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Journal of Cellular Biochemistry 91:459–477 (2004)
Pathological and Molecular Mechanisms of Prostate
Carcinogenesis: Implications for Diagnosis, Detection,
Prevention, and Treatment
Angelo M. De Marzo,* Theodore L. DeWeese, Elizabeth A. Platz, Alan K. Meeker, Masashi Nakayama,
Jonathan I. Epstein, William B. Isaacs, and William G. Nelson
Departments of Oncology, Pathology, Radiation Oncology, Urology,
The Johns Hopkins University School of Medicine, and the Department of Epidemiology,
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
Abstract
Prostate cancer is an increasing threat throughout the world. As a result of a demographic shift in
population, the number of men at risk for developing prostate cancer is growing rapidly. For 2002, an estimated 189,000
prostate cancer cases were diagnosed in the U.S., accompanied by an estimated 30,200 prostate cancer deaths [Jemal
et al., 2002]. Most prostate cancer is now diagnosed in men who were biopsied as a result of an elevated serum PSA
(>4 ng/ml) level detected following routine screening. Autopsy studies [Breslow et al., 1977; Yatani et al., 1982; Sakr
et al., 1993], and the recent results of the Prostate Cancer Prevention Trial (PCPT) [Thompson et al., 2003], a large scale
clinical trial where all men entered the trial without an elevated PSA (<3 ng/ml) were subsequently biopsied, indicate the
prevalence of histologic prostate cancer is much higher than anticipated by PSA screening. Environmental factors, such as
diet and lifestyle, have long been recognized contributors to the development of prostate cancer. Recent studies of the
molecular alterations in prostate cancer cells have begun to provide clues as to how prostate cancer may arise and
progress. For example, while inflammation in the prostate has been suggested previously as a contributor to prostate
cancer development [Gardner and Bennett, 1992; Platz, 1998; De Marzo et al., 1999; Nelson et al., 2003], research
regarding the genetic and pathological aspects of prostate inflammation has only recently begun to receive attention.
Here, we review the subject of inflammation and prostate cancer as part of a ��chronic epithelial injury’’ hypothesis of
prostate carcinogenesis, and the somatic genome and phenotypic changes characteristic of prostate cancer cells. We also
present the implications of these changes for prostate cancer diagnosis, detection, prevention, and treatment. J. Cell.
Biochem. 91: 459–477, 2004. ß 2003 Wiley-Liss, Inc.
Key words: prostate cancer; prostateatrophy; prostatitis; benign prostatic hyperplasia; inflammation
MECHANISMS OF INFLAMMATION
INDUCED CARCINOGENESIS
Chronic or recurrent inflammation is responsible for the development of many human
Grant sponsor: Public Health Services NIH/NCI; Grant
numbers: R01CA084997, R01CA70196; Grant sponsor:
NIH/NCI Specialized Program in Research Excellence
(SPORE) in Prostate Cancer (Johns Hopkins); Grant
number: P50CA58236.
*Correspondence to: Angelo M. De Marzo, Room 153,
Bunting-Blaustein Cancer Research Building, Sidney
Kimmel Comprehensive Cancer Center at Johns Hopkins,
1650 Orleans Street, Baltimore, MD 21231-1000.
E-mail: ademarz@jhmi.edu
Received 16 September 2003; Accepted 17 September 2003
DOI 10.1002/jcb.10747
Гџ 2003 Wiley-Liss, Inc.
cancers, including those affecting the liver,
esophagus, stomach, large intestine, and urinary bladder [Coussens and Werb, 2002]. Inflammation might influence the pathogenesis of
cancers by (i) inflicting cell and genome damage,
(ii) triggering restorative cell proliferation to
replace damaged cells, (iii) elaborating a portfolio of cytokines that promote cell replication,
angiogenesis and tissue repair [Coussens and
Werb, 2002].
Oxidative damage to DNA and other cellular
components accompanying chronic or recurrent
inflammation may connect prostate inflammation with prostate cancer. In response to infections, inflammatory cells produce a variety of
toxic compounds designed to eradicate microorganisms. These include superoxide, hydrogen
peroxide, singlet oxygen, as well as nitric
oxide that can react further to form the highly
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De Marzo et al.
reactive peroxynitrite. Some of these reactive
oxygen and nitrogen species can directly interact with DNA in the host bystander cells, or
react with other cellular components such as
lipid, initiating a free radical chain reaction. If
the damage is severe, these compounds can
kill host bystander cells as well as pathogens,
and can produce DNA damage and mutations
among host cell survivors [Xia and Zweier,
1997; Eiserich et al., 1998]. As a consequence
of an acquired defect in defenses against oxidant and electrophilic carcinogens associated
with GSTP1 CpG island hypermethylation (see
below), prostate cells may acquire a heightened
susceptibility to oxidative genome damage in
an inflammatory milieu, leading to neoplastic
transformation and cancer progression. Other
support for the concept that prostate cancer can
result from excess oxidants and electrophiles
comes from epidemiological studies suggesting
that decreased prostate cancer risk is associated
with intake of various anti-oxidants and nonsteroidal anti-inflammatory drugs [Clark et al.,
1996, 1998; Heinonen et al., 1998; Norrish et al.,
1998; Gann et al., 1999; Nelson and Harris,
2000; Roberts et al., 2002]. In further support
of a critical role for oxidative genome damage
during the pathogenesis of prostate cancer,
variant polymorphic alleles at OGG1, the gene
encoding a DNA glycosylase/AP lyase that
repairs the oxidized base 8-oxo-G in DNA, are
associated with increased prostate cancer risk
[Xu et al., 2002b].
PROSTATE INFLAMMATION AND THE
PATHOGENESIS OF PROSTATE CANCER
At least three major disease processes are extremely common in the prostate—prostatitis,
benign prostatic hyperplasia (BPH), and adenocarcinoma. Why do three apparently distinct
types of lesions occur so commonly in the same
organ, and might these common processes be
linked? Despite the fact that prostate inflammation (histological prostatitis) and prostate
cancer are often found in the same patient,
associations between inflammation and prostate cancer have not been clearly shown. This
may be due in part to the following difficulties
in performing association studies of prostate
cancer and prostatitis: (i) most prostate inflammation does not seem to cause symptoms [True
et al., 1999], (ii) the incidence of asymptomatic
histologic prostatitis in non-selected population
based studies is difficult to ascertain [Giovannucci, 2001], (iii) the clinical diagnosis of chronic
prostatitis itself can be challenging and is often
subjective [Roberts et al., 1998]. Although largescale prospective epidemiological studies are
lacking [Giovannucci, 2001], a recent review of
the available epidemiological literature by
Dennis et al. [2002] indicates that there may
be a small increase in the relative risk of the
development of prostate cancer in men with a
history of clinical prostatitis. Given the high
prevalence of prostate cancer, however, even a
small increase in relative risk can result in a
large number of additional cases.
In terms of the prevalence of clinical prostatitis, a survey of clinical data in Olmstead county
Minnesota reported that symptomatic prostatitis occurred in approximately 9% of men between
40 and 79 years of age, with half of these men
suffering more than one episode, and it was
estimated that 1 in 11 men will be diagnosed
with some form of prostatitis by age 79 years
[Roberts et al., 1998]. In terms of histological
prostatitis, inflammatory infiltrates of varying
intensity and character are readily apparent in
most radical prostatectomy [Gerstenbluth et al.,
2002] and transurethral resection specimens
[Nickel et al., 1999], and prostate needle biopsies
[Schatteman et al., 2000].
The current NIH consensus classification
system of prostatitis divides the cases into four
categories–3 that are associated with genitourinary symptoms and 1 that is not [Krieger et al.,
1999]. Category I, or acute bacterial prostatitis,
is usually caused by Escherichia coli or other
gram-negative bacteria or enterococcus. Acute
bacterial prostatitis is infrequent and consists
of an acutely swollen and tender prostate with
acute inflammatory cells in expressed prostate
fluid. There is usually an associated urinary
tract infection, and, at times systemic symptoms of infection. Acute prostatitis is usually
self-limited after treatment with antibiotics.
Category II, or chronic bacterial prostatitis, is
quite rare, and consists of repeated bouts of
lower urinary tract infection where the source
of infection can be localized to the prostate.
This form is also usually treated with antibiotics, often with multiple courses over time.
Category III is the most common form, accounting for approximately 90% of clinical prostatitis syndromes, and is referred to as chronic
prostatitis/chronic pelvic pain syndrome. The
cardinal feature of this entity is pain, either in
Pathological and Molecular Mechanisms of Prostate Carcinogenesis
the perineum, external genitalia, or other sites
in the pelvis. There is also frequently pain
during or after ejaculation. The symptoms
must be of at least 3 months in duration to be
considered chronic. This form is subdivided into
those cases where leukocytes are identifiable
on expressed prostatic fluids, post-prostate
massage urine, or semen (category IIIA—
inflammatory) and those that do not contain
leukocytes in these fluids (category IIIB—
chronic prostatitis/chronic pelvic pain syndrome). Category IV, or asymptomatic inflammatory prostatitis, represents the presence of
prostate inflammation in histological tissue
sections from men with no history of urinary
symptoms.
In addition to the putative increased risk of
prostate cancer with a history of symptomatic
prostatitis, an increased prostate cancer risk
has been associated in some studies [e.g., Hayes
et al., 2000] with sexually transmitted infections [reviewed in Strickler and Goedert, 2001;
Dennis and Dawson, 2002], independent of the
specific pathogen, supporting the concept that
inflammation itself might facilitate prostatic
carcinogenesis, or, that the associative causative organism(s) has not been identified. Of
significance in this regard, two of the candidate
hereditary prostate cancer susceptibility genes
identified thus far, RNASEL and MSR1, encode
proteins that function in the host responses to a
variety of infectious agents [Zhou et al., 1997;
Platt and Gordon, 2001; Carpten et al., 2002; Xu
et al., 2002a].
Relation of Prostate Cancer, Benign Prostatic
Hyperplasia, and Inflammation
The fact that most prostate cancer and most
inflammatory infiltrates are both present in the
peripheral zone [McNeal, 1997] is consistent
with a link between inflammation and prostate
cancer. What about the transition zone, the site
of development of BPH? Is there a link between
BPH and prostate cancer? Is there a link
between inflammation and BPH?
Approximately 25% of prostate adenocarcinomas appear to arise in the transition zone.
Thus, while the peripheral zone is the site of
origin of prostate cancer in the majority of the
cases, when compared to other organs that seem
to be protected from cancer development (such
as the seminal vesicles), prostate transition
zone cancer is actually quite common. In terms
of epidemiological data, the relation between
461
BPH and prostate cancer has been reviewed
recently, where it was concluded that none of
the epidemiologic studies published to date
have provided clear evidence suggesting an
etiologic role for BPH in the development of
prostate cancer [Guess, 2001]. However, the
author also indicated that most of the studies
had at least some major bias and that it might
be perhaps more important to examine the biology and pathology of any potential connection
[Guess, 2001].
In terms of pathobiology, Bostwick et al.
[1992] summarized the facts that BPH and
prostate cancer tend to occur in the same patient, share similar hormonal requirements for
growth, and can occur in proximity. Pathologically, it appears that transition zone cancers do
indeed appear to arise in the setting of nodules
of BPH [Bostwick et al., 1992; Leav et al., 2003,
and references therein], and occasionally from
adenosis [Bostwick and Qian, 1995; Grignon
and Sakr, 1996], which is also referred to as
atypical adenomatous hyperplasia. While these
transition zone tumors are often of somewhat
lower Gleason score, they are quite common in
radical prostatectomy and TURP specimens
[Leav et al., 2003]. Often in radical prostatectomies transition zone cancers are found incidentally after the diagnosis of prostate cancer in
the peripheral zone, which is much more widely
sampled at needle biopsy. Whether there are an
equal number of transition zone cancers in men
without significant nodular hyperplasia is currently not clear. Thus, although there is no
strong evidence linking the two, the relation
between BPH and prostate cancer remains an
open issue. In addition, it is possible that BPH
and prostate cancer are both caused by similar
exposures, such that they commonly occur together but are not directly linked in a precursorprogeny pathway.
What is the relation between transition zone
cancer and inflammation? While the relation
between inflammation and transition zone
cancer is unknown, it is known that BPH tissue
contains a variable amount of chronic and often
acute inflammation in virtually 100% of specimens [Nickel et al., 1999]. It has been reported
that levels of serum PSA in BPH patients
correlates with the amount of tissue injury associated with inflammation [Hasui et al., 1994;
Irani et al., 1997; Schatteman et al., 2000;
Yaman et al., 2003], and some have submitted
that the pathogenesis [Gleason et al., 1993],
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De Marzo et al.
and/or clinical features [Nickel, 1994] of BPH
may be related to prostate inflammation.
Still unclear, however, is whether inflammation comes prior to BPH nodule formation
or whether it is a response to the altered tissue
architecture resulting from the nodules. While
no firm conclusions can be drawn presently,
the pathological literature is consistent with a
model whereby inflammation, due to infection
or otherwise, is related to the development or
progression of BPH, and in some circumstances
BPH is related to prostate cancer. Although,
more study of this issue is required, it is
plausible that inflammation may be related to
transition zone cancer.
Proliferative Inflammatory Atrophy
Pathologists have long recognized focal areas
of epithelial atrophy in the prostate [Rich, 1934;
Moore, 1936; Franks, 1954]. These focal areas
of epithelial atrophy, distinct from the diffuse
atrophy seen after androgen deprivation, usually appear in the periphery of the prostate, where
prostate cancers typically arise [Rich, 1934;
McNeal, 1988]. Many of these areas of epithelial
atrophy are associated with acute or chronic
inflammation [Franks, 1954; McNeal, 1997;
Ruska et al., 1998; De Marzo et al., 1999],
contain proliferative epithelial cells [Liavag,
1968; Feneley et al., 1996; Ruska et al., 1998; De
Marzo et al., 1999; Shah et al., 2001], and may
show morphological transitions in continuity
with high grade prostatic intraepithelial neoplasia (PIN) lesions [De Marzo et al., 1999;
Putzi and De Marzo, 2000], putative prostate
cancer precursors [McNeal and Bostwick, 1986;
Bostwick, 1996]. At times these atrophic
lesions may show evidence of direct transitions
to minute carcinoma lesions, with little or no
recognizable PIN component [Franks, 1954;
Liavag, 1968; Montironi et al., 2002; Nakayama
et al., 2003]. Focal atrophy of the prostate exists
as a spectrum of morphologies and areas containing it in the prostate can be quite extensive.
Most of these morphological patterns fit into the
categories of simple atrophy, or post-atrophic
hyperplasia, as described by Ruska et al. [1998].
To highlight the common association with
inflammation and the unexpectedly high proliferation index, we have put forth the term
proliferative inflammatory atrophy (PIA) to encompass these lesions [De Marzo et al., 1999]. In
terms of the requirement for inflammatory cells
in PIA, the majority of all focal atrophy lesions
contain at least some increase in chronic and/or
acute inflammation. Also, since the amount of
inflammation from field to field within a given
atrophy lesion can be highly variable we have
recently suggested that to refer to a lesion as
PIA does not require easily recognizable inflammation—thus, most forms of focal glandular
atrophy can be considered PIA [Van Leenders
et al., 2003]. A working group to formalize
terminology of the various atrophic lesions in
the prostate is currently being formed, and a
preliminary meeting with a group of pathologists and other investigators was held at the
NIH campus in February of 2003.
In support of PIA as a prostate cancer precursor, prostate inflammation, accompanied by
focal epithelial atrophy, has been proposed to
contribute to prostate cancer development in
rats [Reznik et al., 1981; Wilson et al., 1990].
Further support comes from the fact that PIA
shares several molecular alterations found in
both PIN and carcinoma. For example, chromosome 8 gain, detected by fluorescence in situ
hybridization (FISH) with a chromosome 8 centromere probe, was found in human PIA, PIN,
and prostate cancer [Macoska et al., 2000;
Shah et al., 2001]. Others have recently documented rare p53 mutations in one variant of
PIA, referred to as post-atrophic hyperplasia
[Tsujimoto et al., 2002] and, our group has
recently shown that approximately 6% of PIA
lesions show evidence of somatic methylation
of the GSPT1 gene promoter [Nakayama et al.,
2003a] (see description of GSTP1 promoter
methylation below). While the cause of focal
atrophy lesions is not known, they may arise
either as a consequence of epithelial damage,
e.g., from infection, ischemia [Billis, 1998], or
toxin exposure (including dietary oxidants/
electrophiles or endogenous chemicals such as
estrogens, etc.), followed by epithelial regeneration and associated secondary inflammation, or
as a direct consequence of inflammatory oxidant
damage to the epithelium [De Marzo et al.,
1999]. The process of aging itself has been
suggested to contribute to some morphological
variants of prostate atrophy [McNeal, 1984].
Regardless of the etiology of PIA, the epithelial
cells in these lesions exhibit many molecular
signs of stress, expressing high levels of GSTP1,
GSTA1, and cyclo-oxygenase 2 (COX-2) [De
Marzo et al., 1999; Putzi and De Marzo, 2000;
Parsons et al., 2001b; Zha et al., 2001]. There
is also mounting evidence that many of the
Pathological and Molecular Mechanisms of Prostate Carcinogenesis
atrophic luminal cells in PIA represent a form of
intermediate epithelial cell [Van Leenders et al.,
2003]—cells with features intermediate between basal and luminal secretory cells. Intermediate epithelial cells have been postulated to
be the targets of neoplastic transformation in
the prostate [Verhagen et al., 1992; De Marzo
et al., 1998a,b; van Leenders et al., 2000].
It should be noted that not all authors have
found associations between prostate atrophy and
prostate cancer [McNeal, 1969; Billis, 1998;
Anton et al., 1999; Billis and Magna, 2003], and
that in our own studies not all high grade PIN or
small carcinoma lesions are associated with
atrophy [Putzi and De Marzo, 2000]. Most
studies of the connection between atrophy and
cancer have focused on peripheral zone cancer
nearly exclusively. Thus, additional studies are
required to more fully understand the relation
between focal atrophy and cancer in the prostate.
Our current concept is that PIA is a common
proliferative response to environmental stimuli
in aging men and that some high grade PIN and
carcinoma lesions arise as a consequence of
genome damage in PIA, while others do not. A
corollary to this is that while only a subset of
atrophy lesions may be pre-neoplastic, the fact
that atrophic areas can be so widespread and
multi-focal in the prostate is consistent with the
hypothesis that many prostate cancers can
indeed arise from PIA.
SOMATIC GENOME
ALTERATIONS ACCOMPANYING
PROSTATIC CARCINOGENESIS
Similar to other types of epithelial cancer,
prostate cancers contain many somatic genomic
alterations, including point mutations, deletions, amplifications, chromosomal rearrangements, and changes in DNA methylation [Isaacs
et al., 1994; Bookstein, 2001; Chung et al., 2001;
Gao and Isaacs, 2002; Meng and Dahiya, 2002;
DeMarzo et al., 2003]. However, unlike some
carcinomas such as those of the colon/rectum
[Kinzler and Vogelstein, 1997] and pancreas
[Jaffee et al., 2002], where specific oncogenes
such as k-ras or tumor suppressor genes such
as p53 are mutated at a very high frequency,
gene mutations reported thus far in prostate
cancer appear quite heterogeneous, from case to
case, or even from lesion to lesion in a single case
[Isaacs et al., 1994; Mirchandani et al., 1995;
Qian et al., 1995; Ruijter et al., 1999; Bookstein,
463
2001; Chung et al., 2001; Gao and Isaacs, 2002;
Meng and Dahiya, 2002]. In addition, genetic
alterations appear to accumulate with prostate
cancer progression. Small prostate cancers are
present in nearly 30% of men between 30–
40 years of age in the U.S., though most men are
diagnosed with prostate cancer at 50–70 years of
age [Sakr et al., 1994]. The progression of these
small prostate cancers to larger life-threatening
cancers, and the accumulation of somatic genome abnormalities, appears sensitive to environmental factors and lifestyle. Prostate cancer
incidence and mortality are very high in the U.S.
and Western Europe, while lower prostate
cancer risks and death rates are characteristic
of Asia [Miller, 1999; Hsing et al., 2000]. In
support of an effect of environment and lifestyle
on prostate cancer development, Asian immigrants to North America tend to acquire higher
prostate cancer risks within one generation
[Haenszel and Kurihara, 1968; Shimizu et al.,
1991; Whittemore et al., 1995]. Whether the
appearance of somatic genome alterations in
prostate cancer cells is the result of chronic or
recurrent exposure to genome-damaging stresses, defective protection against genome
damage, or a combination of both processes,
has not been definitively shown.
GSTP1
Hypermethylation of CpG island sequences
encompassing the promoter region of GSTP1,
encoding the p-class glutathione S-transferase
(GST), is an exceedingly common somatic genome change found in prostate cancer [Lee et al.,
1994; Millar et al., 1999; Lin et al., 2001; Nelson
et al., 2001b]. Immunohistochemistry has demonstrated that GSTP1 protein is normally
expressed in basal epithelial cells in the prostate, but is absent in most luminal columnar
secretory epithelial cells. In PIA lesions, strong
anti-GSTP1 staining is seen in many of the
atrophic luminal epithelial cells, [De Marzo
et al., 1999] consistent with the induction of
expression in response to environmental stress.
The luminal cells in PIA are not simply basal
cells, as shown by their lack of expression of p63
[Parsons et al., 2001a]. In prostate cancer cells,
somatic hypermethylation of GSTP1 CpG
island sequences represses GSTP1 transcription [Lin et al., 2001]. Absence of GSTP1
expression and GSTP1 CpG island hypermethylation are also common in high-grade
PIN lesions [Brooks et al., 1998].
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De Marzo et al.
GSTP1 is not a classical tumor suppressor
gene [Lin et al., 2001]. Rather, GSTP1 more
likely plays a ��caretaker’’ role, protecting
prostate epithelial cells against genome damage mediated by carcinogens [Kinzler and
Vogelstein, 1997]. For example, mice with both
GSTP1 alleles disrupted by gene targeting
exhibit increased skin tumor formation after
topical exposure to the skin carcinogen 7,12dimethylbenz [a] anthracene (DMBA) [Henderson et al., 1998]. One prostate carcinogen that
may be detoxified by GSTP1 is the dietary
heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), which forms
when meats are cooked at high temperatures or
��charbroiled’’ [Lijinsky and Shubik, 1964; Gross
et al., 1993; Morgenthaler and Holzhauser,
1995; Knize et al., 1997]. Dietary PhIP intake
causes prostate cancer in rats [Shirai et al.,
1997; Stuart et al., 2000]. In humans, a study
examining the association between PhIP and
other heterocyclic amine intake and prostate
cancer showed a modest, albeit inconsistent
increased relative risk of prostate cancer with
increasing consumption [Norrish et al., 1999],
although there are a large number of studies
showing an association between an increased
relative risk of overall prostate cancer and the
levels of consumption of red meat [reviewed in
Kolonel, 2001]. In the most recent analysis from
the Health Professionals Follow-Up Study,
consumption of red meats was not associated
with an increased risk of prostate cancer overall, but was associated with increased risk of
metastatic prostate cancer [Michaud et al.,
2001]. GSTP1 can protect prostate cells against
PhIP damage: for LNCaP prostate cancer cells,
which do not express GSTP1, exposure to
metabolically activated PhIP results in the
appearance of pro-mutagenic PhIP–DNA
adducts. Replacement of the GSTP1 gene by
stable transfection prevented PhIP–DNA damage [Nelson et al., 2001a]. GSTP1 may also
protect prostate cells against damage inflicted
directly by oxidants, such as those produced by
protracted low dose ionizing radiation exposure
(DeWeese et al., unpublished observations).
AR
Androgenic hormones and the androgen
receptor (AR) both play critical roles in normal
prostate development and function, and in most
prostate diseases, including prostate cancer.
For example, transgenic mice engineered to
express high levels of the androgen receptor in
the prostate tend to develop PIN [Stanbrough
et al., 2001]. Many somatic alterations of
AR, encoding the androgen receptor, have
been described in human prostate cancers,
particularly ��androgen-independent’’ prostate
cancers appearing after treatment by androgen suppression and/or with anti-androgens
[Veldscholte et al., 1990; Newmark et al., 1992;
Suzuki et al., 1993, 1996; Gaddipati et al.,
1994; Schoenberg et al., 1994; Taplin et al.,
1995, 1999; Visakorpi et al., 1995; Evans
et al., 1996; Tilley et al., 1996; Koivisto et al.,
1997; Marcelli et al., 2000; Haapala et al.,
2001]. ��Androgen-independent’’ prostate cancers usually continue to express the androgen
receptor, maintaining androgen-receptor dependent signaling (i) in response to the reduced
levels of circulating androgens, such as with AR
amplification accompanied by androgen receptor over-expression, (ii) in response to nonandrogens or anti-androgens as agonist ligands,
such as with AR mutations accompanied by
altered androgen receptor ligand specificity, or
(iii) via ligand-independent activation of the
androgen receptor, such as may occur under the
influence of other intracellular signal transduction pathways [Veldscholte et al., 1990; van der
Kwast et al., 1991; Culig et al., 1993; Nazareth
and Weigel, 1996; Koivisto et al., 1997; Tan
et al., 1997; Hobisch et al., 1998; Craft et al.,
1999; Amler et al., 2000; Sadar and Gleave,
2000; Feldman and Feldman, 2001; Mousses
et al., 2001; Zegarra-Moro et al., 2002].
NKX3.1
NKX3.1, located at 8p21, encodes a prostatespecific homeobox gene essential for normal
prostate development [Bieberich et al., 1996;
He et al., 1997; Sciavolino et al., 1997; Prescott
et al., 1998]. In mice, targeted disruption of
Nkx3.1 leads to prostatic epithelial hyperplasia
and dysplasia [Bhatia-Gaur et al., 1999;
Abdulkadir et al., 2002]. In men, although loss
of 8p21 DNA sequences has been reported in as
many as 63% of PIN lesions and in more than
90% of prostate cancers, no NKX3.1 mutations
have been detected, leading to controversy over
whether NKX3.1 is the gene target of somatic
alteration at 8p21 [Emmert-Buck et al., 1995;
He et al., 1997; Voeller et al., 1997; Ornstein
et al., 2001]. Nonetheless, loss of NKX3.1 expression has been reported in as many as 20% of
PIN lesions, 6% of low stage prostate cancers,
Pathological and Molecular Mechanisms of Prostate Carcinogenesis
22% of high stage prostate cancers, 34% of
androgen-independent prostate cancers, and
78% of prostate cancer metastases [Bowen
et al., 2000]. The relationship between somatic
NKX3.1 alterations and reduction in NKX3.1
expression during prostate cancer development
has not been determined.
PTEN
PTEN, located at 10q, another site of frequent
allelic loss in prostate cancer, encodes a phosphatase active against both proteins and lipid
substrates [Li et al., 1997; Myers et al., 1997,
1998; Steck et al., 1997; Teng et al., 1997]. PTEN
has been proposed to function as a general
tumor suppressor by inhibiting the phosphatidylinositol 30 -kinase/protein kinase B (PI3K/
Akt) signaling pathway, thought to be essential
for cell cycle progression and/or cell survival in
many cell types [Li et al., 1997; Furnari et al.,
1998; Ramaswamy et al., 1999; Sun et al., 1999].
Like mice carrying disrupted Nkx3.1 alleles,
mice carrying disrupted Pten alleles manifest
prostatic hyperplasia and dysplasia, and the
progeny of breeding crosses between PtenÆ
mice and Nkx3.1Г† mice develop PIN [BhatiaGaur et al., 1999; Podsypanina et al., 1999; Di
Cristofano et al., 2001; Kim et al., 2002], as well
as invasive carcinoma and lymph node metastases [Abate-Shen et al., 2003]. PTEN, which is
typically expressed by normal epithelial cells,
is often expressed at a reduced level in human prostate cancer cells [McMenamin et al.,
1999]. Many somatic PTEN alterations have
been reported for prostate cancers, including
homozygous deletions, loss of heterozygosity,
mutations, and suspected CpG island hypermethylation [Cairns et al., 1997; Li et al., 1997;
Myers et al., 1997, 1998; Steck et al., 1997; Teng
et al., 1997; Gray et al., 1998; Suzuki et al., 1998;
Wang et al., 1998; Vivanco and Sawyers, 2002].
Associations between somatic PTEN alterations and aberrant PTEN function in prostate
cancer cells have been difficult to establish.
Often, losses of 10q sequences near PTEN do not
appear to be accompanied by somatic mutations
of the remaining PTEN allele. Furthermore,
although somatic PTEN alterations appear
more common in metastatic than in primary
prostate cancer lesions, a marked heterogeneity
in PTEN defects in different metastatic sites
from the same patient has been reported
[Suzuki et al., 1998]. Perhaps, as is evident
in mouse models featuring disrupted Nkx3.1
465
and Pten genes, haploinsufficiency for PTEN
and/or NKX3.1 may be sufficient for a neoplastic phenotype [Bhatia-Gaur et al., 1999;
Podsypanina et al., 1999; Di Cristofano et al.,
2001; Kim et al., 2002].
CBKN1B
p27, a cyclin-dependent kinase inhibitor
encoded by CDKN1B, may also be a somatic
gene target for alteration during prostatic
carcinogenesis. Targeted disruption of Cdkn1b
in mice results in prostatic hyperplasia, while
mice carrying disrupted Pten and Cdkn1b
alleles develop localized prostate cancers [Di
Cristofano et al., 2001]. Reduced p27 expression appears characteristic of human prostate
cancer cells, particularly in prostate cancer
cases with a poor prognosis [Guo et al., 1997;
Cheville et al., 1998; Cordon-Cardo et al., 1998;
Yang et al., 1998; De Marzo et al., 1998a].
Somatic loss of DNA sequences at 12p12-13,
near CDKN1B, have been reported for 23% of
localized prostate cancers, 30% of prostate
cancer lymph node metastases, and 47% of
prostate cancer distant metastases [Kibel
et al., 2000]. The mechanism(s) by which somatic CDKN1B alterations leads to reduced p27
expression have not been elucidated. Provocatively, p27 may be a target for repression by the
PI3K/Akt signaling pathway [Li and Sun, 1998;
Sun et al., 1999; Graff et al., 2000; Gottschalk
et al., 2001]. Thus, loss of PTEN function,
accompanied by increased PI3K/Akt signaling,
might result in decreases in CDKN1B mRNA
and in p27 protein half-life [Nakamura et al.,
2000] Decreased p27 expression has also been
documented in high grade PIN [De Marzo et al.,
1998a; Fernandez et al., 1999] and in PIA
lesions [De Marzo et al., 1998a; Van Leenders
et al., 2003].
Telomeres, Telomere Shortening,
and Telomerase
The karyotype of most human cancers is abnormal. Many types of cancer, including prostate
cancer, show chromosomal instability reflected
by aberrations in both number and structure of
chromosomes. The exceptions to this in solid
tumors are cancers with microsatellite instability, which are genetically unstable at the single
nucleotide level but contain mostly diploid
karyotypes. Chromosomal instability appears
to be an important molecular mechanism driving malignant transformation in many human
466
De Marzo et al.
epithelial tissues [Cahill et al., 1999], yet the
molecular mechanisms responsible for chromosome destabilization during carcinogenesis are
largely unknown. One route to chromosomal
instability is through defective telomeres [Counter et al., 1992; Hackett and Greider, 2002;
Feldser et al., 2003]. Telomeres, which consist of
multiple repeats of a 6 base pair unit (TTAGGG),
complexed with several different binding proteins, protect chromosome ends from fusing with
other chromosome ends or other chromosomes
containing double strand breaks [McClintock,
1941]. However, in the absence of compensatory
mechanisms, telomeric DNA is subject to loss
due to cell division [Harley et al., 1990; Levy
et al., 1992] and possibly oxidative damage [von
Zglinicki et al., 2000]. Critical telomere shortening leads to chromosomal instability that, in
mouse models, causes an increased cancer
incidence that is likely a result of chromosome
fusions, subsequent breakage, and rearrangement [Blasco et al., 1997; Artandi et al., 2000].
Intriguingly, telomeres within human carcinomas are often found to be abnormally reduced in
length [de Lange, 1995], but the timing
of this phenomenon has been unclear. In
human prostate cancer, the telomeres from
prostate cancer tissue were consistently shorter
than those from cells in either the adjacent
normal or BPH tissues [Sommerfeld et al., 1996].
Others have also reported telomere shortening in
prostate cancer [Donaldson et al., 1999].
Most carcinomas arise from pre-invasive intraepithelial precursor lesions, referred to as intraepithelial neoplasias (IEN) [O’Shaughnessy
et al., 2002]. These lesions show morphological
features and molecular alterations characteristic of malignant neoplasia, including evidence of
genetic instability [Shih et al., 2001] but occur
within preexisting epithelia and are confined
within the basement membrane. If genetic instability helps to drive cancer formation, and
telomeres shortening is a major mechanism
leading to genetic instability, then telomere
shortening should be present at the intraepithelial phase of carcinoma. Recently we employed
an in situ telomere FISH technique TEL-FISH
and reported that telomere shortening is evident in the majority of high-grade prostatic
intraepithelial neoplasia (PIN) lesions [Meeker
et al., 2002], which are thought to be cancer
precursor lesions of the prostate. Thus, telomere
shortening is a prevalent biomarker in human
prostate, occurring early in the process of
prostate carcinogenesis. Interestingly, the telomere shortening found in high grade PIN was
restricted to the luminal cells and was not
present in the underlying basal cells. This
finding strongly suggests that basal cells are
not the direct precursor cell to high grade PIN,
but support the above mentioned concept that
cells with an intermediate luminal cell phenotype are the likely direct target cell of transformation in the prostate. Vukovic et al., recently
reported Similar findings of reduced telomere
length in high grade PIN and prostate cancer
[Vukovic et al., 2003].
Hepsin, AMACR, and EZH2
Alterations in gene expression accompanying the development of prostate cancer have
been surveyed using transcriptome profiling
technologies [Huang et al., 1999; Walker et al.,
1999; Nelson et al., 2000; Xu et al., 2000;
Dhanasekaran et al., 2001; Luo et al., 2001,
2002; Magee et al., 2001; Stamey et al., 2001;
Waghray et al., 2001; Welsh et al., 2001]. Among
the many genes exhibiting over- or underexpression in localized prostate cancers, the
products of at least two genes appear consistently increased. Hepsin, located at 19q11-13.2,
encodes a transmembrane serine protease, normally expressed at high levels in the liver and
other tissues [Tsuji et al., 1991]. The contribution of hepsin to the prostate cancer phenotype
has not been discerned. Anti-sense oligonucleotides targeting Hepsin mRNA have been reported to retard the growth of hepatoma cells,
but HepsinГЂ/ГЂ mice develop normally, exhibit
normal liver regeneration, and have no striking
phenotype [Torres-Rosado et al., 1993; Wu et al.,
1998; Yu et al., 2000]. a-Methylacyl-CoA racemase, a mitochondrial and peroxisomal enzyme
that acts on pristanoyl-CoA and C27-bile acylCoA substrates to catalyze the conversion of
R- to S-stereoisomers in order to permit metabolism by b-oxidation [Schmitz et al., 1995], has
been reported to be over-expressed in almost all
prostate cancers [Xu et al., 2000; Dhanasekaran
et al., 2001; Luo et al., 2001, 2002]. Germline
AMACR mutations have been reported to lead to
adult-onset neuropathy [Ferdinandusse et al.,
2000]. Immunohistochemistry studies have
revealed that a-methylacyl-CoA racemase is
occasionally present in normal prostate cells,
increased in prostatic intraepithelial neoplasia
cells, and further elevated in prostate cancer
cells [Jiang et al., 2001, 2002; Beach et al., 2002;
Pathological and Molecular Mechanisms of Prostate Carcinogenesis
Luo et al., 2002; Rubin et al., 2002; Yang et al.,
2002; Leav et al., 2003; Magi-Galluzzi et al.,
2003; Zhou et al., 2003a]. Another gene product
shown to be increased at the mRNA level in
primary and hormone refractory metastatic
prostate cancer using gene expression arrays
is the polycomb group protein enhancer of zeste
homolog 2 (EZH2), which has been postulated to
be involved in the progression of prostate cancer
[Varambally et al., 2002].
IMPLICATIONS FOR PROSTATE CANCER
DIAGNOSIS, DETECTION, PREVENTION,
AND TREATMENT
AMACR, p63, and the Diagnosis
of Prostate Cancer
It is estimated that approximately 1,000,000
prostate needle biopsies are performed per year
in the U.S., and approximately 20% are positive
for cancer. While there is no standard for the
number of cores taken, in many institutions
urologists are submitting 12 or more cores per
patient, which is up from 6 several years ago.
Thus, between 6 and 12 million individual new
needle biopsy cores are examined microscopically by pathologists each year in the U.S. While
at times the diagnosis of prostate cancer on
needle biopsy can be quite straightforward,
many cases present diagnostic challenges. For
example, there are many benign mimics of
prostate cancer that can be misdiagnosed as
prostate cancer [Epstein, 1995; Epstein and
Potter, 2001; DeMarzo et al., 2003]. These include lesions such as atrophy adenosis (atypical
adenomatous hyperplasia), PIN, nephrogenic
adenoma granulomatous prostatitis, and radiation change in benign glands. It has been clear
for many years that prostate basal cells, which
are uniformly present in normal appearing
prostate acini and ducts, and in the vast
majority of benign mimics of prostate cancer,
are absent in prostate cancer [Brawer et al.,
1985]. Thus, ancillary tools such as immunohistochemistry against ��basal cell specific cytokeratins’’1 are often employed in difficult cases
to determine if a particular suspicious lesion
1
Often staining for basal cells is performed with the
monoclonal antibody 34BE12, recognizing a range of high
molecular weight cytokeratins including keratin 5 and 14.
These keratins are highly expressed in basal cells. Other
antibodies against keratin 5 have also been employed.
467
contains basal cells [Hedrick and Epstein,
1989]. More recently it has been shown that
the product of the p63 gene is expressed in basal
cell nuclei in the prostate, but not in prostate
luminal cells nor in the vast majority of prostate
cancers [Signoretti et al., 2000; Parsons et al.,
2001a]. Since this marker may be more robust
in terms of surviving poor fixation or various
types of tissue processing [Weinstein et al.,
2002], many pathologists have begun to employ
p63 staining in clinical practice to further
determine whether basal cells may be present
in a suspicious lesion [Shah et al., 2002]. To
increase the chances of finding basal cells, Zhou
et al. [2003b] have recently suggested using a
cocktail of antibodies against basal cell cytokeratins and p63.
As indicated above, AMACR has been found
by a large number of different investigators to
be overexpressed in prostate cancer cells. Since
negative staining for basal cell markers by itself
is not diagnostic of prostate cancer, positive
staining for AMACR may increase the level of
confidence in establishing a definitive malignant diagnosis in a lesion deemed highly suspicious by standard H&E staining [Jiang et al.,
2001, 2002; Beach et al., 2002; Magi-Galluzzi
et al., 2003; Zhou et al., 2003a]. Thus, many
pathologists have begun to employ this marker.
At our institution we routinely order the p63,
34BE12 (also referred to as keratin 903), and
AMACR on atypical prostate needle biopsies
where the suspicion of cancer is high but
the findings on H&E section are insufficient
to render a clearly malignant diagnosis. In
the research setting, we have also employed
double labeling against p63 (nuclear staining
positive in basal cells) and racemase (cytoplasmic-only staining) in order to delineate both
markers on an individual tissue sections [Luo
et al., 2002], although this double labeling can
be somewhat problematic on needle biopsies
due to background cytoplasmic staining for p63.
As usual with any ancillary test, there are
pitfalls in the use of AMACR in diagnostic
pathology, since certain histological subtypes of
prostatic adenocarcinoma tend to be weak or
negative for this marker [Zhou et al., 2003a],
and, benign glands and high grade PIN may be
positive at times. Since there are so many
diagnostic pitfalls in prostate needle biopsies,
the importance of obtaining second opinions on
prostate biopsy material has been emphasized
[Epstein et al., 1996].
468
De Marzo et al.
GSTP1 CpG Island Hypermethylation
and the Detection of Prostate Cancer
Abnormal genes and gene products appearing
in prostate cancer cells offer great promise as
disease biomarkers. For example, GSTP1 CpG
island hypermethylation, detected in prostate
tissue, blood, urine, or prostate fluid, may be a
molecular biomarker useful for prostate cancer
detection and staging. Although GSTP1 CpG
island hypermethylation has been found in
DNA from more than approximately 90% of
prostate cancers, approximately 70% of liver
cancers, and approximately 30% of breast
cancers, this genome alteration has not been
detected in DNA from any normal tissues [Lee
et al., 1994; Esteller et al., 1998; Tchou et al.,
2000; Lin et al., 2001; Nakayama et al., 2003].
GSTP1 CpG island hypermethylation has also
been detected in 70% of PIN lesions [Brooks
et al., 1998; Nakayama et al., 2003a]. For a
comprehensive review of GSTP1 methylation as
a biomarker in prostate cancer, see the accompanying article by Nakayama et al. [2003b].
Carcinogen Detoxification, Inflammation,
and Prostate Cancer Prevention
Insights into the molecular pathogenesis of
prostate cancer may provide opportunities for
the discovery and development of new agents
for prostate cancer prevention. Loss of GSTP1
��caretaker’’ activity during prostate carcinogenesis emphasizes the critical role of carcinogen
metabolism in protecting prostate cells against neoplastic transformation, and suggests
that therapeutic compensation for inadequate
GSTP1 ��caretaker’’ function may help prevent
prostate cancer. The ��oxidation tolerance’’ phenotype associated with loss of GSTP1 ��caretaker’’ function in LNCaP prostate cancer cells
may provide a mechanistic rationale for buttressing defenses against oxidative genome
damage via anti-oxidant supplementation to
prevent or delay prostate carcinogenesis.
In addition, augmentation of carcinogen-detoxification capacity, using a variety of such
chemoprotective compounds, including isothiocyanates, 1,2-dithiole-3-thiones, terpenoids,
etc., is known to prevent a range of different
cancers in different animal models by triggering
the expression of many different carcinogendetoxification enzymes [Kensler, 1997; RamosGomez et al., 2001]. Oltipraz, an inducer of
carcinogen-detoxification enzymes in liver tis-
sues, has been shown to reduce aflatoxin B1
damage when administered to a human clinical study cohort at high risk for aflatoxin exposure and liver cancer development in China
[Jacobson et al., 1997; Kensler et al., 1998;
Wang et al., 1999]. Sulforaphane, an isothiocyanate present in high amounts in cruciferous
vegetables, is also a potent inducer of carcinogen-detoxification enzymes [Zhang et al., 1992,
1994]. Diets rich in carcinogen-inducers like
sulforaphane have been associated with decreased cancer risks [Cohen et al., 2000].
Such carcinogen-detoxification enzyme inducers need to be developed and tested in prostate
cancer prevention clinical trials.
The recognition that prostate inflammation
may contribute to the earliest steps in prostate
carcinogenesis also has profound implications
for the prevention of prostate cancer. Animal
model studies suggest that non-steroidal antiinflammatory drugs might attenuate both prostate cancer incidence and prostate cancer
progression [Wechter et al., 2000]. In addition,
several epidemiology studies have hinted at a
modest protective effect of non-steroidal antiinflammatory drug intake on either prostate
cancer incidence, or on prostate cancer progression [Norrish et al., 1998; Nelson and Harris,
2000; Habel et al., 2002; Leitzmann et al., 2002;
Roberts et al., 2002]. One target of these drugs,
cyclo-oxygenase-2 (COX-2), may be selectively
expressed in PIA lesions in the prostate [Zha
et al., 2001]. A randomized clinical trial involving the administration of celecoxib, a selective COX-2 inhibitor, or placebo to men with
prostate cancer who undergo radical prostatectomy, has been initiated at the Sidney
Kimmel Comprehensive Cancer Center at
Johns Hopkins. The effects of COX-2 inhibition
on oxidative genome damage on PIA and on
other tissue markers will be ascertained. In the
future, as the process of inflammation in the
prostate, and the pathogenesis of PIA becomes
better defined more specific targets will be
identified, creating new opportunities for the
discovery and development of selective inhibitors of pathways mediating prostate cell and
genome damage used to decrease prostate
cancer risk.
Intracellular Signaling Pathways
and Prostate Cancer Treatment
Finally, progressive elucidation of the molecular mechanisms contributing to prostate
Pathological and Molecular Mechanisms of Prostate Carcinogenesis
cancer cell growth, survival, and metastasis
may lead to better treatments for established
prostate cancer. Of course, androgen signaling
pathways, essential for the growth and survival
of most prostate cancer cells, have already been
successfully targeted for prostate cancer treatment. However, despite treatment with androgen deprivation and/or anti-androgens, most
men with advanced prostate cancer ultimately
suffer cancer progression [van der Kwast et al.,
1991; Amler et al., 2000; Feldman and Feldman,
2001; Mousses et al., 2001]. Since these progressive androgen-independent cancers appear
to still use the androgen receptor to promote
growth and survival, it is possible that the
androgen receptor itself, and some of its posttranslational modifications, might be even
better targeted with new treatment approaches
[Eder et al., 2002; Gioeli et al., 2002; Solit et al.,
2002]. Also, several newly recognized signal
transduction pathways offer new treatment
possibilities. In particular, as described in this
review, loss of PTEN function during prostate
cancer progression implicates PI3K/Akt cell
growth and survival signaling pathway in the
development of life-threatening prostate cancer
[Furnari et al., 1998; Ramaswamy et al., 1999;
Sun et al., 1999]. Several new agents targeting
various components of this pathway are under
development for prostate and other cancers
[Neshat et al., 2001; Podsypanina et al., 2001;
Solit et al., 2002; Vivanco and Sawyers, 2002].
REFERENCES
Abate-Shen C, Banach-Petrosky WA, Sun X, Economides
KD, Desai N, Gregg JP, Borowsky AD, Cardiff RD, Shen
MM. 2003. Nkx3.1; Pten mutant mice develop invasive
prostate adenocarcinoma and lymph node metastases.
Cancer Res 63:3886–3890.
Abdulkadir SA, Magee JA, Peters TJ, Kaleem Z, Naughton
CK, Humphrey PA, Milbrandt J. 2002. Conditional loss of
nkx3.1 in adult mice induces prostatic intraepithelial
neoplasia. Mol Cell Biol 22:1495–1503.
Amler LC, Agus DB, LeDuc C, Sapinoso ML, Fox WD, Kern
S, Lee D, Wang V, Leysens M, Higgins B, Martin J,
Gerald W, Dracopoli N, Cordon-Cardo C, Scher HI,
Hampton GM. 2000. Dysregulated expression of androgen-responsive and nonresponsive genes in the androgen-independent prostate cancer xenograft model
CWR22-R1. Cancer Res 60:6134–6141.
Anton RC, Kattan MW, Chakraborty S, Wheeler TM. 1999.
Postatrophic hyperplasia of the prostate: Lack of association with prostate cancer. Am J Surg Pathol 23:932–936.
Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L,
DePinho RA. 2000. Telomere dysfunction promotes nonreciprocal translocations and epithelial cancers in mice.
Nature 406:641–645.
469
Beach R, Gown AM, De Peralta-Venturina MN, Folpe AL,
Yaziji H, Salles PG, Grignon DJ, Fanger GR, Amin MB.
2002. P504S immunohistochemical detection in 405
prostatic specimens including 376 18-gauge needle
biopsies. Am J Surg Pathol 26:1588–1596.
Bhatia-Gaur R, Donjacour AA, Sciavolino PJ, Kim M, Desai
N, Young P, Norton CR, Gridley T, Cardiff RD, Cunha
GR, Abate-Shen C, Shen MM. 1999. Roles for Nkx3.1 in
prostate development and cancer. Genes Dev 13:966–
977.
Bieberich CJ, Fujita K, He WW, Jay G. 1996. Prostatespecific and androgen-dependent expression of a novel
homeobox gene. J Biol Chem 271:31779–31782.
Billis A. 1998. Prostatic atrophy: An autopsy study of a histologic mimic of adenocarcinoma. Mod Pathol 11:47–54.
Billis A, Magna LA. 2003. Inflammatory atrophy of the
prostate. Prevalence and significance. Arch Pathol Lab
Med 127:840–844.
Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM,
DePinho RA, Greider CW. 1997. Telomere shortening
and tumor formation by mouse cells lacking telomerase
RNA. Cell 91:25–34.
Bookstein R. 2001. Tumor suppressor genes in prostate
cancer. In: Chung LW, Isaacs WB, Simons JW, editors.
Prostate cancer: Biology, genetics, and the new theraputics. Totowa, NJ: Humana press. pp 61–93.
Bostwick DG. 1996. Prospective origins of prostate carcinoma. Prostatic intraepithelial neoplasia and atypical
adenomatous hyperplasia. Cancer 78:330–336.
Bostwick DG, Qian J. 1995. Atypical adenomatous hyperplasia of the prostate. Relationship with carcinoma in 217
whole-mount radical prostatectomies. Am J Surg Pathol
19:506–518.
Bostwick DG, Cooner WH, Denis L, Jones GW, Scardino
PT, Murphy GP. 1992. The association of benign
prostatic hyperplasia and cancer of the prostate. Cancer
70:291–301.
Bowen C, Bubendorf L, Voeller HJ, Slack R, Willi N, Sauter
G, Gasser TC, Koivisto P, Lack EE, Kononen J,
Kallioniemi OP, Gelmann EP. 2000. Loss of NKX3.1
expression in human prostate cancers correlates with
tumor progression [in process citation]. Cancer Res 60:
6111–6115.
Brawer MK, Peehl DM, Stamey TA, Bostwick DG. 1985.
Keratin immunoreactivity in the benign and neoplastic
human prostate. Cancer Res 45:3663–3667.
Breslow N, Chan CW, Dhom G, Drury RA, Franks LM,
Gellei B, Lee YS, Lundberg S, Sparke B, Sternby NH,
Tulinius H. 1977. Latent carcinoma of prostate of autopsy
in seven areas. Int J Cancer 20:680–688.
Brooks JD, Weinstein M, Lin X, Sun Y, Pin SS, Bova GS,
Epstein JI, Isaacs WB, Nelson WG. 1998. CG island
methylation changes near the GSTP1 gene in prostatic
intraepithelial neoplasia. Cancer Epidemiol Biomarkers
Prev 7:531–536.
Cahill DP, Kinzler KW, Vogelstein B, Lengauer C. 1999.
Genetic instability and darwinian selection in tumours.
Trends Cell Biol 9:M57–M60.
Cairns P, Okami K, Halachmi S, Halachmi N, Esteller
M, Herman JG, Jen J, Isaacs WB, Bova GS, Sidransky D.
1997. Frequent inactivation of PTEN/MMAC1 in primary
prostate cancer. Cancer Res 57:4997–5000.
Carpten J, Nupponen N, Isaacs S, Sood R, Robbins C, Xu J,
Faruque M, Moses T, Ewing C, Gillanders E, Hu P,
470
De Marzo et al.
Bujnovszky P, Makalowska I, Baffoe-Bonnie A, Faith D,
Smith J, Stephan D, Wiley K, Brownstein M, Gildea
D, Kelly B, Jenkins R, Hostetter G, Matikainen M,
Schleutker J, Klinger K, Connors T, Xiang Y, Wang Z, De
Marzo A, Papadopoulos N, Kallioniemi OP, Burk R,
Meyers D, Gronberg H, Meltzer P, Silverman R, BaileyWilson J, Walsh P, Isaacs W, Trent J. 2002. Germline
mutations in the ribonuclease L gene in families showing
linkage with HPC1. Nat Genet 30:181–184.
Cheville JC, Lloyd RV, Sebo TJ, Cheng L, Erickson L,
Bostwick DG, Lohse CM, Wollan P. 1998. Expression of
p27kip1 in prostatic adenocarcinoma. Mod Pathol 11:
324–328.
Chung LWK, Isaacs WB, Simons JW. 2001. Prostate
cancer: Biology, genetics, and the new therapeutics.
Totowa, NJ: Humana Press.
Clark LC, Combs GF, Jr., Turnbull BW, Slate EH, Chalker
DK, Chow J, Davis LS, Glover RA, Graham GF, Gross
EG, Krongrad A, Lesher JL, Jr., Park HK, Sanders BB,
Jr., Smith CL, Taylor JR. 1996. Effects of selenium
supplementation for cancer prevention in patients with
carcinoma of the skin. A randomized controlled trial.
Nutritional Prevention of Cancer Study Group [see
comments] [published erratum appears in JAMA 1997
May 21;277(19):1520]. JAMA 276:1957–1963.
Clark LC, Dalkin B, Krongrad A, Combs GF, Jr., Turnbull
BW, Slate EH, Witherington R, Herlong JH, Janosko E,
Carpenter D, Borosso C, Falk S, Rounder J. 1998.
Decreased incidence of prostate cancer with selenium
supplementation: Results of a double-blind cancer prevention trial. Br J Urol 81:730–734.
Cohen JH, Kristal AR, Stanford JL. 2000. Fruit and
vegetable intakes and prostate cancer risk. J Natl Cancer
Inst 92:61–68.
Cordon-Cardo C, Koff A, Drobnjak M, Capodieci P, Osman
I, Millard SS, Gaudin PB, Fazzari M, Zhang ZF,
Massague J, Scher HI. 1998. Distinct altered patterns
of p27KIP1 gene expression in benign prostatic hyperplasia and prostatic carcinoma [in process citation].
J Natl Cancer Inst 90:1284–1291.
Counter CM, Avilion AA, LeFeuvre CE, Stewart NG,
Greider CW, Harley CB, Bacchetti S. 1992. Telomere
shortening associated with chromosome instability is
arrested in immortal cells which express telomerase
activity. EMBO J 11:1921–1929.
Coussens LM, Werb Z. 2002. Inflammation and cancer.
Nature 420:860–867.
Craft N, Shostak Y, Carey M, Sawyers CL. 1999. A
mechanism for hormone-independent prostate cancer
through modulation of androgen receptor signaling by
the HER-2/neu tyrosine kinase. Nat Med 5:280–285.
Culig Z, Hobisch A, Cronauer MV, Cato AC, Hittmair A,
Radmayr C, Eberle J, Bartsch G, Klocker H. 1993.
Mutant androgen receptor detected in an advanced-stage
prostatic carcinoma is activated by adrenal androgens
and progesterone. Mol Endocrinol 7:1541–1550.
de Lange T. 1995. Telomere dynamics and genome instability in human cancer. In: Blackburn EH, Greider
CW, editors. Telomeres. Plainview, NY: Cold Spring
Harbor Laboratory Press. pp 265–293.
De Marzo AM, Meeker AK, Epstein JI, Coffey DS. 1998a.
Prostate stem cell compartments: Expression of the cell
cycle inhibitor p27Kip1 in normal, hyperplastic, and
neoplastic cells. Am J Pathol 153:911–919.
De Marzo AM, Nelson WG, Meeker AK, Coffey DS. 1998b.
Stem cell features of benign and malignant prostate
epithelial cells. J Urol 160:2381–2392.
De Marzo AM, Marchi VL, Epstein JI, Nelson WG. 1999.
Proliferative inflammatory atrophy of the prostate: Implications for prostatic carcinogenesis. Am J Pathol 155:
1985–1992.
DeMarzo AM, Nelson WG, Isaacs WB, Epstein JI. 2003.
Pathological and molecular aspects of prostate cancer.
Lancet 361:955–964.
Dennis LK, Dawson DV. 2002. Meta-analysis of measures
of sexual activity and prostate cancer. Epidemiology
13:72–79.
Dennis LK, Lynch CF, Torner JC. 2002. Epidemiologic
association between prostatitis and prostate cancer.
Urology 60:78–83.
Dhanasekaran SM, Barrette TR, Ghosh D, Shah R,
Varambally S, Kurachi K, Pienta KJ, Rubin MA,
Chinnaiyan AM. 2001. Delineation of prognostic biomarkers in prostate cancer. Nature 412:822–826.
Di Cristofano A, De Acetis M, Koff A, Cordon-Cardo C,
Pandolfi PP. 2001. Pten and p27KIP1 cooperate in
prostate cancer tumor suppression in the mouse. Nat
Genet 27:222–224.
Donaldson L, Fordyce C, Gilliland F, Smith A, Feddersen R,
Joste N, Moyzis R, Griffith J. 1999. Association between
outcome and telomere DNA content in prostate cancer.
J Urol 162:1788–1792.
Eder IE, Hoffmann J, Rogatsch H, Schafer G, Zopf D,
Bartsch G, Klocker H. 2002. Inhibition of LNCaP
prostate tumor growth in vivo by an antisense oligonucleotide directed against the human androgen receptor.
Cancer Gene Ther 9:117–125.
Eiserich JP, Hristova M, Cross CE, Jones AD, Freeman BA,
Halliwell B, van der Vliet A. 1998. Formation of nitric
oxide-derived inflammatory oxidants by myeloperoxidase
in neutrophils. Nature 391:393–397.
Emmert-Buck MR, Vocke CD, Pozzatti RO, Duray PH,
Jennings SB, Florence CD, Zhuang Z, Bostwick DG,
Liotta LA, Linehan WM. 1995. Allelic loss on chromosome 8p12-21 in microdissected prostatic intraepithelial
neoplasia. Cancer Res 55:2959–2962.
Epstein JI. 1995. Prostate biopsy interpretation. New York,
NY: Raven Press.
Epstein JI, Potter SR. 2001. The pathological interpretation and significance of prostate needle biopsy findings:
Implications and current controversies. J Urol 166:402–
410.
Epstein JI, Walsh PC, Sanfilippo F. 1996. Clinical and cost
impact of second-opinion pathology. Review of prostate
biopsies prior to radical prostatectomy. Am J Surg Pathol
20:851–857.
Esteller M, Corn PG, Urena JM, Gabrielson E, Baylin SB,
Herman JG. 1998. Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human
neoplasia. Cancer Res 58:4515–4518.
Evans BA, Harper ME, Daniells CE, Watts CE, Matenhelia
S, Green J, Griffiths K. 1996. Low incidence of androgen
receptor gene mutations in human prostatic tumors
using single strand conformation polymorphism analysis. Prostate 28:162–171.
Feldman BJ, Feldman D. 2001. The development of
androgen-independent prostate cancer. Nat Rev Cancer
1:34–45.
Pathological and Molecular Mechanisms of Prostate Carcinogenesis
Feldser DM, Hackett JA, Greider CW. 2003. Telomere
dysfunction and the initiation of genome instability. Nat
Rev Cancer 3:623–627.
Feneley MR, Young MP, Chinyama C, Kirby RS, Parkinson
MC. 1996. Ki-67 expression in early prostate cancer and
associated pathological lesions. J Clin Pathol 49:741–748.
Ferdinandusse S, Denis S, Clayton PT, Graham A, Rees JE,
Allen JT, McLean BN, Brown AY, Vreken P, Waterham
HR, Wanders RJ. 2000. Mutations in the gene encoding
peroxisomal alpha-methylacyl-CoA racemase cause
adult-onset sensory motor neuropathy. Nat Genet 24:
188–191.
Fernandez PL, Arce Y, Farre X, Martinez A, Nadal A, Rey
MJ, Peir N, Campo E, Cardesa A. 1999. Expression of
p27/kip1 is down-regulated in human prostate carcinoma
progression. J Pathol 187:563–566.
Franks LM. 1954. Atrophy and hyperplasia in the prostate
proper. J Pathol Bacteriol 68:617–621.
Furnari FB, Huang HJ, Cavenee WK. 1998. The phosphoinositol phosphatase activity of PTEN mediates a serumsensitive G1 growth arrest in glioma cells. Cancer Res
58:5002–5008.
Gaddipati JP, McLeod DG, Heidenberg HB, Sesterhenn IA,
Finger MJ, Moul JW, Srivastava S. 1994. Frequent
detection of codon 877 mutation in the androgen receptor
gene in advanced prostate cancers. Cancer Res 54:2861–
2864.
Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM,
Hennekens CH, Stampfer MJ. 1999. Lower prostate
cancer risk in men with elevated plasma lycopene levels:
Results of a prospective analysis. Cancer Res 59:1225–
1230.
Gao AC, Isaacs JT. 2002. Molecular basis of prostate
carcinogenesis. In: Coleman WB, Tsongalis GJ, editors.
The molecular basis of human cancer. Totowa, NJ:
Humana Press. pp 365–379.
Gardner WA, Bennett BD. 1992. The prostate overview:
Recent insights and speculations. In: Weinstein RS,
Garnder WA, editors. Pathology and pathobiology of the
urinary bladder and prostate. Baltimore: Williams and
Wilkens. pp 129–148.
Gerstenbluth RE, Seftel AD, MacLennan GT, Rao RN,
Corty EW, Ferguson K, Resnick MI. 2002. Distribution of
chronic prostatitis in radical prostatectomy specimens
with up-regulation of bcl-2 in areas of inflammation.
J Urol 167:2267–2270.
Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M,
Catling AD, White FM, Christian RE, Settlage RE,
Shabanowitz J, Hunt DF, Weber MJ. 2002. Androgen
receptor phosphorylation. Regulation and identification
of the phosphorylation sites. J Biol Chem 277:29304–
29314.
Giovannucci E. 2001. Medical history and etiology of
prostate cancer. Epidemiol Rev 23:159–162.
Gleason PE, Jones JA, Regan JS, Salvas DB, Eble JN,
Lamph WW, Vlahos CJ, Huang WL, Falcone JF, Hirsch
KS. 1993. Platelet derived growth factor (PDGF), androgens and inflammation: Possible etiologic factors in the
development of prostatic hyperplasia. J Urol 149:1586–
1592.
Gottschalk AR, Basila D, Wong M, Dean NM, Brandts CH,
Stokoe D, Haas-Kogan DA. 2001. p27Kip1 is required for
PTEN-induced G1 growth arrest. Cancer Res 61:2105–
2111.
471
Graff JR, Konicek BW, McNulty AM, Wang Z, Houck K,
Allen S, Paul JD, Hbaiu A, Goode RG, Sandusky GE,
Vessella RL, Neubauer BL. 2000. Increased AKT activity
contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem 275:24500–24505.
Gray IC, Stewart LM, Phillips SM, Hamilton JA, Gray NE,
Watson GJ, Spurr NK, Snary D. 1998. Mutation and
expression analysis of the putative prostate tumoursuppressor gene PTEN. Br J Cancer 78:1296–1300.
Grignon DJ, Sakr WA. 1996. Atypical adenomatous hyperplasia of the prostate: A critical review. Eur Urol 30:
206–211.
Gross GA, Turesky RJ, Fay LB, Stillwell WG, Skipper PL,
Tannenbaum SR. 1993. Heterocyclic aromatic amine
formation in grilled bacon, beef and fish and in grill
scrapings. Carcinogenesis 14:2313–2318.
Guess HA. 2001. Benign prostatic hyperplasia and prostate
cancer. Epidemiol Rev 23:152–158.
Guo YP, Sklar GN, Borkowski A, Kyprianou N. 1997. Loss
of the cyclin-dependent kinase inhibitor P27(Kip1)
protein in human prostate cancer correlates with tumor
grade. Clin Cancer Res 3:2269–2274.
Haapala K, Hyytinen ER, Roiha M, Laurila M, Rantala I,
Helin HJ, Koivisto PA. 2001. Androgen receptor alterations in prostate cancer relapsed during a combined
androgen blockade by orchiectomy and bicalutamide. Lab
Invest 81:1647–1651.
Habel LA, Zhao W, Stanford JL. 2002. Daily aspirin use and
prostate cancer risk in a large, multiracial cohort in the
US. Cancer Causes Control 13:427–434.
Hackett JA, Greider CW. 2002. Balancing instability: Dual
roles for telomerase and telomere dysfunction in tumorigenesis. Oncogene 21:619–626.
Haenszel W, Kurihara M. 1968. Studies of Japanese
migrants. I. Mortality from cancer and other diseases
among Japanese in the United States. J Natl Cancer Inst
40:43–68.
Harley CB, Futcher AB, Greider CW. 1990. Telomeres
shorten during ageing of human fibroblasts. Nature
345:458–460.
Hasui Y, Marutsuka K, Asada Y, Ide H, Nishi S, Osada Y.
1994. Relationship between serum prostate specific
antigen and histological prostatitis in patients with
benign prostatic hyperplasia. Prostate 25:91–96.
Hayes RB, Pottern LM, Strickler H, Rabkin C, Pope V,
Swanson GM, Greenberg RS, Schoenberg JB, Liff J,
Schwartz AG, Hoover RN, Fraumeni JF, Jr. 2000. Sexual
behaviour, STDs and risks for prostate cancer. Br
J Cancer 82:718–725.
He WW, Sciavolino PJ, Wing J, Augustus M, Hudson P,
Meissner PS, Curtis RT, Shell BK, Bostwick DG, Tindall
DJ, Gelmann EP, Abate-Shen C, Carter KC. 1997. A novel
human prostate-specific, androgen-regulated homeobox
gene (NKX3.1) that maps to 8p21, a region frequently
deleted in prostate cancer. Genomics 43:69–77.
Hedrick L, Epstein JI. 1989. Use of keratin 903 as an
adjunct in the diagnosis of prostate carcinoma. Am J Surg
Pathol 13:389–396.
Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen
JK, Hartman AM, Haapakoski J, Malila N, Rautalahti
M, Ripatti S, Maenpaa H, Teerenhovi L, Koss L,
Virolainen M, Edwards BK. 1998. Prostate cancer
and supplementation with alpha-tocopherol and beta-
472
De Marzo et al.
carotene: Incidence and mortality in a controlled trial
[see comments]. J Natl Cancer Inst 90:440–446.
Henderson CJ, Smith AG, Ure J, Brown K, Bacon EJ, Wolf
CR. 1998. Increased skin tumorigenesis in mice lacking
pi class glutathione S-transferases. Proc Natl Acad Sci
USA 95:5275–5280.
Hobisch A, Eder IE, Putz T, Horninger W, Bartsch G,
Klocker H, Culig Z. 1998. Interleukin-6 regulates
prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. Cancer
Res 58:4640–4645.
Hsing AW, Tsao L, Devesa SS. 2000. International trends
and patterns of prostate cancer incidence and mortality.
Int J Cancer 85:60–67.
Huang GM, Ng WL, Farkas J, He L, Liang HA, Gordon D,
Yu J, Hood L. 1999. Prostate cancer expression profiling
by cDNA sequencing analysis. Genomics 59:178–186.
Irani J, Levillain P, Goujon JM, Bon D, Dore B, Aubert J.
1997. Inflammation in benign prostatic hyperplasia:
Correlation with prostate specific antigen value. J Urol
157:1301–1303.
Isaacs WB, Bova GS, Morton RA, Bussemakers MJ, Brooks
JD, Ewing CM. 1994. Molecular biology of prostate
cancer. Semin Oncol 21:514–521.
Jacobson LP, Zhang BC, Zhu YR, Wang JB, Wu Y, Zhang
QN, Yu LY, Qian GS, Kuang SY, Li YF, Fang X, Zarba A,
Chen B, Enger C, Davidson NE, Gorman MB, Gordon
GB, Prochaska HJ, Egner PA, Groopman JD, Munoz A,
Helzlsouer KJ, Kensler TW. 1997. Oltipraz chemoprevention trial in Qidong, People’s Republic of China: Study
design and clinical outcomes. Cancer Epidemiol Biomarkers Prev 6:257–265.
Jaffee EM, Hruban RH, Canto M, Kern SE. 2002. Focus on
pancreas cancer. Cancer Cell 2:25–28.
Jemal A, Thomas A, Murray T, Thun M. 2002. Cancer
statistics, 2002. CA Cancer J Clin 52:23–47.
Jiang Z, Woda BA, Rock KL, Xu Y, Savas L, Khan A, Pihan
G, Cai F, Babcook JS, Rathanaswami P, Reed SG, Xu J,
Fanger GR. 2001. P504S: A new molecular marker for the
detection of prostate carcinoma. Am J Surg Pathol
25:1397–1404.
Jiang Z, Wu CL, Woda BA, Dresser K, Xu J, Fanger GR,
Yang XJ. 2002. P504S/alpha-methylacyl-CoA racemase:
A useful marker for diagnosis of small foci of prostatic
carcinoma on needle biopsy. Am J Surg Pathol 26:1169–
1174.
Kensler TW. 1997. Chemoprevention by inducers of
carcinogen detoxication enzymes. Environ Health Perspect 4(105 Suppl):965–970.
Kensler TW, He X, Otieno M, Egner PA, Jacobson LP, Chen
B, Wang JS, Zhu YR, Zhang BC, Wang JB, Wu Y, Zhang
QN, Qian GS, Kuang SY, Fang X, Li YF, Yu LY,
Prochaska HJ, Davidson NE, Gordon GB, Gorman MB,
Zarba A, Enger C, Munoz A, Helzlsouer KJ, et al. 1998.
Oltipraz chemoprevention trial in Qidong, People’s
Republic of China: Modulation of serum aflatoxin
albumin adduct biomarkers. Cancer Epidemiol Biomarkers Prev 7:127–134.
Kibel AS, Faith DA, Bova GS, Isaacs WB. 2000. Loss of
heterozygosity at 12P12-13 in primary and metastatic
prostate adenocarcinoma. J Urol 164:192–196.
Kim MJ, Cardiff RD, Desai N, Banach-Petrosky WA,
Parsons R, Shen MM, Abate-Shen C. 2002. Cooperativity
of Nkx3.1 and Pten loss of function in a mouse model of
prostate carcinogenesis. Proc Natl Acad Sci USA 99:
2884–2889.
Kinzler KW, Vogelstein B. 1997. Cancer-susceptibility
genes. Gatekeepers and caretakers [news; comment]
[see comments]. Nature 386:761, 763.
Knize MG, Salmon CP, Mehta SS, Felton JS. 1997.
Analysis of cooked muscle meats for heterocyclic aromatic amine carcinogens. Mutat Res 376:129–134.
Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen
E, Isola J, Trapman J, Cleutjens K, Noordzij A, Visakorpi
T, Kallioniemi OP. 1997. Androgen receptor gene
amplification: A possible molecular mechanism for
androgen deprivation therapy failure in prostate cancer.
Cancer Res 57:314–319.
Kolonel LN. 2001. Fat, meat, and prostate cancer. Epidemiol Rev 23:72–81.
Krieger JN, Nyberg L, Jr., Nickel JC. 1999. NIH consensus
definition and classification of prostatitis. JAMA 282:
236–237.
Leav I, McNeal JE, Ho SM, Jiang Z. 2003. Alphamethylacyl-CoA racemase (P504S) expression in evolving
carcinomas within benign prostatic hyperplasia and in
cancers of the transition zone. Hum Pathol 34:228–233.
Lee WH, Morton RA, Epstein JI, Brooks JD, Campbell PA,
Bova GS, Hsieh WS, Isaacs WB, Nelson WG. 1994.
Cytidine methylation of regulatory sequences near the
pi-class glutathione S-transferase gene accompanies
human prostatic carcinogenesis. Proc Natl Acad Sci
USA 91:11733–11737.
Leitzmann MF, Stampfer MJ, Ma J, Chan JM, Colditz GA,
Willett WC, Giovannucci E. 2002. Aspirin use in relation
to risk of prostate cancer. Cancer Epidemiol Biomarkers
Prev 11:1108–1111.
Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB.
1992. Telomere end-replication problem and cell aging.
J Mol Biol 225:951–960.
Li DM, Sun H. 1998. PTEN/MMAC1/TEP1 suppresses the
tumorigenicity and induces G1 cell cycle arrest in human
glioblastoma cells. Proc Natl Acad Sci USA 95:15406–
15411.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc
J, Miliaresis C, Rodgers L, McCombie R, Bigner SH,
Giovanella BC, Ittmann M, Tycko B, Hibshoosh H,
Wigler MH, Parsons R. 1997. PTEN, a putative protein
tyrosine phosphatase gene mutated in human brain,
breast, and prostate cancer. Science 275:1943–1947.
Liavag I. 1968. Atrophy and regeneration in the pathogenesis of prostatic carcinoma. Acta Path Microbiol Scandinav 73:338–350.
Lijinsky W, Shubik P. 1964. Benzo(a)pyrene and other
polynuclear hydrocarbons in charcoal-broiled meat.
Science 145:53–55.
Lin X, Tascilar M, Lee WH, Vles WJ, Lee BH, Veeraswamy
R, Asgari K, Freije D, van Rees B, Gage WR, Bova GS,
Isaacs WB, Brooks JD, DeWeese TL, De Marzo AM,
Nelson WG. 2001. GSTP1 CpG island hypermethylation
is responsible for the absence of GSTP1 expression in
human prostate cancer cells. Am J Pathol 159:1815–
1826.
Luo J, Duggan DJ, Chen Y, Sauvageot J, Ewing CM,
Bittner ML, Trent JM, Isaacs WB. 2001. Human prostate
cancer and benign prostatic hyperplasia: Molecular
dissection by gene expression profiling. Cancer Res 61:
4683–4688.
Pathological and Molecular Mechanisms of Prostate Carcinogenesis
Luo J, Zha S, Gage WR, Dunn TA, Hicks JL, Bennett CJ,
Ewing CM, Platz EA, Ferdinandusse S, Wanders RJ,
Trent JM, Isaacs WB, De Marzo AM. 2002. Alphamethylacyl-CoA racemase: A new molecular marker for
prostate cancer. Cancer Res 62:2220–2226.
Macoska JA, Trybus TM, Wojno KJ. 2000. 8p22 loss
concurrent with 8c gain is associated with poor outcome
in prostate cancer. Urology 55:776–782.
Magee JA, Araki T, Patil S, Ehrig T, True L, Humphrey PA,
Catalona WJ, Watson MA, Milbrandt J. 2001. Expression
profiling reveals hepsin overexpression in prostate
cancer. Cancer Res 61:5692–5696.
Magi-Galluzzi C, Luo J, Isaacs WB, Hicks JL, De Marzo
AM, Epstein JI. 2003. Alpha-methylacyl-CoA racemase:
A variably sensitive immunohistochemical marker for
the diagnosis of small prostate cancer foci on needle
biopsy. Am J Surg Pathol 27:1128–1133.
Marcelli M, Ittmann M, Mariani S, Sutherland R, Nigam R,
Murthy L, Zhao Y, DiConcini D, Puxeddu E, Esen A,
Eastham J, Weigel NL, Lamb DJ. 2000. Androgen
receptor mutations in prostate cancer. Cancer Res 60:
944–949.
McClintock B. 1941. The stability of broken ends of
chromosomes in Zea mays. Genetics 26:234–282.
McMenamin ME, Soung P, Perera S, Kaplan I, Loda M,
Sellers WR. 1999. Loss of PTEN expression in paraffinembedded primary prostate cancer correlates with high
Gleason score and advanced stage. Cancer Res 59:4291–
4296.
McNeal JE. 1969. Origin and development of carcinoma in
the prostate. Cancer 23:24–34.
McNeal JE. 1984. Ageing and the prostate. In: Brocklehurst JC, editor. Urology in the elderly. Edinburgh, UK:
Churhill Livingstone. pp 193–202.
McNeal JE. 1988. Normal histology of the prostate. Am
J Surg Pathol 12:619–633.
McNeal JE. 1997. Prostate. In: Sternberg SS, editor.
Histology for pathologists. Philadelphia, PA: LippincottRaven. pp 997–1017.
McNeal JE, Bostwick DG. 1986. Intraductal dysplasia: A
premalignant lesion of the prostate. Hum Pathol 17:
64–71.
Meeker AK, Hicks JL, Platz EA, March GE, Bennett CJ,
De Marzo AM. 2002. Telomere shortening is an early
somatic DNA alteration in human prostate tumorigenesis. Cancer Res 62:6405–6409.
Meng MV, Dahiya R. 2002. Molecular genetics of prostate
cancer. In: Carroll PR, Grossfeld GD, editors. Prostate
cancer. Hamilton, Ontario, BC: Decker, Inc.
Michaud DS, Augustsson K, Rimm EB, Stampfer MJ,
Willet WC, Giovannucci E. 2001. A prospective study on
intake of animal products and risk of prostate cancer.
Cancer Causes Control 12:557–567.
Millar DS, Ow KK, Paul CL, Russell PJ, Molloy PL, Clark
SJ. 1999. Detailed methylation analysis of the glutathione S-transferase pi (GSTP1) gene in prostate
cancer [in process citation]. Oncogene 18:1313–1324.
Miller GJ. 1999. Prostate cancer among the Chinese:
Pathological and epidemiological and nutritional considerations. In: Resnick MI, Thompson IM, editors. Advanced therapy of prostate disease. Hamilton, Ontario,
BC: Decker, Inc. pp 18–27.
Mirchandani D, Zheng J, Miller GJ, Ghosh AK, Shibata
DK, Cote RJ, Roy-Burman P. 1995. Heterogeneity in
473
intratumor distribution of p53 mutations in human
prostate cancer. Am J Pathol 147:92–101.
Montironi R, Mazzucchelli R, Scarpelli M. 2002. Precancerous lesions and conditions of the prostate: From
morphological and biological characterization to chemoprevention. Ann NY Acad Sci 963:169–184.
Moore RA. 1936. The evolution and involution of the
prostate gland. Am J Pathol 12:599–624.
Morgenthaler PM, Holzhauser D. 1995. Analysis of mutations induced by 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP) in human lymphoblastoid cells. Carcinogenesis 16:713–718.
Mousses S, Wagner U, Chen Y, Kim JW, Bubendorf L,
Bittner M, Pretlow T, Elkahloun AG, Trepel JB,
Kallioniemi OP. 2001. Failure of hormone therapy in
prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin
sensitive signaling. Oncogene 20:6718–6723.
Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH,
Parsons R, Tonks NK. 1997. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity
phosphatase. Proc Natl Acad Sci USA 94:9052–9057.
Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP,
Hemmings BA, Wigler MH, Downes CP, Tonks NK. 1998.
The lipid phosphatase activity of PTEN is critical for its
tumor supressor function. Proc Natl Acad Sci USA 95:
13513–13518.
Nakamura N, Ramaswamy S, Vazquez F, Signoretti S,
Loda M, Sellers WR. 2000. Forkhead transcription factors are critical effectors of cell death and cell cycle arrest
downstream of PTEN. Mol Cell Biol 20:8969–8982.
Nakayama M, Bennett CJ, Hicks JL, Epstein JI, Platz EA,
Nelson WG, De Marzo AM. 2003a. Hypermethylation of
the human 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 163:923–933.
Nakayama M, Gonzalgo ML, Yegnasubramanian S, Lin X,
Demarzo AM, Nelson WG. 2003b. GSTP1 CpG island
hypermethylation as a molecular biomarker for prostate
cancer. J Cell Biochem (in press).
Nazareth LV, Weigel NL. 1996. Activation of the human
androgen receptor through a protein kinase A signaling
pathway. J Biol Chem 271:19900–19907.
Nelson JE, Harris RE. 2000. Inverse association of
prostate cancer and non-steroidal anti-inflammatory
drugs (NSAIDs): Results of a case–control study. Oncol
Rep 7:169–170.
Nelson PS, Han D, Rochon Y, Corthals GL, Lin B, Monson
A, Nguyen V, Franza BR, Plymate SR, Aebersold R,
Hood L. 2000. Comprehensive analyses of prostate gene
expression: Convergence of expressed sequence tag
databases, transcript profiling and proteomics. Electrophoresis 21:1823–1831 [pii].
Nelson CP, Kidd LC, Sauvageot J, Isaacs WB, De Marzo
AM, Groopman JD, Nelson WG, Kensler TW. 2001a.
Protection against 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine cytotoxicity and DNA adduct formation in human prostate by glutathione S-transferase
P1. Cancer Res 61:103–109.
Nelson WG, De Marzo AM, DeWeese TL. 2001b. The
molecular pathogenesis of prostate cancer: Implications
for prostate cancer prevention. Urology 57:39–45.
474
De Marzo et al.
Nelson WG, De Marzo AM, Isaacs WB. 2003. Prostate
cancer. N Engl J Med 349:366–381.
Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G,
Petersen R, Frost P, Gibbons JJ, Wu H, Sawyers CL.
2001. Enhanced sensitivity of PTEN-deficient tumors to
inhibition of FRAP/mTOR. Proc Natl Acad Sci USA
98:10314–10319.
Newmark JR, Hardy DO, Tonb DC, Carter BS, Epstein JI,
Isaacs WB, Brown TR, Barrack ER. 1992. Androgen
receptor gene mutations in human prostate cancer. Proc
Natl Acad Sci USA 89:6319–6323.
Nickel JC. 1994. Prostatic inflammation in benign prostatic hyperplasia—The third component? Can J Urol 1:
1–4.
Nickel JC, Downey J, Young I, Boag S. 1999. Asymptomatic
inflammation and/or infection in benign prostatic hyperplasia. BJU Int 84:976–981.
Norrish AE, Jackson RT, McRae CU. 1998. Non-steroidal
anti-inflammatory drugs and prostate cancer progression. Int J Cancer 77:511–515.
Norrish AE, Ferguson LR, Knize MG, Felton JS, Sharpe SJ,
Jackson RT. 1999. Heterocyclic amine content of cooked
meat and risk of prostate cancer. J Natl Cancer Inst 91:
2038–2044.
O’Shaughnessy JA, Kelloff GJ, Gordon GB, Dannenberg
AJ, Hong WK, Fabian CJ, Sigman CC, Bertagnolli MM,
Stratton SP, Lam S, Nelson WG, Meyskens FL, Alberts
DS, Follen M, Rustgi AK, Papadimitrakopoulou V,
Scardino PT, Gazdar AF, Wattenberg LW, Sporn MB,
Sakr WA, Lippman SM, Von Hoff DD. 2002. Treatment
and prevention of intraepithelial neoplasia: An important target for accelerated new agent development. Clin
Cancer Res 8:314–346.
Ornstein DK, Cinquanta M, Weiler S, Duray PH, EmmertBuck MR, Vocke CD, Linehan WM, Ferretti JA. 2001.
Expression studies and mutational analysis of the
androgen regulated homeobox gene NKX3.1 in benign
and malignant prostate epithelium. J Urol 165:1329–
1334.
Parsons JK, Gage WR, Nelson WG, De Marzo AM. 2001a.
P63 protein expression is rare in prostate adenocarcinoma: Implications for cancer diagnosis and carcinogenesis. Urology 58:619–624.
Parsons JK, Nelson CP, Gage WR, Nelson WG, Kensler
TW, De Marzo AM. 2001b. GSTA1 expression in normal,
preneoplastic, and neoplastic human prostate tissue.
Prostate 49:30–37.
Platt N, Gordon S. 2001. Is the class A macrophage scavenger receptor (SR-A) multifunctional?—The mouse’s
tale. J Clin Invest 108:649–654.
Platz EA. 1998. Prostatitis and prostate cancer. New
Developments in Prostate Cancer Treatment 3:71–73.
Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M,
Yamada KM, Cordon-Cardo C, Catoretti G, Fisher PE,
Parsons R. 1999. Mutation of Pten/Mmac1 in mice causes
neoplasia in multiple organ systems. Proc Natl Acad Sci
USA 96:1563–1568.
Podsypanina K, Lee RT, Politis C, Hennessy I, Crane A,
Puc J, Neshat M, Wang H, Yang L, Gibbons J, Frost P,
Dreisbach V, Blenis J, Gaciong Z, Fisher P, Sawyers C,
Hedrick-Ellenson L, Parsons R. 2001. An inhibitor of
mTOR reduces neoplasia and normalizes p70/S6 kinase
activity in PtenÆ mice. Proc Natl Acad Sci USA 98:
10320–10325.
Prescott JL, Blok L, Tindall DJ. 1998. Isolation and
androgen regulation of the human homeobox cDNA,
NKX3.1. Prostate 35:71–80.
Putzi MJ, De Marzo AM. 2000. Morphologic transitions
between proliferative inflammatory atrophy and highgrade prostatic intraepithelial neoplasia. Urology 56:
828–832.
Qian J, Bostwick DG, Takahashi S, Borell TJ, Herath JF,
Lieber MM, Jenkins RB. 1995. Chromosomal anomalies
in prostatic intraepithelial neoplasia and carcinoma
detected by fluorescence in situ hybridization. Cancer
Res 55:5408–5414.
Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera
S, Roberts TM, Sellers WR. 1999. Regulation of G1
progression by the PTEN tumor suppressor protein is
linked to inhibition of the phosphatidylinositol 3-kinase/
Akt pathway. Proc Natl Acad Sci USA 96:2110–2115.
Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto
M, Talalay P, Kensler TW. 2001. From the cover: Sensitivity to carcinogenesis is increased and chemoprotective
efficacy of enzyme inducers is lost in nrf2 transcription
factor-deficient mice. Proc Natl Acad Sci USA 98:3410–
3415.
Reznik G, Hamlin MH II, Ward JM, Stinson SF. 1981.
Prostatic hyperplasia and neoplasia in aging F344 rats.
Prostate 2:261–268.
Rich AR. 1934. On the frequency of occurrenec of occult
carcinoma of the prostate. J Urol 33:215–223.
Roberts RO, Lieber MM, Rhodes T, Girman CJ, Bostwick
DG, Jacobsen SJ. 1998. Prevalence of a physicianassigned diagnosis of prostatitis: The Olmsted county
study of urinary symptoms and health status among
men. Urology 51:578–584.
Roberts RO, Jacobson DJ, Girman CJ, Rhodes T, Lieber
MM, Jacobsen SJ. 2002. A population-based study of
daily nonsteroidal anti-inflammatory drug use and
prostate cancer. Mayo Clin Proc 77:219–225.
Rubin MA, Zhou M, Dhanasekaran SM, Varambally S,
Barrette TR, Sanda MG, Pienta KJ, Ghosh D, Chinnaiyan AM. 2002. Alpha-methylacyl coenzyme A racemase
as a tissue biomarker for prostate cancer. JAMA 287:
1662–1670.
Ruijter ET, Miller GJ, van de Kaa CA, van Bokhoven A,
Bussemakers MJ, Debruyne FM, Ruiter DJ, Schalken
JA. 1999. Molecular analysis of multifocal prostate
cancer lesions. J Pathol 188:271–277.
Ruska KM, Sauvageot J, Epstein JI. 1998. Histology and
cellular kinetics of prostatic atrophy. Am J Surg Pathol
22:1073–1077.
Sadar MD, Gleave ME. 2000. Ligand-independent activation of the androgen receptor by the differentiation agent
butyrate in human prostate cancer cells. Cancer Res
60:5825–5831.
Sakr WA, Haas GP, Cassin BF, Pontes JE, Crissman JD.
1993. The frequency of carcinoma and intraepithelial
neoplasia of the prostate in young male patients [see
comments]. J Urol 150:379–385.
Sakr WA, Grignon DJ, Crissman JD, Heilbrun LK, Cassin
BJ, Pontes JJ, Haas GP. 1994. High grade prostatic
intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20–69: An autopsy study
of 249 cases. In Vivo 8:439–443.
Schatteman PH, Hoekx L, Wyndaele JJ, Jeuris W, Van
Marck E. 2000. Inflammation in prostate biopsies of men
Pathological and Molecular Mechanisms of Prostate Carcinogenesis
without prostatic malignancy or clinical prostatitis:
Correlation with total serum PSA and PSA density. Eur
Urol 37:404–412.
Schmitz W, Albers C, Fingerhut R, Conzelmann E.
1995. Purification and characterization of an alphamethylacyl-CoA racemase from human liver. Eur J
Biochem 231:815–822.
Schoenberg MP, Hakimi JM, Wang S, Bova GS, Epstein JI,
Fischbeck KH, Isaacs WB, Walsh PC, Barrack ER. 1994.
Microsatellite mutation (CAG24 ! 18) in the androgen
receptor gene in human prostate cancer. Biochem Biophys Res Commun 198:74–80.
Sciavolino PJ, Abrams EW, Yang L, Austenberg LP, Shen
MM, Abate-Shen C. 1997. Tissue-specific expression of
murine Nkx3.1 in the male urogenital system. Dev Dyn
209:127–138.
Shah R, Mucci NR, Amin A, Macoska JA, Rubin MA. 2001.
Postatrophic hyperplasia of the prostate gland: Neoplastic precursor or innocent bystander? Am J Pathol 158:
1767–1773.
Shah RB, Zhou M, LeBlanc M, Snyder M, Rubin MA. 2002.
Comparison of the basal cell-specific markers, 34betaE12
and p63, in the diagnosis of prostate cancer. Am J Surg
Pathol 26:1161–1168.
Shih IM, Zhou W, Goodman SN, Lengauer C, Kinzler KW,
Vogelstein B. 2001. Evidence that genetic instability
occurs at an early stage of colorectal tumorigenesis.
Cancer Res 61:818–822.
Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE,
Mack TM. 1991. Cancers of the prostate and breast
among Japanese and white immigrants in Los Angeles
county. Br J Cancer 63:963–966.
Shirai T, Sano M, Tamano S, Takahashi S, Hirose M,
Futakuchi M, Hasegawa R, Imaida K, Matsumoto K,
Wakabayashi K, Sugimura T, Ito N. 1997. The prostate:
A target for carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) derived from cooked
foods. Cancer Res 57:195–198.
Signoretti S, Waltregny D, Dilks J, Isaac B, Lin D,
Garraway L, Yang A, Montironi R, McKeon F, Loda M.
2000. P63 is a prostate basal cell marker and is required
for prostate development [in process citation]. Am
J Pathol 157:1769–1775.
Solit DB, Zheng FF, Drobnjak M, Munster PN, Higgins B,
Verbel D, Heller G, Tong W, Cordon-Cardo C, Agus DB,
Scher HI, Rosen N. 2002. 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen
receptor and HER-2/neu and inhibits the growth of
prostate cancer xenografts. Clin Cancer Res 8:986–993.
Sommerfeld HJ, Meeker AK, Piatyszek MA, Bova GS, Shay
JW, Coffey DS. 1996. Telomerase activity: A prevalent
marker of malignant human prostate tissue. Cancer Res
56:218–222.
Stamey TA, Warrington JA, Caldwell MC, Chen Z, Fan Z,
Mahadevappa M, McNeal JE, Nolley R, Zhang Z. 2001.
Molecular genetic profiling of Gleason grade 4/5 prostate
cancers compared to benign prostatic hyperplasia. J Urol
166:2171–2177.
Stanbrough M, Leav I, Kwan PW, Bubley GJ, Balk SP.
2001. Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium. Proc Natl Acad Sci USA 98:10823–10828.
Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H,
Ligon AH, Langford LA, Baumgard ML, Hattier T,
475
Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian
SV. 1997. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is
mutated in multiple advanced cancers. Nat Genet
15:356–362.
Strickler HD, Goedert JJ. 2001. Sexual behavior and evidence for an infectious cause of prostate cancer. Epidemiol
Rev 23:144–151.
Stuart GR, Holcroft J, de Boer JG, Glickman BW.
2000. Prostate mutations in rats induced by the suspected human carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Cancer Res 60:266–268.
Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J,
Gavrilova N, Mueller B, Liu X, Wu H. 1999. PTEN
modulates cell cycle progression and cell survival by
regulating phosphatidylinositol 3,4,5,-trisphosphate and
Akt/protein kinase B signaling pathway. Proc Natl Acad
Sci USA 96:6199–6204.
Suzuki H, Sato N, Watabe Y, Masai M, Seino S, Shimazaki
J. 1993. Androgen receptor gene mutations in human
prostate cancer. J Steroid Biochem Mol Biol 46:759–
765.
Suzuki H, Akakura K, Komiya A, Aida S, Akimoto S,
Shimazaki J. 1996. Codon 877 mutation in the androgen
receptor gene in advanced prostate cancer: Relation to
antiandrogen withdrawal syndrome. Prostate 29:153–
158.
Suzuki H, Freije D, Nusskern DR, Okami K, Cairns P,
Sidransky D, Isaacs WB, Bova GS. 1998. Interfocal
heterogeneity of PTEN/MMAC1 gene alterations in
multiple metastatic prostate cancer tissues. Cancer Res
58:204–209.
Tan J, Sharief Y, Hamil KG, Gregory CW, Zang DY, Sar M,
Gumerlock PH, deVere White RW, Pretlow TG, Harris
SE, Wilson EM, Mohler JL, French FS. 1997. Dehydroepiandrosterone activates mutant androgen receptors
expressed in the androgen-dependent human prostate
cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol 11:450–459.
Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner
AE, Ogata GK, Keer HN, Balk SP. 1995. Mutation of the
androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 332:1393–1398.
Taplin ME, Bubley GJ, Ko YJ, Small EJ, Upton M,
Rajeshkumar B, Balk SP. 1999. Selection for androgen
receptor mutations in prostate cancers treated with
androgen antagonist. Cancer Res 59:2511–2515.
Tchou JC, Lin X, Freije D, Isaacs WB, Brooks JD, Rashid A,
De Marzo AM, Kanai Y, Hirohashi S, Nelson WG. 2000.
GSTP1 CpG island DNA hypermethylation in hepatocellular carcinomas. Int J Oncol 16:663–676.
Teng DH, Hu R, Lin H, Davis T, Iliev D, Frye C, Swedlund
B, Hansen KL, Vinson VL, Gumpper KL, Ellis L, ElNaggar A, Frazier M, Jasser S, Langford LA, Lee J, Mills
GB, Pershouse MA, Pollack RE, Tornos C, Troncoso P,
Yung WK, Fujii G, Berson A, Steck PA, et al. 1997.
MMAC1/PTEN mutations in primary tumor specimens
and tumor cell lines. Cancer Res 57:5221–5225.
Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller
GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN,
Lippman SM, Carlin SM, Ryan A, Szczepanek CM,
Crowley JJ, Coltman CA, Jr. 2003. The influence of
Finasteride on the development of prostate cancer. N
Engl J Med 349:215–224.
476
De Marzo et al.
Tilley WD, Buchanan G, Hickey TE, Bentel JM. 1996.
Mutations in the androgen receptor gene are associated
with progression of human prostate cancer to androgen
independence. Clin Cancer Res 2:277–285.
Torres-Rosado A, O’Shea KS, Tsuji A, Chou SH, Kurachi K.
1993. Hepsin, a putative cell-surface serine protease, is
required for mammalian cell growth. Proc Natl Acad Sci
USA 90:7181–7185.
True LD, Berger RE, Rothman I, Ross SO, Krieger JN.
1999. Prostate histopathology and the chronic prostatitis/
chronic pelvic pain syndrome: A prospective biopsy
study. J Urol 162:2014–2018.
Tsuji A, Torres-Rosado A, Arai T, Le Beau MM, Lemons RS,
Chou SH, Kurachi K. 1991. Hepsin, a cell membraneassociated protease. Characterization, tissue distribution, and gene localization. J Biol Chem 266:16948–
16953.
Tsujimoto Y, Takayama H, Nonomura N, Okuyama A,
Aozasa K. 2002. Postatrophic hyperplasia of the prostate
in Japan: Histologic and immunohistochemical features
and p53 gene mutation analysis. Prostate 52:279–287.
van der Kwast TH, Schalken J, Ruizeveld de Winter JA,
van Vroonhoven CC, Mulder E, Boersma W, Trapman J.
1991. Androgen receptors in endocrine-therapy-resistant
human prostate cancer. Int J Cancer 48:189–193.
van Leenders G, Dijkman H, Hulsbergen-van de Kaa C,
Ruiter D, Schalken J. 2000. Demonstration of intermediate cells during human prostate epithelial differentiation
in situ and in vitro using triple-staining confocal
scanning microscopy. Lab Invest 80:1251–1258.
Van Leenders GJ, Gage WR, Hicks JL, Van Balken B,
Aalders TW, Schalken JA, De Marzo AM. 2003. Intermediate cells in human prostate epithelium are enriched
in proliferative inflammatory atrophy. Am J Pathol 162:
1529–1537.
Varambally S, Dhanasekaran SM, Zhou M, Barrette TR,
Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt
RG, Otte AP, Rubin MA, Chinnaiyan AM. 2002. The
polycomb group protein EZH2 is involved in progression
of prostate cancer. Nature 419:624–629.
Veldscholte J, Voorhorst-Ogink MM, Bolt-de Vries J, van
Rooij HC, Trapman J, Mulder E. 1990. Unusual specificity of the androgen receptor in the human prostate
tumor cell line LNCaP: High affinity for progestagenic
and estrogenic steroids. Biochim Biophys Acta 1052:187–
194.
Verhagen AP, Ramaekers FC, Aalders TW, Schaafsma HE,
Debruyne FM, Schalken JA. 1992. Colocalization of basal
and luminal cell-type cytokeratins in human prostate
cancer. Cancer Res 52:6182–6187.
Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen
R, Palmberg C, Palotie A, Tammela T, Isola J, Kallioniemi OP. 1995. In vivo amplification of the androgen
receptor gene and progression of human prostate cancer.
Nat Genet 9:401–406.
Vivanco I, Sawyers CL. 2002. The phosphatidylinositol
3-kinase AKT pathway in human cancer. Nat Rev Cancer
2:489–501.
Voeller HJ, Augustus M, Madike V, Bova GS, Carter KC,
Gelmann EP. 1997. Coding region of NKX3.1, a prostatespecific homeobox gene on 8p21, is not mutated in human
prostate cancers. Cancer Res 57:4455–4459.
von Zglinicki T, Pilger R, Sitte N. 2000. Accumulation of
single-strand breaks is the major cause of telomere
shortening in human fibroblasts. Free Radic Biol Med
28:64–74.
Vukovic B, Park PC, Al-Maghrabi J, Beheshti B, Sweet J,
Evans A, Trachtenberg J, Squire J. 2003. Evidence of
multifocality of telomere erosion in high-grade prostatic
intraepithelial neoplasia (HPIN) and concurrent carcinoma. Oncogene 22:1978–1987.
Waghray A, Schober M, Feroze F, Yao F, Virgin J, Chen
YQ. 2001. Identification of differentially expressed genes
by serial analysis of gene expression in human prostate
cancer. Cancer Res 61:4283–4286.
Walker MG, Volkmuth W, Sprinzak E, Hodgson D, Klingler
T. 1999. Prediction of gene function by genome-scale
expression analysis: Prostate cancer-associated genes.
Genome Res 9:1198–1203.
Wang SI, Parsons R, Ittmann M. 1998. Homozygous
deletion of the PTEN tumor suppressor gene in a subset
of prostate adenocarcinomas. Clin Cancer Res 4:811–
815.
Wang JS, Shen X, He X, Zhu YR, Zhang BC, Wang JB,
Qian GS, Kuang SY, Zarba A, Egner PA, Jacobson
LP, Munoz A, Helzlsouer KJ, Groopman JD, Kensler
TW. 1999. Protective alterations in phase 1 and 2
metabolism of aflatoxin B1 by oltipraz in residents of
Qidong, People’s Republic of China. J Natl Cancer Inst
91:347–354.
Wechter WJ, Leipold DD, Murray ED, Jr., Quiggle D,
McCracken JD, Barrios RS, Greenberg NM. 2000. E-7869
(R-flurbiprofen) inhibits progression of prostate cancer in
the TRAMP mouse. Cancer Res 60:2203–2208.
Weinstein MH, Signoretti S, Loda M. 2002. Diagnostic
utility of immunohistochemical staining for p63, a sensitive marker of prostatic basal cells. Mod Pathol 15:1302–
1308.
Welsh JB, Sapinoso LM, Su AI, Kern SG, Wang-Rodriguez
J, Moskaluk CA, Frierson HF, Jr., Hampton GM. 2001.
Analysis of gene expression identifies candidate markers
and pharmacological targets in prostate cancer. Cancer
Res 61:5974–5978.
Whittemore AS, Kolonel LN, Wu AH, John EM, Gallagher
RP, Howe GR, Burch JD, Hankin J, Dreon DM, West
DW, et al. 1995. Prostate cancer in relation to diet,
physical activity, and body size in blacks, whites, and
Asians in the United States and Canada. J Natl Cancer
Inst 87:652–661.
Wilson MJ, Ditmanson JV, Sinha AA, Estensen RD. 1990.
Plasminogen activator activities in the ventral and
dorsolateral prostatic lobes of aging Fischer 344 rats.
Prostate 16:147–161.
Wu Q, Yu D, Post J, Halks-Miller M, Sadler JE, Morser J.
1998. Generation and characterization of mice deficient
in hepsin, a hepatic transmembrane serine protease.
J Clin Invest 101:321–326.
Xia Y, Zweier JL. 1997. Superoxide and peroxynitrite
generation from inducible nitric oxide synthase in macrophages. Proc Natl Acad Sci USA 94:6954–6958.
Xu J, Stolk JA, Zhang X, Silva SJ, Houghton RL,
Matsumura M, Vedvick TS, Leslie KB, Badaro R, Reed
SG. 2000. Identification of differentially expressed genes
in human prostate cancer using subtraction and microarray. Cancer Res 60:1677–1682.
Xu J, Zheng SL, Komiya A, Mychaleckyj JC, Isaacs SD, Hu
JJ, Sterling D, Lange EM, Hawkins GA, Turner A, Ewing
CM, Faith DA, Johnson JR, Suzuki H, Bujnovszky P,
Pathological and Molecular Mechanisms of Prostate Carcinogenesis
Wiley KE, DeMarzo AM, Bova GS, Chang B, Hall MC,
McCullough DL, Partin AW, Kassabian VS, Carpten JD,
Bailey-Wilson JE, Trent JM, Ohar J, Bleecker ER, Walsh
PC, Isaacs WB, Meyers DA. 2002a. Germline mutations
and sequence variants of the macrophage scavenger
receptor 1 gene are associated with prostate cancer risk.
Nat Genet 32:321–325.
Xu J, Zheng SL, Turner A, Isaacs SD, Wiley KE, Hawkins
GA, Chang BL, Bleecker ER, Walsh PC, Meyers DA,
Isaacs WB. 2002b. Associations between hOGG1 sequence variants and prostate cancer susceptibility.
Cancer Res 62:2253–2257.
Yaman O, Gogus C, Tulunay O, Tokatli Z, Ozden E. 2003.
Increased prostate-specific antigen in subclinical prostatitis: The role of aggressiveness and extension of inflammation. Urol Int 71:160–164.
Yang RM, Naitoh J, Murphy M, Wang HJ, Phillipson J,
deKernion JB, Loda M, Reiter RE. 1998. Low p27
expression predicts poor disease-free survival in patients
with prostate cancer. J Urol 159:941–945.
Yang XJ, Wu CL, Woda BA, Dresser K, Tretiakova M,
Fanger GR, Jiang Z. 2002. Expression of alpha-methylacyl-CoA racemase (P504S) in atypical adenomatous
hyperplasia of the prostate. Am J Surg Pathol 26:921–
925.
Yatani R, Chigusa I, Akazaki K, Stemmermann GN, Welsh
RA, Correa P. 1982. Geographic pathology of latent
prostatic carcinoma. Int J Cancer 29:611–616.
Yu IS, Chen HJ, Lee YS, Huang PH, Lin SR, Tsai TW,
Lin SW. 2000. Mice deficient in hepsin, a serine protease, exhibit normal embryogenesis and unchanged
477
hepatocyte regeneration ability. Thromb Haemost 84:
865–870.
Zegarra-Moro OL, Schmidt LJ, Huang H, Tindall DJ. 2002.
Disruption of androgen receptor function inhibits proliferation of androgen-refractory prostate cancer cells.
Cancer Res 62:1008–1013.
Zha S, Gage WR, Sauvageot J, Saria EA, Putzi MJ, Ewing
CM, Faith DA, Nelson WG, De Marzo AM, Isaacs WB.
2001. Cyclooxygenase-2 is up-regulated in proliferative
inflammatory atrophy of the prostate, but not in prostate
carcinoma. Cancer Res 61:8617–8623.
Zhang Y, Talalay P, Cho CG, Posner GH. 1992. A major
inducer of anticarcinogenic protective enzymes from
broccoli: Isolation and elucidation of structure. Proc Natl
Acad Sci USA 89:2399–2403.
Zhang Y, Kensler TW, Cho CG, Posner GH, Talalay P.
1994. Anticarcinogenic activities of sulforaphane and
structurally related synthetic norbornyl isothiocyanates.
Proc Natl Acad Sci USA 91:3147–3150.
Zhou A, Paranjape J, Brown TL, Nie H, Naik S, Dong B,
Chang A, Trapp B, Fairchild R, Colmenares C, Silverman
RH. 1997. Interferon action and apoptosis are defective in
mice devoid of 20 ,50 -oligoadenylate-dependent RNase L.
EMBO J 16:6355–6363.
Zhou M, Jiang Z, Epstein JI. 2003a. Expression and
diagnostic utility of alpha-methylacyl-CoA-racemase
(P504S) in foamy gland and pseudohyperplastic prostate
cancer. Am J Surg Pathol 27:772–778.
Zhou M, Shah R, Shen R, Rubin MA. 2003b. Basal cell
cocktail (34betaE12 Гѕ p63) improves the detection of
prostate basal cells. Am J Surg Pathol 27:365–371.