Date Published: November 19, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Boyi Zhang, Eric W.‐F. Lam, Yu Sun.
Cellular senescence is a typical tumor‐suppressive mechanism that restricts the proliferation of premalignant cells. However, mounting evidence suggests that senescent cells, which also persist in vivo, can promote the incidence of aging‐related disorders principally via the senescence‐associated secretory phenotype (SASP), among which cancer is particularly devastating. Despite the beneficial effects of the SASP on certain physiological events such as wound healing and tissue repair, more studies have demonstrated that senescent cells can substantially contribute to pathological conditions and accelerate disease exacerbation, particularly cancer resistance, relapse and metastasis. To limit the detrimental properties while retaining the beneficial aspects of senescent cells, research advancements that support screening, design and optimization of anti‐aging therapeutic agents are in rapid progress in the setting of prospective development of clinical strategies, which together represent a new wave of efforts to control human malignancies or mitigate degenerative complications.
In response to various intrinsic and/or extrinsic stimuli, cells enter an essentially irreversible senescent state, which is regulated and maintained by the p53/p21CIP1 and p16INK4a/pRB pathways to prevent the occurrence of sporadic events, particularly transformation. Senescent cells display several distinct features including a flattened and enlarged morphology, DNA segments with chromatin alterations reinforcing senescence (DNA SCARS), nuclear heterochromatin foci and senescence‐associated β‐galactosidase (SA‐β‐Gal) activity (Ozcan et al., 2016). However, senescent cells are frequently implicated in multiple disorders, mainly through secretion of numerous bioactive molecules, a distinctive phenomenon found a decade ago and termed as the senescence‐associated secretory phenotype (SASP; Acosta et al., 2008; Coppe et al., 2008; Kuilman et al., 2008). The full SASP spectrum comprises a myriad of soluble factors including pro‐inflammatory cytokines, chemokines, growth factors and proteases, whose functional involvement can be classified into several aspects including but not limited to extracellular matrix formation, metabolic processes, ox‐redox events and gene expression regulation (Ozcan et al., 2016). The SASP promotes embryonic development, tissue repair and wound healing, serving as an evolutionarily adapted mechanism in maintaining tissue and/or organ homeostasis (Davaapil, Brockes, & Yun, 2017; Demaria et al., 2014; Jun & Lau, 2010; Munoz‐Espin et al., 2013; Storer et al., 2013). Senescent cells communicate with their surrounding environment by expressing the SASP, with the potential to boost immune surveillance by mounting specific inflammatory responses including those mediated by CD4+ T cells against antigens expressed in senescent cells, particularly those observed in premalignant lesions (Georgilis et al., 2018; Kang et al., 2011; Toso et al., 2014). Although the SASP is beneficial to several health‐associated events, more evidence has showed that it actively contributes to the formation of a pro‐carcinogenic tumor microenvironment (TME). Long‐term secretion of the SASP factors by senescent cells can impair the functional integrity of adjacent normal cells in the local tissue, serving as a major cause of chronic inflammation which drives aging‐related degeneration of multiple organs (He & Sharpless, 2017). Thus, senescent cells and their unique phenotype, the SASP, can be defined as a form of antagonistic pleiotropy, a property that is beneficial in early life and during tissue turnover, but deleterious over time with advanced age, making both mechanistic investigation and therapeutic intervention of paramount significance in current era of precision medicine.