Context-dependent effects of cellular senescence in cancer development

Abstract

Cellular senescence is an established tumour-suppressive mechanism that prevents the proliferation of premalignant cells. However, several lines of evidence show that senescent cells, which often persist in vivo, can also promote tumour progression in addition to other age-related pathologies via the senescence-associated secretory phenotype (SASP). Moreover, new insights suggest the SASP can facilitate tissue repair. Here, we review the beneficial and detrimental roles of senescent cells, highlighting conditions under which the senescence response does and does not promote pathology, particularly cancer. By better understanding the context-dependent effects of cellular senescence, it may be feasible to limit its detrimental properties while preserving its beneficial effects, and develop novel therapeutic strategies to prevent or treat cancer and possibly other age-associated diseases.

Figure 1

Bright and dark sides of cellular senescence.The bright side (left). Senescence growth arrest prevents tumorigenesis (senescence growth arrest effects=blue arrows). Senescence also limits fibrosis by preventing proliferation of cells that secrete ECM, whereas the SASP includes matrix metalloproteinases that digest fibrotic lesions (SASP effects=red arrows). Certain features of normal embryonic development are promoted by senescent cells, though it is unclear if this is dependent on the SASP. Components of the SASP accelerate wound closure and attract immune cells. The dark side (right). The loss of proliferative potential that accompanies senescence impairs tissue regeneration and promotes aging, whereas the SASP also promotes aging at least in part by inducing a chronic inflammatory state in the tissue microenvironment. The SASP also contains factors that promote angiogenesis, cell proliferation, and cancer cell invasiveness. Furthermore, immune cells attracted by the SASP can disrupt the local microenvironment and promote tumour cell invasion. These final activities result in cancer progression.