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Review
. 2019 Oct;18(19):2385-2397.
doi: 10.1080/15384101.2019.1652047. Epub 2019 Aug 9.

Chemotherapy-induced senescence, an adaptive mechanism driving resistance and tumor heterogeneity

Jordan Guillon  1   2 , Coralie Petit  1   2 , Bertrand Toutain  1   2 , Catherine Guette  1   2 , Eric Lelièvre  1   2 , Olivier Coqueret  1   2
Affiliations
Review

Chemotherapy-induced senescence, an adaptive mechanism driving resistance and tumor heterogeneity

Jordan Guillon et al. Cell Cycle. 2019 Oct.

Abstract

Senescence is activated in response to chemotherapy to prevent the propagation of cancer cells. In transformed cells, recent studies have shown that this response is not always definitive and that persistent populations can use senescence as an adaptive pathway to restart proliferation and become more aggressive. Here we discuss the results showing that an incomplete and heterogeneous senescence response plays a key role in chemotherapy resistance. Surviving to successive chemotherapy regimens, chronically existing senescent cells can create a survival niche through paracrine cooperations with neighboring cells. This favors chemotherapy escape of premalignant clones but might also allow the survival of adjacent clones presenting a lower fitness. A better characterization of senescence heterogeneity in transformed cells is therefore necessary. This will help us to understand this incomplete response to therapy and how it could generate clones with increased tumor capacity leading to disease relapse.

Keywords: Chemotherapy; cancer relapse; drug resistance; senescence; tumor escape.

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Figures

Figure 1.
Figure 1.
A paracrine activation of STAT1 pathway by cGAS-STING and IFN induces CIS resistance in neighboring cells ? In senescent cells, cytoplasmic chromatin fragments activate the cGAS-STING pathway which results in upregulation of NFkB and IRF3 and the production of IFN. This is expected to induce the activation of the STAT1 pathway in neighboring cells which has been associated with chemotherapy resistance.
Figure 2.
Figure 2.
Chemotherapy-induced senescence is an heterogeneous response in cancer cells. In response to chemotherapy, senescence normally induces a definitive proliferative arrest. As a consequence of cell transformation, the CIS response can be incomplete, generating specific clones that restart proliferation and become more aggressive (top). CIS escape can be explained by the genetic and epigenetic modifications of transformed cells but also by non-cell autonomous interactions that allow the survival of cells with a lower fitness, either through a direct activation or through the modification of the microenvironment (bottom).
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