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From the Department of Pathology,*
the James Buchanan
Brady Urological Institute,
and the Johns
Hopkins Oncology Center,
The Johns Hopkins
University Medical Institutions, Baltimore, Maryland
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-class glutathione
S-transferase (GSTP1), a carcinogen-detoxifying
enzyme, is not expressed in >90% of prostate carcinomas
(CaPs). GSTP1 promoter hypermethylation, which
appears to permanently silence transcription, is the most
frequently detected genomic alteration in CaP (Lee et al, Proc
Natl Acad Sci USA 1994, 91:11733–11737; >90% of cases). In
high-grade prostatic intraepithelial neoplasia (PIN), this
alteration is present in at least 70% of cases (Brooks et al,
Cancer Epidemiol Biomarkers Prev, 1998, 7:531–536).
Although normal-appearing prostate secretory cells rarely express
GSTP1, they remain capable of expression, inasmuch as
GSTP1 promoter hypermethylation is not detected in
normal prostate. Fifty-five lesions from paraffin-embedded
prostatectomy specimens (n = 42) were stained for
GSTP1, using immunohistochemistry. Adjacent sections were
stained for p27Kip1, Ki-67, androgen
receptor (AR), prostate-specific antigen (PSA),
prostate-specific acid phosphatase (PSAP), Bcl-2, and
basal cell-specific cytokeratins (34ßE12). With normal prostate
epithelium as the internal standard, staining was scored for
each marker in the atrophic epithelium. The lesions showed two cell
types, basal cells staining positive for 34ßE12, and
atrophic secretory-type cells staining weakly negative for 34ßE12.
All lesions showed elevated levels of Bcl-2 in many of the
secretory-type cells. All lesions had an elevated staining index for
the proliferation marker Ki-67 in the secretory layer and decreased
expression of p27Kip1, a finding reminiscent of
high-grade PIN (De Marzo et al, Am J Pathol 1998,
153:911–919). Consistent with partial secretory cell
differentiation, the luminal cells showed weak to moderate
staining for androgen receptor and the secretory proteins PSA and PSAP.
All atrophic lesions showed elevated GSTP1 expression in many of the
luminal secretory-type cells. Because all lesions are
hyperproliferative, are associated with inflammation,
and have the distinct morphological appearance recognized as prostatic
atrophy, we suggest the term "proliferative inflammatory
atrophy" (PIA). Elevated levels of GSTP1 may reflect its inducible
nature in secretory cells, possibly in response to increased
electrophile or oxidant stress. Elevated Bcl-2 expression may be
responsible for the very low apoptotic rate in PIA and is
consistent with the conclusion that PIA is a regenerative lesion. We
discuss our proposal to integrate the atrophy and high-grade
PIN hypotheses of prostate carcinogenesis by suggesting that
atrophy may give rise to carcinoma either directly, as
previously postulated, or indirectly by first developing into
high-grade PIN.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Atrophy of the prostate is identified as a reduction in the volume of preexisting glands and stroma and can be divided into two major patterns, diffuse and focal.12,14 Diffuse atrophy results from a decrease in circulating androgens and involves the entire prostate in a relatively uniform manner.15 In contrast, focal atrophy is not related to decreased circulating androgens, and it occurs as patches of atrophic epithelium within a background of surrounding normal-appearing nonatrophic epithelium.12 Franks10 indicated that focal prostatic atrophy lesions occur chiefly in the "outer" portion of the prostate (referred to by McNeal as the "peripheral zone")12 and that they increase in frequency with advancing age. Others confirmed these findings.11,13,16,17
How might atrophic cells be linked to carcinoma, which also occurs principally in the peripheral zone? While most focal prostatic atrophy lesions have been considered to be quiescent,13 cells in some atrophy lesions appear proliferative.10,11,18,19 In a comparison between benign nonatrophic epithelium and focal prostatic atrophy, Ruska et al recently demonstrated that, while there was no increase in the apoptotic index, atrophy exhibited a markedly increased immunohistochemical staining index for the proliferation marker, Ki-67.20 This finding supports the contention that focal atrophy represents either a de novo proliferative lesion or a regenerative lesion resulting from replacement of cellular loss, as suggested previously.11
Most cell division in the normal human prostate epithelium occurs in the basal cell compartment.21,22 Yet high-grade PIN, the presumed precursor of many prostatic adenocarcinomas,23 and adenocarcinoma cells possess phenotypic and morphological features of secretory cells. Thus cell proliferation has been shifted up from the basal into the secretory compartment in high-grade PIN and in carcinoma.21,22 Based on this "topographic infidelity of proliferation" (TIP),24 as well as patterns of cytokeratin expression,25 it has been postulated that the prostatic cell type that is the target of neoplastic transformation is an intermediate cell, with some features of basal cells and some of secretory cells.
No prior studies have specifically examined the immunophenotype of the
cells within focal atrophy of the prostate. To better elucidate the
cell types present and to further explore the possibility that cells in
focal atrophy of the prostate may be related to carcinoma and
high-grade PIN, we performed a detailed morphological and
immunohistochemical analysis. We examined expression of both basal
cell-specific and secretory cell-specific markers. In addition, we
examined the expression patterns of other molecular markers implicated
in prostatic carcinogenesis: p27Kip1, Bcl-2, and the
-class glutathione S-transferase (GSTP1).
p27Kip1 is a cyclin-dependent kinase inhibitor whose expression is reduced in the majority of prostatic adenocarcinomas26-32 and in high-grade PIN.26 GSTP1, which functions as an inducible phase II detoxifying enzyme for reactive oxygen species and organic electrophiles,33,34 is inactivated by promoter hypermethylation in human prostatic carcinoma.35-37 Expression of GSTP1 is also absent in high-grade PIN,37 with promoter hypermethylation occurring in at least 70% of cases.37 In this study, we report a down-regulation of p27Kip1 in prostatic atrophy, consistent with its proposed role as a suppressor of prostatic epithelial cell proliferation. We also report increased expression of Bcl-2, which is consistent with the observed very low levels of apoptosis.20 Finally, there was a striking increase in the expression of GSTP1 in many of the atrophic cells, indicative of a stress-induced response. Potential mechanisms of formation of prostatic atrophy are discussed, as well as the implications for prostatic carcinogenesis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The anti-androgen receptor antibody was obtained and used as
undiluted mouse monoclonal antibody hybridoma supernatant from clone
AR-441 (a gift from Dean P. Edwards, Ph.D., University of Colorado HSC,
Denver, CO). Antibodies against prostate-specific antigen (PSA) (mouse
monoclonal, clone ER-PR8, dilution 1:50), prostate-specific acid
phosphatase (PSAP) (rabbit polyclonal, dilution 1:10,000), Bcl-2 (mouse
monoclonal, dilution 1:25), CD20 (mouse monoclonal, clone L26, dilution
1:200), CD3 (mouse monoclonal, clone UCHT1, dilution 1:150), and
CD68 (mouse monoclonal, clone KP-1, dilution 1:4000) were from Dako
(Carpinteria, CA). Anti-p27Kip1 (mouse monoclonal, dilution
1:800) and anti-PCNA (mouse monoclonal, dilution 1:250) were from
Transduction Laboratories (Lexington, KY). Anti-Ki-67 (mouse
monoclonal, clone Mib-1, dilution 1:100) was from Immunotech (Miami,
FL). The basal cell-specific cytokeratin antibody (mouse monoclonal,
clone 34ßE12, dilution 1:50) was from Enzo Biochem (Farmingdale, NY).
Anti-cytokeratins 8 and 18 (mouse monoclonal, clone Cam 5.2,
prediluted) was from Becton Dickinson (Franklin Lakes, NJ).
Anti-topoisomerase II 
(mouse monoclonal, clone AB-1, dilution
1:100) was from Calbiochem (San Diego, CA). Anti-GSTP1 (rabbit
polyclonal, dilution 1:40,000) was from Medical and Biological
Laboratories (Watertown, MA).
Immunohistochemistry
Immunohistochemistry was performed using the Biotek Techmate 1000 (Ventana Medical Systems, Tucson, AZ) robotic immunostainer as described.38 Briefly, all primary antibody incubations were carried out for 45 minutes at room temperature, except for GSTP1, which was at 4°C overnight. Biotinylated secondary antibody incubation was carried out for 30 minutes at room temperature. Histochemical localization using avidin-biotin horseradish peroxidase complex (ABC) was carried out using 3,3'-diaminobenzidine tetrahydrochloride (DAB) as the chromagen. Slides were couterstained with hematoxylin. For 34ßE12 and Cam 5.2 cytokeratin staining, the sections were pretreated with protease type 27 (Sigma, St. Louis, MO) at 2 mg/ml for 20 minutes at 37°C before incubation with the primary antibodies.
Surgical Specimens
Formalin-fixed, paraffin-embedded tissues were obtained from The Johns Hopkins Hospital. All specimens were from radical prostatectomies (n = 42 patients) and consisted of portions of tissue dissected immediately after surgical removal and immersed in 10% neutral buffered formalin.
Scoring of Morphological and Immunohistochemical Features
Intensity of inflammation was recorded using a numerical 0–6 scale, with 0 representing no inflammation, 1–2 representing mild, 3–4 representing moderate, and 5–6 representing severe inflammation. All lesions were heterogeneous in terms of inflammation, in that different areas within an individual focus of atrophy had different amounts of inflammatory cells. Thus the scores recorded represented an overall average for each lesion. For each lesion we recorded the size and the following variables, using a 0–6 scale for each variable, where 0 is negative and 6 is the highest value: the extent of epithelial disruption, the relative number of intraluminal macrophages, and the extent of periglandular fibrosis. For each lesion we also recorded whether any part of the lesion was adjacent to or was away from high-grade PIN or carcinoma.
Apoptosis was accessed by light microscopic examination for apoptotic bodies, using hematoxylin and eosin (H&E)-stained sections. For both PIA and adjacent normal epithelium, we recorded the number of apoptotic bodies within the epithelium per 20 high-power fields (hpf), using an Olympus BX-40 microscope with a 40x objective.
The intensity of immunohistochemical staining for GSTP1 and Bcl-2 was scored on a numerical 0–6 scale system, with 0 representing background staining in benign normal-appearing nonatrophic secretory cells, 1–2 representing mild elevations, 3–4 representing moderate elevations, and 5–6 representing marked elevations. GSTP1 and Bcl-2 staining was also heterogeneous in that individual atrophy lesions contained areas with intense staining and other areas with somewhat less staining. Because lesions were heterogeneous, the overall score assigned represented the average for the entire lesion. For p27Kip1, AR, PSA, and PSAP, an identical scoring approach was used, except that negative numbers were used to indicate reduced expression. In 22 lesions, a Ki-67 labeling index was determined by counting the number of positively staining cells per total cells counted, with a minimum of 500 cells counted (range 500-2000). For this, the entire lesion was scanned at x400 magnification with a BLISS imaging microscope (Bacus Laboratories, Lombard, IL). A minimum of five screen shots representing individual microscopic fields at x400 were selected for counting at random. Each screen shot, consisting of a microscopic field, was copied and transferred to Adobe Photoshop 5.0 for Microsoft Windows 95/98. As the individual cells were counted, each nucleus was overlayed with a small green dot. In addition, cells staining positively for Ki-67 were overlayed with a red dot. By saving the file to disk, we obtained a permanent record of exactly which cells in the lesion were counted. In these 22 cases, normal epithelium away from the lesion was used as an internal reference for each lesion, and cells were similarly counted. Statistical analysis was carried out using the STATA 5.0 software package for Microsoft Windows 95.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. The majority of the PIA lesions
(n = 41/55) were considered simple atrophy as
described,20
which consisted of glands with variable
acinar caliber (Figures 1–5)
.
The majority of acini in simple atrophy acini were stellate in
architecture and lacked papillary infoldings. Often the lesions
contained corpora amylacea of varying sizes. Three of the lesions
(n = 3/55) were classified as postatrophic
hyperplasia (PAH),39
consisting of foci of crowded glands
with small-caliber, round atrophic acini. Some of the lesions
(n = 11/55) contained both PAH and simple
atrophy.
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. The luminal cells appeared
as attenuated cuboidal secretory-type cells that were generally
hyperchromatic but which contained somewhat more cytoplasm than the
basal layer of cells. As compared with surrounding normal epithelium,
the cytoplasm in the luminal cells ranged from markedly reduced and
basophilic to slightly reduced and pale to clear (partial
atrophy40
; see Figure 5
). Most lesions contained at least
some atrophic acini that were so attenuated as to appear to have only
one layer of markedly flattened epithelial cells. The latter structures
were often cystically dilated and have been referred to as cystic
atrophy.10
No cases consisted purely of cystic atrophy.
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, consisting of an
infiltrate of lymphocytes with varying numbers of macrophages involving
both the epithelium and surrounding stroma to varying degrees (Table 1)
. The majority (~80–85%) of the
lymphocytes represented CD3-positive T cells with scattered and
variable numbers of CD20-positive B cells and CD68-positive macrophages
(data not shown). While none of the cases contained granulomata, some
of the lesions contained a few eosinophils and plasma cells. In 33/55
(60%) lesions, there was acute (active) inflammation involving the
stroma, acinar lumens, and epithelium (Table 2)
. There was a strong correlation
between the extent of acute and chronic inflammation
(r = 0.683, P < 0.0001,
n = 55). Furthermore, there was a correlation between
the amount of intraluminal macrophages and the overall extent of acute
(r = 0.4978, P = 0.0001,
n = 55) and chronic (r = 0.4666,
P = 0.003, n = 55) inflammation.
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Immunohistochemical staining for basal cell-specific
cytokeratins41
(34ßE12) revealed a predominantly intact
basal cell layer in most acini from most lesions (Figure 2)
. In the
vast majority of acini, the luminal layer of cuboidal cells contained
reduced immunoreactivity for 34ßE12 or were completely negative for
this marker (Figure 2)
. Rarely both the luminal and basal-most layers
of cells stained strongly for 34ßE12. The cuboidal atrophic luminal
cells consistently stained intensely with the monoclonal antibody Cam
5.2.42
This antibody recognizes cytokeratins 8 and 18,
which are highly expressed in secretory cells, with somewhat weaker
expression in basal cells (De Marzo et al, unpublished
observations).43
Many of the luminal cells also stained positively for nuclear AR, with
the majority of the cells staining weakly and some staining strongly
(Figure 4A)
. The level of AR appeared to be related to the extent of
clear cytoplasm present; in general those cells with the clearest
cytoplasm contained the strongest AR staining. As further evidence for
partial secretory cell differentiation in PIA, positive staining for
PSA and PSAP was found in the luminal layer of cells, although staining
was generally weak in intensity as compared to surrounding normal
glands (Figure 3C)
. There was a positive correlation between the extent
of AR expression and the extent of expression of the secretory markers
PSA (r = 0.5894, P = 0.0001,
n = 38) and PSAP (r = 0.5748,
P = 0.0002, n = 38). There were weak
negative correlations between extent of expression of AR and the extent
of acute (r = -0.2847, P =
0.0369) and chronic (r = -0.3579,
P = 0.0035, n = 54) inflammation.
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. Immunohistochemistry against two other markers of proliferating
cells, PCNA44
and topoisomerase II ,45
was
performed in 10 of the same cases on adjacent sections, and a pattern
of increased staining in PIA similar to that obtained with Ki-67 was
noted. Consistent with an overall increase in the proportion of cells
that are proliferating in PIA, all lesions showed reduced levels of the
cyclin-dependent kinase inhibitor p27Kip1 in many of the
attenuated secretory-type cells, as compared with surrounding
normal-appearing nonatrophic secretory cells (Figure 3B)
. In agreement with prior studies showing very low levels of apoptosis by the terminal deoxynucleotidyl transferase nick end labeling (TUNEL) method,20 very few apoptotic bodies were identified within the epithelial layers in the PIA lesions examined (n = 55, mean = 0.072 apoptotic bodies/20 hpf) or in the surrounding normal appearing prostate epithelium (n = 41, mean = 0.146 apoptotic bodies/20 hpf). There was no significant difference between the number of apoptotic bodies in PIA versus matched normal epithelial (paired Student’s t-test, t = 0.703, df = 40, P = 0.4863). There were occasional apoptotic bodies found within the lumens of some of the PIA lesions; however, it was not possible to determine whether these represented epithelial or inflammatory cells.
As shown previously, staining against Bcl-2 in normal prostate
epithelium was strong in the basal cells and negative to weak in the
majority of secretory cells.46-49
In all PIA lesions
evaluated (n = 55), although staining was
heterogeneous, there was an overall increase in staining as compared to
secretory cells of the adjacent normal epithelium (Figure 4B)
. Similar
to that reported in normal prostate epithelium,50
in all
specimens examined for both markers (n = 51),
there was an inverse relation between the expression of Bcl-2 and AR in
the epithelial cells of PIA (Figure 4)
in many of the glands. There was
a significant relation between the extent of Bcl-2 expression and the
type of lesion, with those lesions containing PAH showing higher
overall levels of Bcl-2 (mean Bcl-2 score = 4.8, n
= 14) than lesions not containing PAH (mean Bcl-2 score = 3.8,
n = 38) (two-tailed Student’s t-test,
t = -3.1046, df = 50, P =
0.0031).
As compared with the vast majority of normal-appearing nonatrophic
secretory epithelial cells of the prostate that do not express GSTP1
(Figure 1B)
,35,36,51-53
all PIA lesions showed elevated
levels of GSTP1 in many of the secretory-type cells (Figures 1B and 5)
.
There was a range of expression of GSTP1, and often the individual
glands showed a pattern of cells staining positively for GSTP1 in the
vicinity of cells staining negatively (Figure 5)
. GSTP1 expression
levels in PIA were not associated with acute or chronic inflammation,
Ki-67 index, or fibrosis. As with Bcl-2, there was an association
between the levels of GSTP1 and the type of lesion, with those lesions
containing PAH showing higher levels of GSTP1 (mean GSTP1 score =
4.36, n = 11) than those not containing PAH (mean GSTP1
score = 3.49, n = 41) (two-tailed Student’s
t-test, t = -2968, df = 53,
P = 0.0045). Levels of GSTP1 expression in PIA were
unrelated to whether the lesions were adjacent to or remote from
high-grade PIN or carcinoma.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In normal, nonatrophic prostatic epithelium, GSTP1, which is an inducible enzyme that appears to protect cells from DNA damage, is expressed predominantly in basal cells.35-37 The fact that many of the secretory-type cells in PIA express elevated levels of GSTP1 is highly suggestive of a stress-induced response in these cells.
Although we expect that many of the cells in PIA are largely protected
from incurring oxidative or electrophilic DNA damage as a result of
increased expression of GSTP1, some of the proliferative secretory-type
cells that lack expression of GSTP1 (Figure 5)
may be targets for
genetic alterations and hence neoplastic transformation. Currently we
are performing microdissection and molecular analysis to determine the
status of methylation of the GSTP1 promoter in PIA.
How might the prior hypothesis indicating that focal atrophy gives rise to carcinoma10 be reconciled with the modern contention that most carcinomas, at least in the peripheral zone of the prostate, arise from high-grade PIN?23 We suggest that PIA may indeed give rise to carcinoma directly as hypothesized previously10 or that PIA may lead to carcinoma indirectly via development into PIN. Four separate findings provide supportive evidence for this novel hypothesis that PIA may represent a PIN precursor: 1) We demonstrate that a shift in the topographic fidelity of proliferation occurs in PIA. 2) We show that the phenotype of many of the cells in PIA is most consistent with that of an immature secretory-type cell,24-26,55 similar to that for the cells of high-grade PIN and carcinoma. 3) PIA, high-grade PIN, and carcinoma all occur with high prevalence in the peripheral zone and low prevalence in the central zone of the human prostate.13 4) In preliminary studies, we find in randomly sampled PIA lesions from radical prostatectomy patients that 34.5.% (n = 19/55, data not shown) show areas of atrophy merging directly with areas of high-grade PIN within the same glands. This preliminary finding appears at odds with a recent study,17 and we are currently employing fully embedded prostates with and without PIN and carcinoma to determine the frequency and extent of PIA and the frequency with which PIN lesions arise within foci of PIA.
If cells in PIA are proliferating rapidly, why are the lesions not apparently growing in volume? Because there appears to be no increase in the rate of apoptosis in focal atrophy of the prostate, then either Ki-67 staining does not reflect cell proliferation, or cellular loss is balancing proliferation but the loss is not occurring via an apoptotic mechanism. Because other "proliferation markers" were also elevated in the present study, we submit that it is highly unlikely there is not an increased proliferative rate in PIA. Furthermore, others have used more direct measures of mitosis to indicate that focal prostatic atrophy has increased cell replication over that of normal-appearing epithelium.18 Because our preliminary studies show frequent Cam 5.2-positive epithelial cells and CD68-positive macrophages in the lumens of atrophic glands, as opposed to normal-appearing glands (data not shown), we favor the concept of regeneration in PIA,11 with the loss of epithelial cells occurring through direct cell injury, in which the injured cells are shed intraluminally and expressed in the ejaculate or engulfed by intraluminal macrophages. It has been previously pointed out that regenerating epithelium is expected to suppress programmed cell death, at least temporarily, to replace lost cells.56 The increase in Bcl-2 expression in PIA may explain the very low levels of apoptosis and supports the concept that PIA is a regenerative lesion. The marked increase in the proliferation index in PIA may reflect a response to local growth factor release due to lost epithelial cells. Alternatively, more direct growth-promoting factors, such as platelet-derived growth factor, that are released from the inflammatory cells may stimulate epithelial proliferation.57,58
Still open to debate is whether the inflammation produces tissue damage and regenerative atrophy or whether some other insult induces the tissue damage and/or atrophy directly, with inflammation occurring secondarily. Preliminary support indicating that inflammation occurs before PIA is provided by Bennett et al,6 who found in autopsies of 125 young males that more foci of inflammation were present at a younger age than foci of atrophy, which tended to occur somewhat later. Additional studies using animal models of inflammation and atrophy may help resolve this question.
In summary, we confirm that essentially all forms of focal atrophy (PIA) are proliferative, the vast majority are associated with inflammation, and many of the proliferating cells appear to have an immature secretory cell phenotype—a phenotype with similarities to PIN and prostate carcinoma. We interpret this very common lesion in a new light and postulate that it arises in the setting of increased oxidative stress, most likely derived from the proximate inflammatory cells. Furthermore, we postulate that PIA may represent a precursor lesion to prostatic intraepithelial neoplasia and, therefore, prostatic carcinoma.
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Acknowledgements |
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Note added in proof: While this manuscript was in press, it came to our attention that a previously published manuscript appears to have been the first to show an elevated Ki-67 staining index in focal atrophy of the prostate (Feneley MR, Young MP, Chinyama C, Kirby RS, Parkinson MC: Ki-67 expression in early prostate cancer pathological lesions. J Clin Pathol 1996, 49:741–748).
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Footnotes |
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Supported in part by United States Public Health Service Specialized Program in Research Excellence (SPORE) in Prostate Cancer Grants P50CA58236 and 1K08CA78588-01 (to A. M. D.).
Accepted for publication August 24, 1999.
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References |
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: a new marker of cell proliferation in invasive breast cancer. Hum Pathol 1997, 28:1180-1188[Medline]
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S. Sutcliffe, E. Giovannucci, A. M. De Marzo, M. F. Leitzmann, W. C. Willett, and E. A. Platz Gonorrhea, Syphilis, Clinical Prostatitis, and the Risk of Prostate Cancer. Cancer Epidemiol. Biomarkers Prev., November 1, 2006; 15(11): 2160 - 2166. [Abstract] [Full Text] [PDF]
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B. Knudsen Migrating with Myosin VI Am. J. Pathol., November 1, 2006; 169(5): 1523 - 1526. [Full Text] [PDF]
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 A. S Perry, R. Foley, K. Woodson, and M. Lawler The emerging roles of DNA methylation in the clinical management of prostate cancer. Endocr. Relat. Cancer, June 1, 2006; 13(2): 357 - 377. [Abstract] [Full Text] [PDF]
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V. M. Hayes, G. Severi, M. C. Southey, E. J.D. Padilla, D. R. English, J. L. Hopper, G. G. Giles, and R. L. Sutherland Macrophage Inhibitory Cytokine-1 H6D Polymorphism, Prostate Cancer Risk, and Survival. Cancer Epidemiol. Biomarkers Prev., June 1, 2006; 15(6): 1223 - 1225. [Abstract] [Full Text] [PDF]
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J. J. Bianco, S. J. McPherson, H. Wang, G. S. Prins, and G. P. Risbridger Transient Neonatal Estrogen Exposure to Estrogen-Deficient Mice (Aromatase Knockout) Reduces Prostate Weight and Induces Inflammation in Late Life Am. J. Pathol., June 1, 2006; 168(6): 1869 - 1878. [Abstract] [Full Text] [PDF]
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 D. Schottenfeld and J. Beebe-Dimmer Chronic inflammation: a common and important factor in the pathogenesis of neoplasia. CA Cancer J Clin, March 1, 2006; 56(2): 69 - 83. [Abstract] [Full Text] [PDF]
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 N. Rosenzweig-Bublil and A. Abramovici Stromal Fibrosis Reaction in Rat Prostates Induced by Alpha 1 Adrenergic Stimulation J Androl, March 1, 2006; 27(2): 276 - 284. [Abstract] [Full Text] [PDF]
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G D Dakubo, R L Parr, L C Costello, R B Franklin, and R E Thayer Altered metabolism and mitochondrial genome in prostate cancer J. Clin. Pathol., January 1, 2006; 59(1): 10 - 16. [Abstract] [Full Text] [PDF]
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 T. M. Katona, B. L. Neubauer, P. W. Iversen, S. Zhang, L. A. Baldridge, and L. Cheng Elevated Expression of Angiogenin in Prostate Cancer and Its Precursors Clin. Cancer Res., December 1, 2005; 11(23): 8358 - 8363. [Abstract] [Full Text] [PDF]
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J. Xu, J. Lowey, F. Wiklund, J. Sun, F. Lindmark, F.-C. Hsu, L. Dimitrov, B. Chang, A. R. Turner, W. Liu, et al. The Interaction of Four Genes in the Inflammation Pathway Significantly Predicts Prostate Cancer Risk Cancer Epidemiol. Biomarkers Prev., November 1, 2005; 14(11): 2563 - 2568. [Abstract] [Full Text] [PDF]
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J. T. Arnold and M. R. Blackman Does DHEA Exert Direct Effects on Androgen and Estrogen Receptors, and Does It Promote or Prevent Prostate Cancer? Endocrinology, November 1, 2005; 146(11): 4565 - 4567. [Full Text] [PDF]
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 A. Prando, J. Kurhanewicz, A. P. Borges, E. M. Oliveira Jr, and E. Figueiredo Prostatic Biopsy Directed with Endorectal MR Spectroscopic Imaging Findings in Patients with Elevated Prostate Specific Antigen Levels and Prior Negative Biopsy Findings: Early Experience Radiology, September 1, 2005; 236(3): 903 - 910. [Abstract] [Full Text] [PDF]
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C Hughes, A Murphy, C Martin, O Sheils, and J O'Leary Molecular pathology of prostate cancer J. Clin. Pathol., July 1, 2005; 58(7): 673 - 684. [Abstract] [Full Text] [PDF]
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 G. S. Palapattu, S. Sutcliffe, P. J. Bastian, E. A. Platz, A. M. De Marzo, W. B. Isaacs, and W. G. Nelson Prostate carcinogenesis and inflammation: emerging insights Carcinogenesis, July 1, 2005; 26(7): 1170 - 1181. [Abstract] [Full Text] [PDF]
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 P. E. Burger, X. Xiong, S. Coetzee, S. N. Salm, D. Moscatelli, K. Goto, and E. L. Wilson Sca-1 expression identifies stem cells in the proximal region of prostatic ducts with high capacity to reconstitute prostatic tissue PNAS, May 17, 2005; 102(20): 7180 - 7185. [Abstract] [Full Text] [PDF]
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 N. Atanassova, C. McKinnell, J. Fisher, and R. M Sharpe Neonatal treatment of rats with diethylstilboestrol (DES) induces stromal-epithelial abnormalities of the vas deferens and cauda epididymis in adulthood following delayed basal cell development Reproduction, May 1, 2005; 129(5): 589 - 601. [Abstract] [Full Text] [PDF]
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 J. Sun, F. Wiklund, S. L. Zheng, B. Chang, K. Balter, L. Li, J.-E. Johansson, G. Li, H.-O. Adami, W. Liu, et al. Sequence Variants in Toll-Like Receptor Gene Cluster (TLR6-TLR1-TLR10) and Prostate Cancer Risk J Natl Cancer Inst, April 6, 2005; 97(7): 525 - 532. [Abstract] [Full Text] [PDF]
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E. A. Platz, S. Rohrmann, J. D. Pearson, M. M. Corrada, D. J. Watson, A. M. De Marzo, P. K. Landis, E. J. Metter, and H. B. Carter Nonsteroidal Anti-inflammatory Drugs and Risk of Prostate Cancer in the Baltimore Longitudinal Study of Aging Cancer Epidemiol. Biomarkers Prev., February 1, 2005; 14(2): 390 - 396. [Abstract] [Full Text] [PDF]
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W. G. Nelson Prostate Cancer Prevention J. Nutr., November 1, 2004; 134(11): 3211S - 3212S. [Full Text] [PDF]
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F. Lindmark, S. L. Zheng, F. Wiklund, J. Bensen, K. A. Balter, B. Chang, M. Hedelin, J. Clark, P. Stattin, D. A. Meyers, et al. H6D Polymorphism in Macrophage-Inhibitory Cytokine-1 Gene Associated With Prostate Cancer J Natl Cancer Inst, August 18, 2004; 96(16): 1248 - 1254. [Abstract] [Full Text] [PDF]
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S. L. Zheng, K. Augustsson-Balter, B. Chang, M. Hedelin, L. Li, H.-O. Adami, J. Bensen, G. Li, J.-E. Johnasson, A. R. Turner, et al. Sequence Variants of Toll-Like Receptor 4 Are Associated with Prostate Cancer Risk: Results from the CAncer Prostate in Sweden Study Cancer Res., April 15, 2004; 64(8): 2918 - 2922. [Abstract] [Full Text] [PDF]
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G. Yang, J. Addai, W.-h. Tian, A. Frolov, T. M. Wheeler, and T. C. Thompson Reduced Infiltration of Class A Scavenger Receptor Positive Antigen-Presenting Cells Is Associated with Prostate Cancer Progression Cancer Res., March 15, 2004; 64(6): 2076 - 2082. [Abstract] [Full Text] [PDF]
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S. B. Shappell, G. V. Thomas, R. L. Roberts, R. Herbert, M. M. Ittmann, M. A. Rubin, P. A. Humphrey, J. P. Sundberg, N. Rozengurt, R. Barrios, et al. Prostate Pathology of Genetically Engineered Mice: Definitions and Classification. The Consensus Report from the Bar Harbor Meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee Cancer Res., March 15, 2004; 64(6): 2270 - 2305. [Abstract] [Full Text] [PDF]
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M. D. Hofer, R. Kuefer, S. Varambally, H. Li, J. Ma, G. I. Shapiro, J. E. Gschwend, R. E. Hautmann, M. G. Sanda, K. Giehl, et al. The Role of Metastasis-Associated Protein 1 in Prostate Cancer Progression Cancer Res., February 1, 2004; 64(3): 825 - 829. [Abstract] [Full Text] [PDF]
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 Inflammation, Dietary Carcinogens, Glutathione S-Transferase {pi}, and Prostatic Carcinogenesis: WILLIAM G. NELSON, ANGELO M. DE MARZO, THEODORE L. DEWEESE, AND WILLIAM B. ISAACS, The Departments of Oncology, Urology, Pathology, Pharmacology, and Medicine, The Johns Hopkins University School of Medicine, and The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland Toxicol Pathol, January 1, 2004; 32(1): 143 - 144. [PDF]
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E. H. Seppala, T. Ikonen, V. Autio, A. Rokman, N. Mononen, M. P. Matikainen, T. L. J. Tammela, and J. Schleutker Germ-Line Alterations in MSR1 Gene and Prostate Cancer Risk Clin. Cancer Res., November 1, 2003; 9(14): 5252 - 5256. [Abstract] [Full Text] [PDF]
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M. Nakayama, C. J. Bennett, J. L. Hicks, J. I. Epstein, E. A. Platz, W. G. Nelson, and A. M. De Marzo Hypermethylation of the Human Glutathione S-Transferase-{pi} Gene (GSTP1) CpG Island Is Present in a Subset of Proliferative Inflammatory Atrophy Lesions but Not in Normal or Hyperplastic Epithelium of the Prostate: A Detailed Study Using Laser-Capture Microdissection Am. J. Pathol., September 1, 2003; 163(3): 923 - 933. [Abstract] [Full Text] [PDF]
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 W. G. Nelson, A. M. De Marzo, and W. B. Isaacs Prostate Cancer N. Engl. J. Med., July 24, 2003; 349(4): 366 - 381. [Full Text] [PDF]
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 I. V. Litvinov, A. M. De Marzo, and J. T. Isaacs Is the Achilles' Heel for Prostate Cancer Therapy a Gain of Function in Androgen Receptor Signaling? J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 2972 - 2982. [Full Text] [PDF]
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J. P. Gilleran, O. Putz, M. DeJong, S. DeJong, L. Birch, Y. Pu, L. Huang, and G. S. Prins The Role of Prolactin in the Prostatic Inflammatory Response to Neonatal Estrogen Endocrinology, May 1, 2003; 144(5): 2046 - 2054. [Abstract] [Full Text] [PDF]
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G. J. L. H. van Leenders, W. R. Gage, J. L. Hicks, B. van Balken, T. W. Aalders, J. A. Schalken, and A. M. De Marzo Intermediate Cells in Human Prostate Epithelium Are Enriched in Proliferative Inflammatory Atrophy Am. J. Pathol., May 1, 2003; 162(5): 1529 - 1537. [Abstract] [Full Text] [PDF]
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 M. Mareel and A. Leroy Clinical, Cellular, and Molecular Aspects of Cancer Invasion Physiol Rev, April 1, 2003; 83(2): 337 - 376. [Abstract] [Full Text] [PDF]
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P. M. Campbell and M. Szyf Human DNA methyltransferase gene DNMT1 is regulated by the APC pathway Carcinogenesis, January 1, 2003; 24(1): 17 - 24. [Abstract] [Full Text] [PDF]
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A. K. Meeker, J. L. Hicks, E. A. Platz, G. E. March, C. J. Bennett, M. J. Delannoy, and A. M. De Marzo Telomere Shortening Is an Early Somatic DNA Alteration in Human Prostate Tumorigenesis Cancer Res., November 15, 2002; 62(22): 6405 - 6409. [Abstract] [Full Text] [PDF]
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E. A. Platz Energy Imbalance and Prostate Cancer J. Nutr., November 1, 2002; 132(11): 3471S - 3481. [Abstract] [Full Text] [PDF]
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J. D. Brooks, M. F. Goldberg, L. A. Nelson, D. Wu, and W. G. Nelson Identification of Potential Prostate Cancer Preventive Agents through Induction of Quinone Reductase in Vitro Cancer Epidemiol. Biomarkers Prev., September 1, 2002; 11(9): 868 - 875. [Abstract] [Full Text] [PDF]
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T. Ernst, M. Hergenhahn, M. Kenzelmann, C. D. Cohen, M. Bonrouhi, A. Weninger, R. Klaren, E. F. Grone, M. Wiesel, C. Gudemann, et al. Decrease and Gain of Gene Expression Are Equally Discriminatory Markers for Prostate Carcinoma : A Gene Expression Analysis on Total and Microdissected Prostate Tissue Am. J. Pathol., June 1, 2002; 160(6): 2169 - 2180. [Abstract] [Full Text] [PDF]
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J. Xu, S. L. Zheng, A. Turner, S. D. Isaacs, K. E. Wiley, G. A. Hawkins, B.-l. Chang, E. R. Bleecker, P. C. Walsh, D. A. Meyers, et al. Associations between hOGG1 Sequence Variants and Prostate Cancer Susceptibility Cancer Res., April 1, 2002; 62(8): 2253 - 2257. [Abstract] [Full Text] [PDF]
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X. Lin, K. Asgari, M. J. Putzi, W. R. Gage, X. Yu, B. S. Cornblatt, A. Kumar, S. Piantadosi, T. L. DeWeese, A. M. De Marzo, et al. Reversal of GSTP1 CpG Island Hypermethylation and Reactivation of {pi}-Class Glutathione S-Transferase (GSTP1) Expression in Human Prostate Cancer Cells by Treatment with Procainamide Cancer Res., December 1, 2001; 61(24): 8611 - 8616. [Abstract] [Full Text] [PDF]
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S. Zha, W. R. Gage, J. Sauvageot, E. A. Saria, M. J. Putzi, C. M. Ewing, D. A. Faith, W. G. Nelson, A. M. De Marzo, and W. B. Isaacs Cyclooxygenase-2 Is Up-Regulated in Proliferative Inflammatory Atrophy of the Prostate, but not in Prostate Carcinoma Cancer Res., December 1, 2001; 61(24): 8617 - 8623. [Abstract] [Full Text] [PDF]
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 B. C. Gottschling, R. R. Maronpot, J. R. Hailey, S. Peddada, C. R. Moomaw, J. E. Klaunig, and A. Nyska The Role of Oxidative Stress in Indium Phosphide-Induced Lung Carcinogenesis in Rats Toxicol. Sci., November 1, 2001; 64(1): 28 - 40. [Abstract] [Full Text] [PDF]
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X. Lin, M. Tascilar, W.-H. Lee, W. J. Vles, B. H. Lee, R. Veeraswamy, K. Asgari, D. Freije, B. van Rees, W. R. Gage, et al. GSTP1 CpG Island Hypermethylation Is Responsible for the Absence of GSTP1 Expression in Human Prostate Cancer Cells Am. J. Pathol., November 1, 2001; 159(5): 1815 - 1826. [Abstract] [Full Text] [PDF]
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M. A. Ficazzola, M. Fraiman, J. Gitlin, K. Woo, J. Melamed, M. A. Rubin, and P. D. Walden Antiproliferative B cell translocation gene 2 protein is down-regulated post-transcriptionally as an early event in prostate carcinogenesis Carcinogenesis, August 1, 2001; 22(8): 1271 - 1279. [Abstract] [Full Text] [PDF]
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G. A. Gmyrek, M. Walburg, C. P. Webb, H.-M. Yu, X. You, E. D. Vaughan, G. F. Vande Woude, and B. S. Knudsen Normal and Malignant Prostate Epithelial Cells Differ in Their Response to Hepatocyte Growth Factor/Scatter Factor Am. J. Pathol., August 1, 2001; 159(2): 579 - 590. [Abstract] [Full Text]
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R. Shah, N. R. Mucci, A. Amin, J. A. Macoska, and M. A. Rubin Postatrophic Hyperplasia of the Prostate Gland : Neoplastic Precursor or Innocent Bystander? Am. J. Pathol., May 1, 2001; 158(5): 1767 - 1773. [Abstract] [Full Text] [PDF]
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 L. M. Coussens and Z. Werb Inflammatory Cells and Cancer: Think Different! J. Exp. Med., March 19, 2001; 193(6): F23 - F26. [Full Text] [PDF]
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E. Giovannucci {{gamma}}-Tocopherol: a New Player in Prostate Cancer Prevention? J Natl Cancer Inst, December 20, 2000; 92(24): 1966 - 1967. [Full Text] [PDF]
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 C. Abate-Shen and M. M. Shen Molecular genetics of prostate cancer Genes & Dev., October 1, 2000; 14(19): 2410 - 2434. [Full Text]
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