Cytokine-induced ‘bystander’ senescence in DDR and immuno-surveillance

Zdenek Hodny,Sona Hubackova,Jiri Bartek

doi:10.18632/oncotarget.1487

Abstract

Cells with damaged and unrepaired genomes represent a potential threat for the organism and therefore their elimination is beneficial. The biological safeguard barriers responsible for elimination of such hazardous cells rely on two principles: intrinsic - achieved through cellular senescence/apoptosis, and extrinsic - performed by the immune system. The concept of immune system-mediated clearance of senescent cells is well established [1], however the exact mechanisms and modes of mutual interplay between cellular senescence and immune surveillance are only emerging. Research performed in the last two decades shows that cellular senescence as an essentially irreversible block of cell proliferation can be triggered or bypassed via manipulation of expression levels of several dozens of genes indicating the complexity and redundancy of regulatory machineries controlling this antitumor barrier. While the regulatory circuits are not understood in much detail, the unifying feature of cellular senescence is the activation of cell cycle checkpoints that block cell-cycle progression at G1/S or G2/M boundary. Checkpoint activation reflects suprathreshold long-term expression, commonly triggered by persistent DNA damage response (DDR) signaling, of protein inhibitors of cyclin-dependent kinases (CDKs), the key drivers of cell-cycle progression. The multiple pathways leading to the induction of individual (or several) inhibitors of CDKs (CDKi) form the basis for redundancy of mechanisms for induction and maintenance of senescence. The robustness of response, manifested as the possibility to impose senescence even in tumor cells lacking two pivotal senescence mediators p53 and Rb, stems from the fact that the regulatory circuits are interconnected by numerous cross-talks of signaling pathways and several feedback mechanisms [2].

Highlights

Research performed in the last two decades shows that cellular senescence as an essentially irreversible block of cell proliferation can be triggered or bypassed via manipulation of expression levels of several dozens of genes indicating the complexity and redundancy of regulatory machineries controlling this antitumor barrier
Cytokines secreted by senescent cells play here the important role in shaping the senescent phenotype by autocrine and paracrine signaling and reinforcing the cell-cycle block by secondary induction of diverse CDKi, and, as Hubackova et al reported recently [3], by causing genotoxic stress capable of inducing cellular senescence per se (Fig. 1)
Exposure of BJ fibroblasts in vitro to either of the two cytokines led to development of persistent DNA damage response (DDR) originating from increased cellular levels of reactive oxygen species (ROS)

Summary

Introduction

Research performed in the last two decades shows that cellular senescence as an essentially irreversible block of cell proliferation can be triggered or bypassed via manipulation of expression levels of several dozens of genes indicating the complexity and redundancy of regulatory machineries controlling this antitumor barrier. Cytokines secreted by senescent cells play here the important role in shaping the senescent phenotype by autocrine and paracrine signaling and reinforcing the cell-cycle block by secondary induction of diverse CDKi, and, as Hubackova et al reported recently [3], by causing genotoxic stress capable of inducing cellular senescence per se (Fig. 1). Exposure of BJ fibroblasts in vitro to either of the two cytokines led to development of persistent DDR originating from increased cellular levels of reactive oxygen species (ROS).

Results

Conclusion