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Cell Biology International (2008) 32, 1031–1043 (Printed in Great Britain)

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Tumor cells can escape DNA-damaging cisplatin through DNA endoreduplication and reversible polyploidy

Pierre‑Emmanuel Puig^ab, Marie‑Noëlle Guilly^c, André Bouchot^d, Nathalie Droin^ab, Dominique Cathelin^ab, Florence Bouyer^ab, Laure Favier^a, François Ghiringhelli^ab, Guido Kroemer^e, Eric Solary^ab, François Martin^ab and Bruno Chauffert^abf*

^aINSERM, UMR 866, F-21079 Dijon, France
^bUniversity of Burgundy, F-21079 Dijon, France
^cCEA, DSV, iRCM, SREIT, LCE, F-92265 Fontenay-aux-Roses, France
^dUniversity of Burgundy, IFR 100, Plateau Technique d'Imagerie Cellulaire, F-21079 Dijon, France
^eINSERM, UMR 848, Institut Gustave Roussy, F-94805 Villejuif, France
^fCentre de Lutte contre le Cancer GF Leclerc, F-21079 Dijon, France

Abstract

Cancer chemotherapy can induce tumor regression followed, in many cases, by relapse in the long-term. Thus this study was performed to assess the determinants of such phenomenon using an in vivo cancer model and in vitro approaches. When animals bearing an established tumor are treated by cisplatin, the tumor initially undergoes a dramatic shrinkage and is characterized by giant tumor cells that do not proliferate but maintain DNA synthesis. After several weeks of latency, the tumor resumes its progression and consists of small proliferating cells. Similarly, when tumor cells are exposed in vitro to pharmacological concentrations of cisplatin, mitotic activity stops initially but cells maintain DNA duplication. This DNA endoreduplication generates giant polyploid cells that then initiate abortive mitoses and can die through mitotic catastrophe. However, many polyploid cells survive for weeks as non-proliferating mono- or multi-nucleated giant cells which acquire a senescence phenotype. Prolonged observation of these cells sheds light on the delayed emergence of a limited number of extensive colonies which originate from polyploid cells, as demonstrated by cell sorting analysis. Theses colonies are made of small diploid cells which differ from parental cells by stereotyped chromosomal aberrations and an increased resistance to cytotoxic drugs. These data suggest that a multistep pathway, including DNA endoreduplication, polyploidy, then depolyploidization and generation of clonogenic escape cells can account for tumor relapse after initial efficient chemotherapy.

Key words: Cancer, Chemotherapy, Resistance, Polyploidy, Endoreduplication, Mitotic catastrophe.

^*Corresponding author. Pr. INSERM, UMR 866, Faculté de Médecine, 7 Bvd Jeanne d'Arc, BP 87900, F-21079 Dijon, France. Tel.: +33 380 393 353; fax: +33 380 393 434.

Received 22 January 2008/21 March 2008; accepted 25 April 2008