202
Cancer of the Prostate: Molecular Genetics
that hTR and hTERT mRNA levels are
signifcantly (
p
<
0
.
002) correlated sug-
gests some common mechanisms in the
upregulation oF hTR and hTERT expres-
sion. Because
in situ
hybridization revealed
strong hTERT expression not only in all
cells oF the tumor glands but also in high-
grade PIN Foci, this upregulation seems to
occur early in prostate carcinogenesis.
8
Growth Factors
Growth Factors in the prostate have been
studied in two settings: the production
oF Factors within the tissue and the eF-
Fects oF exogenous Factors on prostate
cells in culture. It should be noted that
virtually all studies relating to growth Fac-
tor expression have been perFormed in
normal adult prostates, which are either
grow
thqu
iescen
toron
lys
low
lygrow
ing
.
However, one report used prostates From
young rats (6 to 8 weeks) to character-
ize expression oF heparin-binding growth
Factors. Most studies in human tissue
have used BPH specimens From older
men, in whom growth is exceedingly slow.
Thus, the Function oF growth Factors in
the adult prostate, as determined by cur-
rent data, is likely more homeostatic than
stimulatory. ±urther description oF growth
Factor expression in the growing prostate
is required to clariFy these issues and in-
consistencies. Polypeptide growth Factors
and their receptors play a role in both
normal prostate growth and prostate can-
cer development. These growth Factors
act in either an autocrine or paracrine
F
a
s
h
i
onan
dp
l
a
yar
o
l
eins
t
im
u
l
a
t
in
g
or inhibiting proliFeration, diFFerentiation,
development, chemotaxis, and tissue re-
pair. They are divided into Four major
Families: EG±, fbroblast growth Factor
(±G±), insulin-like growth Factor (IG±),
and transForming growth Factor-
α
(TG±-
α
). The EG± Family includes EG±, TG±-
α
,
amphiregulin, heparin-binding EG±, and
cripto
. Both EG± and TG±-
α
have been
implicated in prostate cancer and act on
the EG± receptor in a paracine man-
ner. Autocrine stimulation oF the EG±
receptor may also be important in the reg-
ulation oF prostate epithelial proliFeration
and diFFerentiation, although this remains
controversial. Prostate cancer cell proliF-
eration is strongly reduced by the EG±
receptor tyrosine kinase inhibitor ZD1839
in vitro
on human cell lines and primary
cultures. TG±-
α
whose overexpression in
transgenic mice results in hyperplasia and
dysplasia oF the anterior prostate, has been
Found in tumor cells but not in normal
prostatic cells.
The ±G± Family has at least 9 members;
only ±G±1, 2, 3, 7, and 8 have been Found
in prostate tissue. Moreover, their role in
prostate cancer is currently unclear. In-
creased expression oF both ±G±7 and ±G±8
has been reported in adenocarcinoma and
was associated with hormone-reFractory
disease and higher grade, respectively.
Interestingly, the stroma produces ±G±7
exclusively and is the site oF most ±G±
messenger RNA (mRNA) expression. This
Further confrms the vital role oF the pro-
static stoma and fbroblasts in aFFecting
epithelial cell behavior and carcinogen-
esis. In the presence oF an active AR,
the combined production oF ±G±2 and
±G±-BP may play an important role in
the progression oF prostate cancer through
the selection oF AR-clones expressing high
levels oF Bcl-2. By using the Transgenic
adenocarcinoma mouse prostate (TRAMP)
model, the expression oF ±G±R1iiib in
intraductal vasculature and the expres-
sion oF ±G±-2 protein were Found to
be concomitant with the emergence oF
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