Cancer of the Prostate: Molecular Genetics
203
PIN. These observations implicate specifc
changes in the FGF axis with the initia-
tion and progression o± prostate cancer,
and underscore the utility o± animal mod-
els to identi±y specifc molecular changes
in early disease. Fibroblast growth ±actor,
also known as keratinocyte growth ±ac-
tor, is expressed only by epithelial cells,
and studies in the developing mouse
seminal vesicle have shown it to be an
important paracrine mediator o± androgen
action. Similar e±±ects may be important
in prostate cancer and in epithelial cell
proli±eration and morphology.
The IGF ±amily, comprised o± IGF-I,
IGF-II, and relaxin, is involved in cell
growth,
cell
division,
and
apoptosis.
Insulin-like growth ±actor-II is an au-
tocrine and paracrine regulator o± cell
proli±eration in the adult prostate. In
androgen-insensitive prostate cancer, the
IGF-I receptor is overexpressed, and IGF-
II autocrine stimulation results in uncon-
trolled proli±eration. Typically, the IGF-II
gene demonstrates imprinting, in which
one allele is inactivated and silent. Bi-allelic
expression in cases o± cancer has been
reported and it has also been suggested
that loss o± imprinting may be involved
in abnormal growth in prostatic tissue.
The Physician’s Health Study prospec-
tively examined a matched population o±
152 men ±or IGF-I. The study concluded
that higher plasma IGF-I levels were asso-
ciated with higher rates o± prostate cancer;
men in the highest quartile were 4.3 times
more likely to develop prostate cancer.
These fndings were independent o± PSA
level, stage, and grade. The TGF-
β
±am-
ily has three iso±orms in humans and
regulates cell cycle kinetics by acting on
RB, MYC, and cyclin-dependent kinase
inhibitor activity. Trans±orming growth
±actor-
β
, detected in normal and neoplastic
prostate tissue, is an inhibitor o± normal
prostate epithelial cell growth, and its activ-
ity is modulated by other growth ±actors,
androgens, and the extracellular matrix.
Conversely, TGF-
β
can also stimulate cell
growth and contribute to tumor aggres-
siveness. Immunohistochemistry revealed
increasing levels o± TGF-
β
1int
um
o
r
s
with metastatic and nodal involvement.
Plasma TGF-
β
1 levels may have use as
a tumor marker or predictor o± clinical
prognosis. The TGF-
β
e±±ects are medi-
ated through the heteromeric complex o±
th
et
yp
eIan
dI
Ir
e
c
ep
t
o
r
s
.Thu
s
,l
o
s
s
o± ±unction o± either receptor results in
resistance to TGF-
β
inhibitory signals. De-
creased levels o± type I and II receptors are
correlated with higher grade and advanced
disease. Activation o± TGF-
β
signaling in
human prostate cancer cells suppresses
tumorigenicity via deregulation o± cell cy-
cle progression and induction o± caspase-1
mediated apoptosis.
Other growth ±actors implicated include
hepatocyte growth ±actor, platelet-derived
growth ±actor, nerve growth ±actor, and
interleukin-6. Further investigation is re-
quired to elucidate their exact roles in
prostate carcinogenesis.
9
Metastasis Suppressor Genes
The invasive nature o± prostate cancer is
dependent on the loss o± usual cell–cell
and cell–matrix interactions. Several can-
didate genes involved in this process have
been identifed in prostate cancer that
typically act as tumor suppressor genes.
Ultimately, a metastatic phenotype may be
acquired a±ter inactivation o± one or many
o± these genes. As discussed above, loss at
chromosome 16q, as detected by all meth-
ods, is ±requent in prostate cancer and
led to the search ±or a tumor suppressor
previous page 877 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 879 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off