Abstract
Cellular senescence is a stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stimuli, as well as developmental signals. Senescence is considered to be a highly dynamic, multi-step process, during which the properties of senescent cells continuously evolve and diversify in a context dependent manner. It is associated with multiple cellular and molecular changes and distinct phenotypic alterations, including a stable proliferation arrest unresponsive to mitogenic stimuli. Senescent cells remain viable, have alterations in metabolic activity and undergo dramatic changes in gene expression and develop a complex senescence-associated secretory phenotype. Cellular senescence can compromise tissue repair and regeneration, thereby contributing toward aging. Removal of senescent cells can attenuate age-related tissue dysfunction and extend health span. Senescence can also act as a potent anti-tumor mechanism, by preventing proliferation of potentially cancerous cells. It is a cellular program which acts as a double-edged sword, with both beneficial and detrimental effects on the health of the organism, and considered to be an example of evolutionary antagonistic pleiotropy. Activation of the p53/p21WAF1/CIP1 and p16INK4A/pRB tumor suppressor pathways play a central role in regulating senescence. Several other pathways have recently been implicated in mediating senescence and the senescent phenotype. Herein we review the molecular mechanisms that underlie cellular senescence and the senescence associated growth arrest with a particular focus on why cells stop dividing, the stability of the growth arrest, the hypersecretory phenotype and how the different pathways are all integrated.
Highlights
Cellular senescence, a seminal discovery of Hayflick and Moorhead (1961) is a process that globally regulates cell fate and can be considered a hallmark of aging (Hayflick and Moorhead, 1961; López-Otín et al, 2013)
senescence-associated secretory phenotype (SASP) mediated autocrine and paracrine signaling that reinforces senescence contribute to tumor suppressive functions of SASP by limiting the proliferation of cells at risk followed by immune clearance of the premalignant cells (Acosta et al, 2008, 2013; Kuilman et al, 2008; Wajapeyee et al, 2008; Kang et al, 2011; Hubackova et al, 2012; Nelson et al, 2012; Toso et al, 2014)
Inflammatory SASP components and accumulation of immature immunosuppressive myeloid cells in solid tumors promote tumorigenesis by driving cell migration, growth, invasion, angiogenesis and eventually metastasis (Krtolica et al, 2001; Coppé et al, 2006; Yoshimoto et al, 2013; Di Mitri et al, 2014; Eggert et al, 2016; Demaria et al, 2017; Kim Y.H. et al, 2017; Chen et al, 2018). This demonstrates the multifaceted interaction between SASP, immune cells and cancer, in accordance with Eggert et al (2016), where in the initial stages, SASP mediated recruitment of immature myeloid cells which when differentiated into macrophages clear the premalignant senescence cells to prevent cancer initiation
Summary
A seminal discovery of Hayflick and Moorhead (1961) is a process that globally regulates cell fate and can be considered a hallmark of aging (Hayflick and Moorhead, 1961; López-Otín et al, 2013). We detail the complexity of the mechanisms involved in SASP regulation, focus on the key mediators, characteristic hallmarks and the different pathways involved in manifesting cellular senescence as well as the cell cycle arrest and its key regulators along with the role of the DREAM complex and its associated components.
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