What has senescence got to do with cancer?

Abstract

Cancer therapeutics are primarily thought to work by inducing apoptosis in tumor cells. However, various tumor suppressors and oncogenes have been shown to regulate senescence in normal cells, and senescence bypass appears to be an important step in the development of cancer. Cellular senescence limits the replicative capacity of cells, thus preventing the proliferation of cells that are at different stages of malignancy. A recent body of evidence suggests that induction of senescence can be exploited as a basis for cancer therapy.

Figure 1

Presenescent cells undergo senescence in response to telomeric and nontelomeric signals Telomeric signals such as telomere shortening and uncapping of telomere ends, as well as nontelomeric signals such as DNA damaging agents, oncogenic/mitogenic signaling, and undefined stress signals, induce senescence. Undefined stress signals are signals that come from a variety of sources, such as culture media. Senescent cells in culture are often identified by large, flat cell morphology, and stain positively for SA-β-gal marker.

Figure 2

Telomeric and nontelomeric signals induce senescence via tumor suppressor pathways in human and mouse cells Induction of p21 and p16 by senescence-inducing signals results in inhibition of activity of CDK2 and CDK4/6. Downregulation of activity of these pRB kinases leads to pRB hypophosphorylation, which results in cell cycle arrest during senescence. Regulators of senescence pathways in human and mouse cells include PML, MDM2, ID1, Bmi-1, CBX7, and Seladin-1. In mouse cells, tumor suppressor ARF is negatively regulated by two potential oncogenes, TBX2 and Pokemon, and positively regulated by DMP-1. A: In human cells, telomeric and nontelomeric signals induce senescence primarily via the p53-p21-pRB pathway. Nontelomeric signals also induce the p16-pRB pathway of senescence in human cells. B: Mouse cells undergo senescence via the ARF-p53-p21-pRB pathway in response to nontelomeric signals. Mouse cells do not senesce by the telomeric signal-induced pathway of senescence. Solid lines indicate principal pathways of senescence, while dotted lines indicate auxiliary pathways that can modulate senescence. The red letters indicate tumor suppressors and growth inhibitors, while the green letters indicate oncogenes and growth promoters.