Short-term gain, long-term pain: the senescence life cycle and cancer

Abstract

Originally thought of as a stress response end point, the view of cellular senescence has since evolved into one encompassing a wide range of physiological and pathological functions, including both protumorignic and antitumorigenic features. It has also become evident that senescence is a highly dynamic and heterogenous process. Efforts to reconcile the beneficial and detrimental features of senescence suggest that physiological functions require the transient presence of senescent cells in the tissue microenvironment. Here, we propose the concept of a physiological "senescence life cycle," which has pathological consequences if not executed in its entirety.

Keywords: cancer; epigenetics; inflammation; senescence.

Figure 1.

Senescence “life cycle.” Phases of the “senescence life cycle”: Cells undergo senescence in response to stress in normal (noncancerous) tissues. As part of the senescence program, the secretome is modified to include up-regulation of proinflammatory cytokines and chemokines, which modulate the tissue microenvironment. This recruits immune cells and facilitates clearance of senescent cells, mediating resolution and restoring tissue homeostasis. Deviation from this fail-safe mechanism can instead lead to age-related pathology or cancer. In some cases, cells become activated/proliferative before senescence establishment, and senescence signaling can be amplified locally through nonautonomous activities (for simplicity, these points are not reflected in the figure).

Figure 2.

OIS as a model of spontaneous up-regulation of somatically mutated oncogenic signaling. Using oncogenic Ras as an example, an age-dependent increase of somatic mutation of oncogenes and their clonal expansion are common, but high-levels of oncogenic signaling are necessary for both OIS and full malignant transformation. Typically, spontaneous up-regulation of oncogenic signaling (to the levels sufficient for malignancy) triggers the OIS program, which is tumor-suppressive as long as the “senescence life cycle” is executed to completion. Conversely, failure to clear OIS cells can be tumor-promoting, as these cells are at risk of senescence escape, having acquired tumor-facilitating cellular changes as well as having shaped a protumorigenic microenvironment.

Figure 3.

Multiple nonunidirectional levels through which autophagy-related processes in senescence affect regulation of SASP genes, often via NFkB activation. Activation of macroautophagy as an effector of senescence and spatial coupling of mTOR with autolysosomes lead to mTOR activation, which has been proposed to modulate SASP expression through multiple mechanisms. Autophagy-mediated degradation of Lamin B1 also promotes CCF formation, which up-regulates SASP genes through the cGAS–STING pathway. This has been suggested to occur by both nuclear membrane blebbing, which shuttles LADs to the cytoplasm, and loss of nuclear envelope integrity, which allows the escape of chromatin fragments. However, the activation of general autophagy during senescence is accompanied by an inhibition of p62-mediated selective autophagy, allowing stabilization of the GATA4 transcription factor, which regulates SASP genes via NFkB.