Cellular senescence: putting the paradoxes in perspective

Abstract

Cellular senescence arrests the proliferation of potential cancer cells, and so is a potent tumor suppressive mechanism, akin to apoptosis. Or is it? Why did cells evolve an anti-cancer mechanism that arrests, rather than kills, would-be tumor cells? Recent discoveries that senescent cells secrete growth factors, proteases and cytokines provide a shifting view--from senescence as a cell autonomous suppressor of tumorigenesis to senescence as a means to mobilize the systemic and local tissue milieu for repair. In some instances, this mobilization benefits the organism, but in others it can be detrimental. These discoveries provide potential mechanisms by which cellular senescence might contribute to the diverse, and seemingly incongruent, processes of tumor suppression, tumor promotion, tissue repair, and aging.

Figure 1. Characteristics and documented presence of senescent cells

Potentially oncogenic stimuli induce cellular senescence via activation of the p53 and pRB tumor suppressor pathways. The senescent phenotype develops over several days in culture, and, depending on the type of cell and stimulus, includes expression of SA-Bgal activity and p16INK4a, development of DNA-SCARS that provide continuous DDR signals and SAHF, and the expression of a SASP. To varying extents, these senescence-associated characteristics have been used to identify senescent cells in vivo in mouse, non-human primate and human tissues. Conditions under which senescence cells have been identified in vivo include normal aging, damaged or wounded tissues, degenerative pathologies of aging, and hyperplastic, preneoplastic and early neoplastic lesions.

Figure 2. Selected and unselected activities of senescent cells

Cellular senescence contributes to four biological processes through the cell autonomous growth arrest and paracrine activities of the SASP. We hypothesize that the growth arrest and SASP are selected traits that ensure tumor suppression and facilitate tissue repair, respectively. However, the SASP also has unselected activities that can cause or contribute to tumor promotion and aging.