The age-associated increase in the incidence of disease development and cancer occurrence is often thought to be due to the gradual accumulation of damage over the lifetime of an organism. However, an alternative opinion is that damaged cells are effectively eliminated and replaced by the immune system and regenerative cells (stem cells) and only when this “remove and replace” system failures, do organisms begin to show signs of ageing.
The presence of persistent DNA damage triggers cells to enter senescence (irreversible growth arrest) to protect the cell from becoming cancerous. The presence of the persistent DNA damage in these growth-arrested cells appears to activate pathways leading to cytokine/chemokine secretion and presentation of cell surface ligands (i.e MICA, MICB, ULBP2) which can be recognized by natural killer cells (NK) and some T-cells. This may allow damaged/senescent cells to communicate with immune cells for their removal (although more evidence of this is required).
For cells to become cancerous, they need to bypass senescence (following irreparable DNA damage), often achieved by acquiring mutations in genes associated with activation and maintenance of the senescence growth arrest. When such cells bypass senescence, the persistence of DNA damage may also activate pathways leading to cytokine/chemokine secretion and presentation of NK ligands.
It is also possible that cells can become cancerous if they instead escape senescence. “Escaping” is different from “bypassing” in that these cells were once senescent. If senescent cells persist in tissues without immune clearance, it is possible that stochastic genetic/epigenetic changes may lead to activation/inactivation of genes that allow the once senescent cell to reneter the cell cycle. A consequence of this escape may be the maintenance of the pro-survival phenotype and the pro-inflammatory phenotype associated with senescence. Escaping senescence may be more pertinent in cancer cells that have become senescent in response to therapy. Escape from senescence in this instance may lead to the progression of more aggressive cancers.
I am not aware of any studies that have investigated the similarities/differences in the secretory phenotype/NK ligand activation of senescent verses cancer cells. However, if both exist due the DNA damage response activating the immune response (DDR-AIR), then they are probably very similar.
If senescent and cancer cells were always effectively being removed then the incidence of cancer and disease would greatly be reduced. However, age-associated cancer and disease does occur and this may in part be due to a failure in the immune system to effectively remove senescent/cancer cells as we age. Additionally, cancer cells can develop various strategies for evading the immune response (i.e secretion of immunosuppressive cytokines). Whether the same strategies occur in senescent cells remains to be discovered.
Although purely speculative, it is possible that some of these strategies for evading immune surveillance is a result of pro-longed exposure to the pro-inflammatory phenotype of these cells. There may be a limited biological time frame whereby the presence of the inflammatory phenotype is beneficial for cell removal. Longer exposure may lead to an adaptive response through autocrine signalling leading to changes that evade immune surveillance. For example, the secretion of immunosuppressive cytokines may be an adaptive response for preventing detrimental damage from long exposure to pro-inflammatory cytokines.
Ongoing and future investigations should aim to provide solid evidence of whether (1) the secretory phenotype of senescent cells is for the purpose of immune clearance, (2) and if so, does immune clearance fail or become impaired with age and (3) if it does fail, what are the mechanisms?