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ANDROGENS AND ANDROGEN SIGNALING IN PROSTATE CANCER
Mark R Feneley
Institute of Urology and Nephrology, 4 Riding House Street, London,
W1W7EY,UK mark.feneley@uclh.org
The androgen sensitivity of the adult prostate holds a fundamental
place in the treatment of benign and malignant prostatic disease.
Human prostate is unique in its tendency to develop "malignant"
foci having limited or no tendency to progress in spite of the presence
of androgen. Furthermore, in spite of their morphological appearance,
these foci are recognised as not necessarily pathologically significant.
Confounding diagnostic uncertainty, cells forming these indolent
foci are indistinguishable from truly malignant cells that will
give rise to life-threatening cancer.
The response of the prostate to androgens at various stages of its
development including foetal morphogenesis, perinatal imprinting,
adult maturation and pathological changes of old age are specific
for gender and ageing of the human species. The changing sensitivity
and response of the normal prostate to endogenous circulating androgens
with age provide valuable insights into fundamental aspects of androgen
signaling. These include the androgen dependence of benign and malignant
prostatic diseases of the adult, the reawakening of foetal growth
mechanisms, and the possibility of endocrine feedback from the prostate
to the hypothalamic-pituitary axis.
Systemic androgen deprivation remains the mainstay of therapeutic
opportunity to delay progression of high-risk prostate cancer, in
some cases improving prognosis for survival. However, the physiological
and pathological effects of various anti-androgenic interventions
in the early stages of prostate cancer - particularly organ-confined
disease - are poorly understood, with potentially important differential
effects on DHT, T and other ligand binding to androgen receptor.
The effect of 5 alpha-reductase inhibition on prostate cancer detection
appears to relate to the morphological pattern of disease, while
expression of the isozymes alters with malignant progression. The
progression of early stage tumours may also relate to differential
association of higher tumour grade with lower systemic testosterone
and local downregulation of androgen signalling. Concerns regarding
the effect of systemic androgen deprivation and lack of oncological
benefit in organ-confined prostate cancer now preclude use of the
antiandrogen bicalutamide for treatment at this clinical stage.
In contrast to the reversible effects of androgen deprivation in
normal adult prostatic tissue, the initial often-dramatic impact
of continuous androgen deprivation on prostate cancer is usually
not sustained. Mechanisms that underlie this adaptation are not
well understood, but they appear to represent evolution to a disease
phenotype that enables malignant cells to escape a systemic restriction
of androgen bioavailability. This adaptation maintains intracellular
androgen-dependent processing in an environment of restricted bioavailable
androgen, and results in eventual dominance of so called "androgen-independent
cancer".
The significance of androgen signaling in early prostate cancer for
prevention or progression of early stage prostate cancer and the
changes responsible for "androgen independence" remain controversial.
Genetic and environmental factors contribute to the risk for clinical
disease, both also influencing androgen activity and molecular signalling.
For the individual patient, however, the significance of these aspects
is difficult to predict alongside age-related changes in androgen
signalling and the uncertain malignant potential of age-related
pathology.
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