Abstract
Cellular senescence was first described as a physiological tumor cell suppressor mechanism that leads to cell growth arrest with production of the senescence-associated secretory phenotype known as SASP. The main role of SASP in physiological conditions is to attract immune cells to clear senescent cells avoiding tumor development. However, senescence can be damage-associated and, depending on the nature of these stimuli, additional types of senescence have been described. In the context of cancer, damage-associated senescence has been described as a consequence of chemotherapy treatments that were initially thought of as a tumor suppressor mechanism. However, in certain contexts, senescence after chemotherapy can promote cancer progression, especially when immune cells become senescent and cannot clear senescent tumor cells. Moreover, aging itself leads to continuous inflammaging and immunosenescence which are responsible for rewiring immune cells to become defective in their functionality. Here, we define different types of senescence, pathways that activate them, and functions of SASP in these events. Additionally, we describe the role of senescence in cancer and its treatments, including how aging and chemotherapy contribute to senescence in tumor cells, before focusing on immune cell senescence and its role in cancer. Finally, we discuss potential therapeutic interventions to reverse cell senescence.
Highlights
Cellular senescence is a cell fate that has the defining feature of stable growth arrest that is refractory to mitogenic stimulation
Cellular senescence was first described as a physiological tumor cell suppressor mechanism that leads to cell growth arrest with production of the senescence-associated secretory phenotype known as senescence-associated secretory phenotypes (SASP)
The SASP can be a double-edged sword in cancer treatment, as it is required by immune cells to mediate antitumor responses [27,28,29] promoting “senescence surveillance” and preventing tumor initiation [30,31], and at chronic levels and pathological conditions such as established tumors, SASP components, such as vascular endothelial growth factor (VEGF), CCL5, and IL-6, can induce cancer, drug resistance, cancer progression, and associated side effects such as cachexia [20,32,33,34,35,36,37,38,39,40,41]
Summary
Cellular senescence is a cell fate that has the defining feature of stable growth arrest that is refractory to mitogenic stimulation. Senescence was first identified in vitro by Hayflick and Moorhead in 1961 when they observed during serial passage of human diploid fibroblasts that these cultures had limited replicative potential, becoming irreversibly arrested [3] This impaired proliferation seemed to be associated with a progressive shortage of telomeres, which induced a persistent DNA damage response (DDR) and activated signals including p53 and p16 [4]. Physiological cellular senescence occurring both during normal embryonic development and upon tissue damage follows a cycle of “senescence–clearance–regeneration” to trigger tissue remodeling and removal of senescent cells maintaining tissue homeostasis. This cycle is achieved with the help of the immune system that performs clearance of senescent cells. During aging, which is a relevant risk factor for cancer, a decline in the immune response termed “immunosenescence” causes these stages to not complete, compromising the clearance of senescent cells and exacerbating inflammation with detrimental effects [7,11]
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