Exploiting tumor cell senescence in anticancer therapy

Abstract

Cellular senescence is a physiological process of irreversible cell-cycle arrest that contributes to various physiological and pathological processes of aging. Whereas replicative senescence is associated with telomere attrition after repeated cell division, stress-induced premature senescence occurs in response to aberrant oncogenic signaling, oxidative stress, and DNA damage which is independent of telomere dysfunction. Recent evidence indicates that cellular senescence provides a barrier to tumorigenesis and is a determinant of the outcome of cancer treatment. However, the senescence-associated secretory phenotype, which contributes to multiple facets of senescent cancer cells, may influence both cancer-inhibitory and cancer-promoting mechanisms of neighboring cells. Conventional treatments, such as chemo- and radiotherapies, preferentially induce premature senescence instead of apoptosis in the appropriate cellular context. In addition, treatment-induced premature senescence could compensate for resistance to apoptosis via alternative signaling pathways. Therefore, we believe that an intensive effort to understand cancer cell senescence could facilitate the development of novel therapeutic strategies for improving the efficacy of anticancer therapies. This review summarizes the current understanding of molecular mechanisms, functions, and clinical applications of cellular senescence for anticancer therapy.

Fig. 1.. Stress-induced premature senescence (SIPS) signaling pathway. A variety of stimuli, such as telomere erosion, DNA damage, oncogene activation, oxidative stress, anticancer drugs and ionizing radiation, induce cell-cycle arrest and transcription of senescence-associated genes. Senescence signaling and growth arrest-response signaling pathways have been shown to overlap. Upon sensing senescence signals, the cell cycle checkpoint machinery can force the cell to exit the cell cycle via the CDK4 inhibitor p16 and the MDM2 inhibitor ARF. Senescence-inducing stimuli lead to upregulation of p21, which blocks the cyclin D/CDK4-mediated hyperphosphorylation of pRb, and provokes cell cycle arrest and, ultimately, cellular senescence. Alternatively, these events induce ARF, which blocks the activity of the p53 inhibitor MDM2 and thereby activates p53. One of the characteristics of senescent cells is a change in morphology, such as enlargement, flattening, and increased granularity. In addition, senescent cells or tissue exhibit increased activity of senescence-associated β-galactosidase (SA-β-gal), a reliable biomarker of senescence.

Fig. 2.. Pleiotropic nature of senescent cells. Senescent cancer cells positively and negatively affect the tumor microenvironment. In particular, the senescence-associated secretory phenotype (SASP) contributes to maintenance of the senescent state and the growth arrest (autocrine effect) of senescent cells. Senescent cells also exhibit pro-inflammatory responses through the production of cytokines and chemokines. In addition to inflammatory factors, matrix-remodeling factors alter the tissue microenvironment and enhance cancer cell proliferation, angiogenesis, and metastasis. Anti-inflammatory cytokines, which are released into the extracellular compartment by senescent cells, mediate the elimination of tumor cells by recruiting immune cells to the tumor tissues. On the other hand, pro-inflammatory cytokines exert a cancer-promoting activity on nearby cancer cells by enhancing tumorigenesis (paracrine effects).