The Pathology of Prostate Cancer: From Population Studies to the Molecule
Moderators: Dr. John R. Srigley and Dr. Rodolfo Montironi
Section 3 -
The Molecular Pathogenesis Of Early Prostate Cancer
Angelo M. De Marzo MD PhD, Charles J. Bieberich, PhD, Robert Jenkins MD, Fusheng Lan MD, Yasutomo Nakai, MD PhD, Alan K. Meeker PhD, and William G. Nelson MD PhD
The Johns Hopkins University School of Medicine Departments of Pathology, Urology and Oncology, The
Sidney Kimmel Comprehensive Cancer Center and The Brady Urological Research Institute
The Johns Hopkins University School of Medicine Departments of Pathology, Urology and Oncology, The
Sidney Kimmel Comprehensive Cancer Center and The Brady Urological Research Institute. email:
Prostate cancer is the most common non-cutaneous malignancy in men and remains a leading cause of
cancer-related death in the United States. Although the etiology of prostate cancer remains unknown, the
most consistent risk factor is advancing age. While genetic factors play a significant role in the
development of this disease, reports documenting an increased risk of prostate cancer in men who
immigrated to the United States from China and Japan, where the prevalence of the disease is low,
strongly implicate environmental exposures.
Numerous epidemiological studies of prostate
cancer have identified associations between the consumption of particular dietary constituents, such as
red meat and charred meats, and prostate cancer incidence and mortality.
Approximately 20-30% of the world's cancer burden can be traced to infectious agents, that are thought
to act through the production of chronic infections and subsequent chronic inflammation.
For example, adenocarcinoma of the stomach is characterized by a series of sequential events comprising:
H. Pylori infection, resultant long standing persistent inflammation,
atrophic gastritis, dysplasia and, finally, carcinoma.
The molecular mechanisms of
inflammation-induced cancer relate to the action of phagocytic inflammatory cells (neutrophils and
macrophages) that release a variety of chemical agents designed to kill pathogens . These agents include
superoxide, hydrogen peroxide, singlet oxygen, and nitric oxide that can further react to form the highly
Some of these reactive oxygen and nitrogen species can directly
interact with DNA in host bystander cells or react with other epithelial cellular components such as
phospholipids, initiating a free radical chain reaction—the end result being cell injury and cell death.
Lost epithelial cells must quickly regenerate by DNA replication and cell division in order to maintain
their barrier function. This increased DNA synthesis, which is also stimulated locally via cytokines
released from inflammatory cells, places epithelial cells at high risk for acquiring
oxidative/nitrosative DNA damage and subsequent mutations.
A growing body of work from studies of families with hereditary prostate cancer as well as data from
the fields of genetic epidemiology, histopathology and molecular pathology have begun to suggest that a
link may exist between chronic inflammation and prostate cancer.
case-control epidemiological studies have found an increased relative risk of prostate cancer in men with
a prior history of certain sexually transmitted infections or prostatitis.
genetic epidemiological data have implicated germline variants of several genes directly involved in the
response to infection (e.g., RNAseL, MSR1) in
modulating prostate cancer risk.  In addition, the overwhelming majority (>90%) of
prostate cancers contain CpG island hypermethylation within the upstream promoter of GSTP1, resulting in the inactivation of a gene involved in defenses against
oxidant and electrophilic damage.  Finally, a large proportion of prostate tissues that are
obtained by needle biopsy, transurethral resection, radical prostatectomy or cystoprostatectomy have been
noted to contain multiple foci of chronic and/or acute inflammation.
SOMATIC ALTERATIONS IN GENE FUNCTION 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 24,25,26,27,28,29. 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 . 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
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
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.
Epigenetic genome alterations may be the first to appear during prostate cancer development
. Several genes have now been reported to carry somatic hypermethylation of CpG island
sequences in prostate cancers, likely causing epigenetic gene silencing, preventing gene transcription in
response to appropriate signals
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
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 prostate cancer cells, somatic hypermethylation of GSTP1 CpG island sequences represses GSTP1
transcription . Absence of GSTP1 expression and GSTP1
CpG island hypermethylation are also common in high grade PIN lesions .
Mice with both GSTP1 alleles disrupted by gene targeting exhibit
increased skin tumor formation after topical exposure to skin carcinogen 7,12 dimethylbenz[a]anthracene
(DMBA) . 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"
Dietary PhIP intake causes
prostate cancer in rats
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 , 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 ). GSTP1 can protect prostate cells
against PhIP-DNA damage .
AR and Newly Described Prostate Cancer Gene Fusions
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 . 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
"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 non-androgens 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
One explanation for the benefits of treatments targeting the androgen signaling axis may be provided
by the finding of recurrent chromosomal deletions and translocations in prostate cancers resulting in the
production of fusion transcripts of the 5' untranslated region of TMPRSS2,
an androgen-regulated gene, and ERG or to ETV1,
likely growth-stimulating ETS family members . Such chromosomal rearrangements have been
detected in 79% of prostate cancer cases, but seem to be rarely present in prostate cancer precursor
NKX3.1 is located on chromosome 8p21.2 within a region that shows loss
of heterozygosity (LOH) in prostate cancer in approximately 50 to 85% of cases
that mutations in the remaining allele of NKX3.1 have not been detected
NKX3.1 may function as a haplo-insufficient tumor
suppressor gene. That loss of one allele of NKX3.1 may occur early in
prostate carcinogenesis is evidenced by the finding that LOH on chromosome 8p has been reported to occur
in high grade prostatic intraepithelial neoplasia (PIN) at a frequency between 20-80%
Targeted disruption of Nkx3.1 in mice results in abnormal prostate ductal
morphogenesis and protein secretion
homozygous mutant mice do not develop invasive carcinoma, epithelial hyperplasia and PIN lesions arise
with age. Compound mutant mouse studies indicate that cooperativity exists between Nkx3.1 and the tumor suppressors Pten and Cdkn1b (encoding p27)
These compound mutants develop PIN
lesions that progress to invasive carcinomas and at times to metastatic disease. Since the effects are
seen in Nkx3.1 heterozygotes, haplo-insufficiency of Nkx3.1 also appears to plays a role in tumor progression.
We recently reported  that NKX3.1 protein was decreased in focal atrophy (see below) and
in most cases this related to steady state mRNA levels, but did not relate to gene dosage as assessed by
FISH. In PIN lesions, NKX3.1 was reduced but this too did not correlate with loss of chromosome 8p
sequences. Indeed, only 12 % of high grade PIN lesions, and no low grade PIN lesions, showed 8p21.3 loss
by FISH, which is a lower value then even the lowest (20%) that had been reported previously. By
contrast, 33% of Gleason pattern 3 and 74% of Gleason pattern 4/5 carcinomas contained 8p deletions using
the same FISH protocol, and the deletions correlated with NKX3.1 levels protein in carcinoma. Thus, this
new information indicates that deletion of sequences on chromosome 8p21.3 may be involved more with
progression of invasive disease than in initiation of disease.
PTEN, located at 10q, another site of frequent allelic loss in prostate
cancer, encodes a phosphatase active against both proteins and lipid substrates
has been proposed to function as a general tumor suppressor by inhibiting the phosphatidylinositol
3'-kinase/protein kinase B (PI3K/Akt) signaling pathway, thought to be essential for cell cycle
progression and/or cell survival in many cell types
Mice carrying disrupted Pten alleles manifest prostatic hyperplasia and dysplasia, and the progeny of
breeding crosses between Pten+/- mice and Nkx3.1+/-
mice develop PIN
as well as invasive carcinoma and lymph node
metastases . PTEN, which is typically expressed by normal epithelial cells, is often
expressed at a reduced level in human prostate cancer cells . Many somatic PTEN alterations have been reported for prostate cancers, including homozygous
deletions, loss of heterozygosity, mutations, and suspected CpG island
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 .
Perhaps, as is evident in mouse models featuring disrupted Nkx3.1 and Pten genes, haploinsufficiency for PTEN and/or NKX3.1 may be sufficient for a the neoplastic phenotype
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 Cdkn1balleles rapidly
develop localized prostate cancers . Reduced p27 expression appears characteristic of human
prostate cancer cells, particularly in prostate cancer cases with a poor prognosis
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 . 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
Thus, loss of PTEN function, accompanied by increased PI3K/Akt signaling, might result in
decreases in CDKN1B mRNA and in p27 protein half-life 
Decreased p27 expression has also been documented in high grade PIN
and in focal
C-MYC is a target for amplification on 8q24 during prostate
carcinogenesis and 8q24 gain correlates with a worse prognosis in prostate cancer
Also, elevated levels of C-MYC mRNA have been reported in prostate cancer when compared to normal
appearing prostate . Finally, transgenic targeting of the human C-MYC gene in the mouse prostate (Pro-Myc mice) resulted in PIN, prostate
carcinoma and metastatic disease .
Telomeres, and Telomere Shortening
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.
Chromosomal instability appears to be an important molecular mechanism driving malignant transformation
in many human epithelial tissues , yet the molecular mechanisms responsible for chromosome
destabilization during carcinogenesis are largely unknown. One route to chromosomal instability is
through defective telomeres
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 .
However, in the absence of compensatory mechanisms, telomeric DNA is subject to loss due to cell
oxidative damage . 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
Intriguingly, telomeres within human carcinomas are often found to be abnormally reduced in
length , 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 . Others have also reported telomere shortening in prostate
Recently we employed an in situ telomere FISH technique and reported that telomere shortening is
evident in the majority of high grade prostatic intraepithelial neoplasia (PIN) lesions ,
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.
Focal Prostate Atrophy as a Morphological Manifestation of a "Field Effect" and a Potential Prostate Cancer Precursor
Pathologists have long recognized focal areas of epithelial atrophy in the prostate
that appear more commonly in the peripheral zone of the prostate, where prostate cancers typically
. These lesions may occupy a significant fraction of the prostate, and many are
associated with chronic inflammation, and less commonly with acute inflammation
To standardize studies across different research groups, an International "Working Group" classification
of focal atrophy lesions was developed  . Many of these atrophic cells are not
quiescent--they are generally quite proliferative, with the number of cells undergoing cell division
being increased from 3 to 80 fold over matched normal appearing epithelium
highlight the common association with inflammation and the high proliferation index, we put forth the
term proliferative inflammatory atrophy (PIA) for most of these lesions
. Like normal
appearing prostate epithelium, PIA contains two cell layers. In normal prostate epithelium, basal cells
express p63, keratins 5 and 14 ("basal specific"), while luminal cells express none of these markers.
Similar to normal epithelium, luminal cells in focal atrophy do not express p63, indicating that these
cells are not simply basal cells  . Luminal cells in focal atrophy often express keratin 5,
but not 14, while they co-express keratins 8 and 18, which are expressed mostly in luminal cells in
. The atrophic luminal compartment cells that express keratin 5
(intermediate cells) also frequently show decreased p27Kip1 and increased Ki-67 . Luminal
cells in focal atrophy also show weak yet variable staining for androgen receptors, PSA, and PSAP. Taken
together, these data suggest many of the luminal cells in focal atrophy possess a phenotype that is
intermediate between basal and luminal cells. Intermediate epithelial cells have been postulated to be
the targets of neoplastic transformation in the prostate
. How these cells relate
to prostate epithelial stem cells is currently an area of active investigation, as prostate stem cells in
the human are as yet only poorly characterized in terms of markers that can be used to localize them in
tissue sections. Once appropriate markers are available for cellular localization in tissues for
prostate stem cells, it will be of major interest to determine whether prostate stem cells are increased
in focal atrophy lesions.
In terms of programmed cell death, we also previously reported increased BCL-2 protein in the luminal
cells in PIA that may block apoptosis  . Many luminal cells in PIA show reduced
staining for NKX3.1, which is a homeobox gene implicated as a tumor suppressor in prostate
cancer  . Preliminary data also shows that another tumor suppressor gene, strongly implicated
in prostate carcinogenesis, PTEN, is downregulated in PIA luminal cells. Therefore, 3 known prostate
tumor suppressor genes (p27 Kip1, PTEN, and NKX3.1) are known to be down regulated in expression in PIA
relative to normal appearing luminal cells . These findings provide mechanistic clues as to the abnormal
increase in proliferation in these cells and suggest that these atrophic cells are at times on their way
towards neoplastic transformation.
In morphological studies we have observed frequent merging of areas of focal atrophy directly with
high grade PIN
, which has been presumed to be the direct precursor to at least a
significant fraction of prostatic adenocarcinomas
. We and others have also
frequently observed these atrophic lesions near early carcinoma lesions (defined by their extremely
minute size), at times with direct merging between atrophic epithelium in PIA and
. Additionally, PIA cells show elevated levels of
GSTP1  ,
glutathione S transferase alpha (GSTA1) 
and COX-2  in
many, albeit not all of the cells, suggesting that these cells are responding to increased
In terms of somatic DNA alterations, we reported that while normal epithelium from cancer patients did
not contain methylated GSTP1 alleles, approximately 6% of PIA lesions harbor
cells with methylated GSTP1  . Another group found apparently
non-clonal mutated p53  and
androgen receptor alleles  in PAH, PIN and
carcinoma, but not in normal prostate. While one group found a small increase in chromosome 8 centromere
signals in focal atrophy , and another found loss of chromosome 8p in a fraction of focal
atrophy lesions , suggesting chromosomal abnormalities consistent with PIN and carcinoma, we
recently found no evidence for clonal alterations in chromosome 8 centromeric region, 8p loss or 8q24
gain in focal prostate atrophy .
In terms of geographic studies, we have collected preliminary data that show there is more cancer,
PIN, BPH, chronic inflammation and PIA in prostates of men from North America than in age-matched
Southeast Asian men
Exposure of Fisher 344 rats to PhIP, results in high grade PIN and intraductal carcinoma lesions in
the ventral lobe after 52 weeks, but no such neoplastic response in the dorsal-lateral or anterior
lobes. In a paradigm of short term exposure to PhIP, using a transgenic Fisher 344 rat, all prostate
lobes showed a similar increase in the mutation frequency, yet, the ventral lobe selectively responded to
PhIP with increased cell proliferation and cell death . Thus PhIP acts in the rat as both a
lobe-specific classical tumor "initiator" as well as a tumor "promoter". Increased epithelial cell
proliferation was accompanied by an increase in stromal mast cells, and stromal and intraepithelial
macrophages. At 12 weeks of PhIP exposure, the ventral lobe developed widespread simple atrophy, similar
in appearance to the human--PIN and intraductal carcinomas were observed to develop directly from the
atrophic epithelium at later time points (AM De Marzo, Y Nakai, WG Nelson, manuscript in process). Thus,
this animal model serves as a physiologically relevant, dietary-induced model of PIA/focal atrophy that
develops into PIN and early carcinoma.
"Injury and Regeneration" Hypothesis of Prostate Carcinogenesis
Our currently working model that suggests that repeated bouts of injury to the prostate epithelium
occur either as a result of inflammation in response to unknown pathogens or autoimmune disease, and/or
from direct injury from ingested circulating toxins from the diet, result in proliferation and a massive
increase in epithelial cells that possess a phenotype intermediate between basal cells and mature luminal
These cells are hypothesized to undergoing tissue repair and the lesions manifest
morphologically as focal prostate atrophy. This is supported by the finding that several proteins known
to be involved in tissue repair, such as C-met  and
HAI-1  show elevated
expression in focal atrophy. These atrophic areas are often widely dispersed throughout the prostate,
suggesting that they represent the morphological manifestations of a "field effect". The model predicts
that in a small subset of cells, perhaps cells with an intermediate phenotype that contain at least some
"stem cell" properties, somatic genome alterations occur, such as such as cytosine hypermethylation
within the CpG island of the GSTP1 gene and telomere shortening, that drive
genetic instability and initiate high grade PIN and prostate cancer formation.
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