Persistent activation of the DNA-damage
response (DDR) can trigger cells to undergo cellular senescence, a state of
irreversible, immune evoking, growth arrest.
In such a way, cellular senescence can prevent tumourigenesis firstly by
blocking cells from replicating and producing abnormal and potentially
cancerous daughter cells and secondly by coordinating their removal by immune
cells. Additionally, senescent cells can
aid tissue repair by preventing extensive cellular proliferation leading to
fibrosis, possibly triggered by replication stressed-induced DNA damage. However, if this orchestrated removal of
senescent cells becomes dysregulated, then persistent senescent cells can
promote tumourigenesis and tissue damage.
An aspect of the DDR in senescent cells is
the induction of an array of secretory factors, including
cytokines/chemokine’s, which are important in attracting/activating immune
cells to their vicinity. When immune
cells reach the locality of senescent cells, they can then specifically
recognize them by the expression of immune ligands on the cell membrane, a
process that may also be regulated primarily by the DDR. The specific ligands recognized and the
mechanism of senescent cell death will then be dependent upon the type of
immune cell interacting with the senescent cell.
However, cells induced to undergo permanent
growth arrest in vitro by the overexpression
of the cyclin dependent kinase inhibitor p16ink4a, do not develop an immune evoking
secretory phenotype until the addition of DNA damage. If cells in physiological or pathological
conditions can indeed undergo permanent cell cycle arrest in a p16 dependent,
DDR-independent manner, then these cells are unlikely to evoke an immune
response for their clearance. In support
of this, a recent study demonstrated that cells overexpressing p14(ARF) in the
epidermis of mice remained present for weeks after transgene silencing (Tokarsky-Amiel
et al 2013). Even if p16-induced
senescent cells do not display a pro-inflammatory phenotype, they can still
cause physiological problems simply by their inability to proliferate, an
essential feature required for tissue regeneration and maintenance. In this regard, the growth arrest and
pro-inflammatory phenotype of senescent cells can be investigated separately to
determine which feature is important in different physiological contexts.
Until the phenotype of p16-induced senescent
cells in vivo have been researched
more extensively, cellular senescence could be divided into two
separate types. Firstly, immunogenic senescence
related to a DNA damage response, consisting of a pro-inflammatory
phenotype and the presence of immune ligands, triggered by telomere shortening,
oncogene-activation, and chemical stressors.
Secondly, sterile senescence which lacks a pro-inflammatory
phenotype and the inability to evoke an immune response.
If this distinction is made, then studies
focused on the effect of cellular senescence on ageing, disease and cancer
development can better design their experiments and avoid confusion between
conflicting results due to differences in the types of senescence used.
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