Protection versus Harm: Cellular Senescence in the Context of Cancer
A little cellular senescence is a good thing. When a cell enters the state of senescence in response to potentially cancerous mutational damage it shuts down replication and secretes signals that attract the immune system. Immune cells destroy any such senescent, damaged, potentially dangerous cells that fail to destroy themselves. When senescent cells accumulate with age, however, as the immune system falters in its task of clearance, the inflammatory secretions of these errant cells - the senescence-associated secretory phenotype (SASP) - make the environment much more favorable for the creation and growth of cancer.
Cellular senescence provides a significant benefit to the host by inducing irreversible cell cycle arrest and eliciting potent immune-mediated incipient tumor cell clearance, which is characterized by reduced incidence of cancer and halted tumor development. Senescence provides an alternative strategy to overcome the limitations of traditional cancer treatment because low dose of drugs can achieve the purpose of inducing senescence. However, senescent cells and SASP components can directly or indirectly promote tumor cells growth, invasion, and metastasis, and tumor vascularization. The senescence phenotype is complicated, and the production rate and clearance rate of senescent cells may be the influencing factors of the effects of senescence on tumor progression. One of the possibilities is that senescent cells are only beneficial when they are transient, and the accumulation of senescent cells and SASP cause increased susceptibility to tumorigenesis.
The in-depth understanding and utilization of senescence in cancer therapy has gained increasing attention and has become an important research field. A growing number of studies have convincingly demonstrated a paradoxical role for spontaneous senescence and therapy-induced senescence (TIS), that senescence may involve both cancer prevention and cancer aggressiveness. Previous findings have indicated that TIS is a positive outcome of therapy, since senescence is a state of growth arrest reflecting the loss of reproductive potential. In order to overcome the negative effects of TIS in cancer treatment, the concept of combining senescence-inducing therapies and removal of senescent cells, both normal and tumor derived, via senolytic therapies, or manipulating the paracrine effects of SASP is proposed. However, before clinical application, we must balance the validity and potential risks, and determine the overall advantages of this treatment concept.