory cells in PIN that are p27Kip1 negative support the hypothesis that central to the neoplastic process is the disruption of the tightly controlled spatial organization of proliferation and differentiation. This was suggested previously for the colon by el-Deiry et al58 and Polyak et al,59 who have shown that the compartmentalization of expression of the proliferative marker Ki-67 and the differentiation marker p21/waf1/cip1 is altered in precancerous colon lesions, the aberrant crypt focus, and tubulovillous adenoma, but not in nonneoplastic hyperplastic polyps. In cancer precursor lesions, neoplastic cells appear to bypass the normal topological signals that restrict proliferation to the crypts, such that the proliferating neoplastic cells are found as high up as the luminal surface. Similar alterations occur in preinvasive neoplastic lesions of the uterine cervix, where a long-standing criterion for the diagnosis of cervical squamous intraepithelial neoplasia has been abnormal localization of mitotic cells, away from the parabasal region toward the surface. We postulate that abnormal down-regulation of p27Kip1 in secretory cells of high-grade PIN may be responsible, at least in part, for the markedly increased proliferation rate of these secretory cells.
In summary, we report that lack of expression of p27Kip1 in prostate epithelium may be a specific indicator for TP cells of the normal human prostate. We postulate that p27Kip1 levels play a major role in regulating the cell cycle in normal, hyperplastic, and neoplastic prostate epithelial cells and that down-regulation of p27Kip1 renders these cells competent for proliferation. We also report that down-regulation of p27Kip1 occurs in all examined cases of high-grade PIN and in invasive primary and metastatic prostate carcinomas. These findings suggest that p27Kip1 down-regulation is an essential step in the development and maintenance of the malignant prostatic epithelial cell phenotype.
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Acknowledgements |
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Footnotes |
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Supported in part by Public Health Services Grants DK22000-25 and CA-58236-04.
Accepted for publication May 22, 1998.
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