Monday, July 20, 2009
This book serves as a tribute to the work of the many investigators who have
attempted to understand the role of the androgen receptor (AR) in the development
and progression of prostate cancer. The relationship between prostate cancer and
androgen status was initially appreciated in the late 1800s, and then awareness
reawakened in the 1940s (Huggins and Hodges 2002) by the studies of Charles
Huggins and colleagues, for which the Nobel prize was awarded in 1966. Androgen
deprivation therapy by surgical or medical means using methods that remove the
source of testicular androgens or inhibit the production of testicular androgens,
respectively, produced remission in most, but not all, men. Moreover, clinical
studies have cast doubt on whether ‘‘combined androgen blockade’’ (Labrie et al.
1982) is any more effective than androgen deprivation monotherapy (Prostate
Cancer Trialists’ Collaborative Group, 1995), except when an antiandrogen is
used to block testosterone flair in men with bulky metastatic disease. Nonetheless,
responses to androgen deprivation therapy vary widely. In order to explain this
clinical variation, it was proposed initially that prostate cancer consists of ‘‘androgen-
dependent’’ and ‘‘androgen-independent’’ cells (Carter and Isaacs 1988; Isaacs
and Coffey 1981). The argument went as follows:
The relative distribution of prostate cancer cells between these two phenotypes determine
whether there is a clinical response to androgen deprivation therapy and the duration of any
response. If the tumor consists of androgen-dependent cells entirely, androgen deprivation
therapy would prove curative since all androgen-dependent cells would undergo apoptosis
upon androgen deprivation. If a prostate cancer is composed exclusively of androgenindependent
cells, then no clinical response to androgen deprivation therapy would occur
and that patient would ‘‘resist’’ androgen deprivation therapy and succumb to his prostate
cancer as if androgen deprivation therapy had never been administered. Almost, if not,
all patients fall between these two extremes and exhibit clinical remissions, which may be
complete and sustained if the androgen-dependent cells far outnumber the androgenindependent
cells. Because apoptosis does not occur in as high a proportion of cells as
predicted, a third phenotype of prostate cancer cell was proposed, the androgen-sensitive
cell (Pollack et al. 1983; Grossman 1986). The ‘‘androgen-sensitive’’ cell is responsive to
androgen deprivation therapy by becoming quiescent until such time that androgens
become available. Thus, the extent of regression of prostate cancer after androgen
deprivation therapy is influenced by the relative proportion of androgen-dependent,
androgen-sensitive and androgen-independent cells. The eventual emergence of the
‘‘androgen-independent phenotype’’ is predicted by the proportion of androgen-independent
cells.
James L. Mohler and Donald J. Tindall
