The induction of
cellular senescence is often seen a beneficial therapeutic strategy for
preventing the growth of cancer. This
may certainly be the case in the short-term, but the biological impact of
senescent cells in the long-term is greatly understudied. Senescent cells are more than just a
permanent state of growth arrest; they also display an immune-evoking pro-inflammatory
secretory phenotype. However, for some
yet unknown reason, senescent cells can evade immune clearance and potentially
alter their microenvironment by continuously secreting of pro-inflammatory
factors. These pro-inflammatory factors
are thus one possible mechanism by which senescent cells could promote the
reoccurrence of cancer following senescence therapy.
Prostate
cancer (PCa) is one of the most common cancers in American men and a leading
cause of cancer- related death. Initial
PCa tumours are dependent upon the presence of androgen, such as testosterone,
for growth. As such, undergoing androgen
deprivation therapy (ADT) is currently the most effective procedure for suppressing
tumour progression. ADT not only causes tumour cell death leading to reduction
in tumour size, but also induces a proliferative arrest in a large fraction of
tumour cells. Within a few years
following ADT, the PCa can reemerge, that are no longer dependent on androgen
for growth, and for which there are currently no effective therapeutic
treatment strategies. Recurrence of nonresponsive or androgen-refractory
tumours reduces patient life expectancy to less than two years.
To
investigate the mechanisms of PCa reoccurrence, Burton et al focused their
efforts on the cells undergoing proliferative arrest in response to ADT. They provide evidence that androgen
deprivation-induced proliferative arrest is in fact cellular senescence, termed
ADIS (androgen deprivation-induced senescence).
The induction of ADIS appears to be due to intracellular up-regulation
of ROS and consequently DNA damage. Their data show that continuous exposure of
an androgen-sensitive PCa cell line (LNCaP) to the senescent microenvironment,
leads to the appearance of cells with androgen-independent characteristics. Further, it is shown that pharmacologic
enforcement of the p53-Bax pro-death pathway prior to androgen deprivation (AD)
preferentially triggers cellular death rather than cellular senescence. It is
thus postulated that the use of drug therapies prior/during ADT that promote
cell death rather than cellular senescence may prevent/reduce androgen
refractory PCa.
The more difficult
question to answer concerns the mechanisms that facilitate the appearance of cells
with androgen-refractory characteristics. One possibility is that the secretory
phenotype of senescent cells stimulates the proliferation of so called, cancer
stem cells (CSCs). The senescent
secretory profile is similar to that which occurs during a wound healing
response, suggesting CSC may proliferate to facilitate wound repair but in this
context facilitates tumour formation. Interestingly,
TAp63, a marker of basal prostatic cells, a progenitor population known to
survive androgen ablation and is involved in the maintenance of adult stem
cells is elevated in the emerging androgen-refractory cells. TAp63
overexpression has also been associated with resistance to premature senescence,
suggesting the emerging androgen-refractory cells, at least in part, may be the
result of selective pressure favoring the proliferation of cells resistant to
ADIS. Further, the secretory phenotype
of the surrounding senescent cells may facilitate the expansion of ADIS
resistant cells.
This work is important because it addresses the controversial issue
of whether AD-induced senescence in cancer cells promotes the progression of
the disease; if this is the case, these phenomena can provide therapeutic
targets to prevent progression. Additionally,
this study provides a method for generating and expanding androgen-refractory
cells in a shorter period of time, cells which can be used for further
study.
Link to Article: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0068003
DOI: 10.1371/journal.pone.0068003
DOI: 10.1371/journal.pone.0068003
