Four faces of cellular senescence - PubMed (original) (raw)

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Four faces of cellular senescence

Francis Rodier et al. J Cell Biol. 2011.

Abstract

Cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. Recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. In addition to suppressing tumorigenesis, cellular senescence might also promote tissue repair and fuel inflammation associated with aging and cancer progression. Thus, cellular senescence might participate in four complex biological processes (tumor suppression, tumor promotion, aging, and tissue repair), some of which have apparently opposing effects. The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks.

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Figures

Figure 1.

Figure 1.

Hallmarks of senescent cells. Senescent cells differ from other nondividing (quiescent, terminally differentiated) cells in several ways, although no single feature of the senescent phenotype is exclusively specific. Hallmarks of senescent cells include an essentially irreversible growth arrest; expression of SA-Bgal and p16INK4a; robust secretion of numerous growth factors, cytokines, proteases, and other proteins (SASP); and nuclear foci containing DDR proteins (DNA-SCARS/TIF) or heterochromatin (SAHF). The pink circles in the nonsenescent cell (left) and senescent cell (right) represent the nucleus.

Figure 2.

Figure 2.

Biological activities of cellular senescence. Senescent cells arrest growth owing to cell autonomous mechanisms, imposed by the p53 and p16INK4a/pRB tumor suppressor pathways, and cell nonautonomous mechanisms, imposed by some of the proteins that comprise the SASP. The growth arrest is the main feature by which cellular senescence suppresses malignant tumorigenesis but can contribute to the depletion of proliferative (stem/progenitor) cell pools. Additionally, components of the SASP can promote tumor progression, facilitate wound healing, and, possibly, contribute to aging.

Figure 3.

Figure 3.

Temporal organization of the senescent phenotype. Upon experiencing a potentially oncogenic insult, cells assess the stress and must “decide” whether to attempt repair and recovery, or undergo senescence. After an interval (decision period), the length of which is imprecisely known, the senescence growth arrest becomes essentially permanent, effectively suppressing the ability of the stressed cell to form a malignant tumor. One early manifestation of the senescent phenotype is the expression of cell surface–bound IL-1α. This cytokine acts in a juxtacrine manner to bind the cell surface–bound IL-1 receptor, which initiates a signaling cascade that activates transcription factors (NF-κB, C/EBPβ). The transcription factors subsequently stimulate the expression of many secreted (SASP) proteins, including increasing the expression of IL-1α and inducing expression of the inflammatory cytokines IL-6 and IL-8. These positive cytokine feedback loops intensify the SASP until it reaches levels found in senescent cells. SASP components such as IL-6, IL-8, and MMPs can promote tissue repair, but also cancer progression. Some SASP proteins, in conjunction with cell surface ligands and adhesion molecules expressed by senescent cells, eventually attract immune cells that kill and clear senescent cells. A late manifestation of the senescent phenotype is the expression of microRNAs (mir-146a and mir-146b), which tune down the expression IL-6, IL-8, and possibly other SASP proteins, presumably to prevent the SASP from generating a persistent acute inflammatory response. Despite this dampening effect, the SASP can nonetheless continue to generate low-level chronic inflammation. The accumulation of senescent cells that either escape or outpace immune clearance and express a SASP at chronic low levels is hypothesized to drive aging phenotypes. Thus, senescent cells, over time (yellow line), develop a phenotype that becomes increasingly complex (blue triangle), with both beneficial (tumor suppression and tissue repair) and deleterious (tumor promotion and aging) effects on the health of the organism.

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