Cancer Response to Therapy-Induced Senescence: A Matter of Dose and Timing

SIMPLE SUMMARY: Cellular senescence consists of a permanent block of cell proliferation in the presence of an active metabolism. It is a physiological process occurring when cells exhaust their proliferative potential, as signaled by critical telomere erosion. Additionally, cell senescence might be triggered as a response to different stresses: DNA damage, oxidative stress and oncogenic activation. Whatever the senescence-inducing stress is, a peculiarity of senescent cells is the production of an altered secretome, the Senescence-Associated Secretory Phenotype (SASP), which profoundly affects the cellular microenvironment. Cancer therapy, either ionizing radiations or chemotherapy, induces cellular senescence, the so-called therapy-induced senescence (TIS). The issue of whether TIS is a pro- or anti-tumorigenic process is a current and open question. ABSTRACT: Cellular senescence participates to fundamental processes like tissue remodeling in embryo development, wound healing and inhibition of preneoplastic cell growth. Most senescent cells display common hallmarks, among which the most characteristic is a permanent (or long lasting) arrest of cell division. However, upon senescence, different cell types acquire distinct phenotypes, which also depend on the specific inducing stimuli. Senescent cells are metabolically active and secrete a collection of growth factors, cytokines, proteases, and matrix-remodeling proteins collectively defined as senescence-associated secretory phenotype, SASP. Through SASP, senescent cells modify their microenvironment and engage in a dynamic dialog with neighbor cells. Senescence of neoplastic cells, at least temporarily, reduces tumor expansion, but SASP of senescent cancer cells as well as SASP of senescent stromal cells in the tumor microenvironment may promote the growth of more aggressive cancer subclones. Here, we will review recent data on the mechanisms and the consequences of cancer-therapy induced senescence, enlightening the potentiality and the risk of senescence inducing treatments.