206
Cancer of the Prostate: Molecular Genetics
primary cancer specimens and in almost
all patients with lymph node metastases
or hormone-refractory disease. A recent
study showed that KAI1 expression could
be a predictor of stage A prostate cancer
progression. Allelic loss or mutations do
not appear to be the mechanism of KAI1
decrease. EWI2/PGRL, a KAI1 associated
protein, was recently found to be important
for KAI1-mediated suppression of cancer
cell migration.
Located near
KAI1
,CD44isatransmem-
brane protein associated with cell–cell
and cell–extracellular matrix interactions.
Conflicting data exist regarding CD44’s
function
in
prostate
cancer.
Loss
of
expression of
CD44
standard
isoform
(CD44s) correlated with
poor progno-
sis in several studies, whereas others
demonstrate increased CD44 expression
associated with high-grade and metastatic
potential. Neutralizing antibodies to CD44
inhibited
cell
proliferation
and
base-
ment membrane invasion. In another
report, transfection-enhanced expression
suppressed metastatic ability in the AT3.1
cell line without affecting
in vivo
growth
or tumorigenicity. Recent study indicates
the important role of CD44 methylation in
the progression and metastasis of prostate
cancer. Pentaerythritol tetranitrate is a
tyrosine phosphatase, mapping to chromo-
some 10q23 that negatively regulates cell
migration and cell survival. In addition,
its homology to a protein that interacts
with actin Flaments at focal adhesions
suggests that PTEN may regulate cell in-
vasion and metastasis. Loss of
PTEN
may
occur in 13 to 37% of primary prostate can-
cers. Increased frequency of mutations and
LOH is found in cases with metastases.
Recent immunohistochemistry conFrms
these observations. Total absence of PTEN
expression correlated signiFcantly with
Gleason score and advanced pathologic
stage. Pentaerythritol tetranitrate, along
with CD44 and KAI1, has potential as
a marker to evaluate the metastatic abil-
ity of prostate cancer, and further studies
are warranted.
10
DNA Methylation
Abnormal patterns of DNA methylation
often characterize human cancer cells.
These include hypermethylation, redistri-
bution of methylation, and demethylation
of normally methylated regions. Although
hypomethylation has been reported in
prostate cancer, its signiFcance is un-
clear. More recently, hypermethylation of
particular areas has been noted and char-
acterized. The most important sites of
hypermethylation are the CpG islands,
with a high density of C-G dinucleotide
sequences, found in the 5
0
regions of
genes. Methylation of CpG-rich islands
may be associated with transcriptional in-
activation of the associated gene. This has
been demonstrated for the CDKN2 (
P16
)
gene at chromosome 9p21. The product,
a cyclin-dependent kinase inhibitory pro-
tein, controls passage through the G1
phase of the cell cycle. Inactivation by
homozygous deletion, found in 20% of
prostate specimens studied, may induce
progression through the cell cycle in tu-
mors. Analysis of the CpG-rich promoter
region in exon 1 of
P16
in the prostate
cancer cell lines PC-3, PPC1, and TSU re-
vealed dense methylation in these areas.
In addition, this hypermethylation corre-
lated with lack of mRNA expression as
determined by reverse transcriptase PCR.
In vitro
treatment with the demethyla-
tion agent 5-aza-2
0
-deoxycytidine induced
reexpression of CDKN2 transcripts. Pro-
moter methylation has been found in 13
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