Cancer of the Prostate: Molecular Genetics
201
predominant in most prostate cancers but
may be associated with high-grade and
advanced tumors, although this remains
controversial.
7
Telomerase
Telomeres are repetitive, noncoding DNA
sequences found at the ends of all eu-
karyotic chromosomes that play a role in
protection and replication of the chromo-
somes, as well as prevent loss of genetic
coding regions. In humans, hundreds of
TTAGGG tandem repeats compose the
telomeres. Normal cells lose between 50
and 200 of these nucleotides at each mi-
tosis and, after 50 to 100 cell doublings, a
critical amount of sequence is lost and the
cells senesce. Thus, telomeres and their
shortening serve as a mitotic clock. Telom-
erase, a ribonucleoprotein enzyme, is able
to add telomeric sequences to the ends of
newly replicating DNA and can compen-
sate for telomere shortening. Germ-line
cells and fetal cells typically have high
telomerase activity, whereas normal so-
matic cells have undetectable telomerase
activity. It is postulated that increased
telomerase activity allows unlimited cell
division and, therefore, is associated with
cellular immortalization, an important
phenotypic feature in the progression of
normal cells to malignant ones. Normal
prostate tissue does not exhibit telomerase
activity. In an assay of benign and malig-
nant tissue for telomerase activity using a
sensitive PCR technique, a large number
(84%) of cancers were strongly positive,
as well as all lymph nodes with metas-
tases. All human prostate cancer cell lines
tested (DU145, LNCaP, PC3, PPC1, TSU)
demonstrated telomerase activity. In con-
trast, no normal tissue from the cancer
specimens or BPH samples from patients
without evidence of cancer demonstrated
telomerase activity. Benign prostatic hy-
perplasia tissue adjacent to areas of cancer
demonstrated weak telomerase activity
in 12% of cases. Paradoxically, telomere
length from cancer tissue was signiFcantly
and consistently shorter than that detected
in either adjacent normal or BPH tissue.
Other studies have conFrmed the high in-
cidence of telomerase activity in prostate
cancer, and some data suggest a corre-
lation with Gleason grade. Interestingly,
telomerase activity has been found fre-
quently in adjacent areas of PIN (74%).
These Fndings lead to several conclusions.
┬▒irst, telomerase activity in a majority
of PIN and cancer further supports the
hypothesis than PIN is a precursor of
cancer and harbors early genetic changes.
Second, telomerase activity is nearly ubiq-
uitous in prostate cancer, and expression
occurs early in prostate carcinogenesis.
Third, the Fnding of telomerase activity
in associated areas that appear histolog-
ically normal suggests that telomerase
activity may be useful as a sensitive di-
agnostic marker for malignant tissue prior
to visible, microscopic changes. The re-
lationships between telomerase activity
and expression levels of human telom-
erase RNA (hTR) and human telomerase
reverse transcriptase (hTERT) mRNA in
benign and malignant alterations of the
human prostate gland has been investi-
gated. Remarkably, one-third of all cancer
and BPH tissue samples with hTR and
hTERT expression lack telomerase activ-
ity. Quantitative analyses contradict the
assumption that a certain threshold level
of hTR or hTERT mRNA is required for
telomerase activation, thus indicating that
telomerase regulation in prostate cancer
occurs more likely on a posttranscrip-
tional level. Nevertheless, the observation
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