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Echappement à la chimiothérapie et émergence de cellules plus agressives : Importance de l’hétérogénéité tumorale

Abstract : Activated by chemotherapy, senescence is a suppressive response which prevents cell cycle progress through activation of the p53-p21 and p16-Rb signaling pathways. However, despite the efficiency of this suppression, cancer cells can emerge to induce clinical relapse. In this study, we analyzed senescence escape in response to irinotecan, one of the first line treatment used in colorectal cancer. After treatment, senescence is induced in LS174T cell but a subpopulation of cells finally resume proliferation. Persistent cells (PLCs) are composed of an heterogenous mixture of senescent (PLS) and dividing cells (PLD). In spite of PLS, PLCs are able to grow in vivo as efficiently as parental LS174T cells. Importantly, persistence induced the emergence of more transformed cells characterized by the ability to grow in low adhesion conditions. PLD emergence and anoikis resistance depend on Mcl-1, Bcl-xL and p21. PLD and PLS enrichment, by flow cytometry, allowed us to identify PLS as essential for anoikis resistance. Our results suggest that PLS establish a favorable environment for the transformation of unaffected cells. Mcl-1 and Bcl-xL role in each population remains to be determined, but inhibitors of these protein used in combination with irinotecan should restrict the heterogeneity of the response and tumoral aggressiveness.
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Barbara Jonchère. Echappement à la chimiothérapie et émergence de cellules plus agressives : Importance de l’hétérogénéité tumorale. Médecine humaine et pathologie. Université d'Angers, 2014. Français. ⟨NNT : 2014ANGE0008⟩. ⟨tel-01228521⟩

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