Tumor cells can escape DNA-damaging cisplatin through DNA endoreduplication and reversible polyploidy.
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.
Puig
Pierre-Emmanuel
PE
INSERM, UMR 866, F-21079 Dijon, France.
Guilly
Marie-Noëlle
MN
Bouchot
André
A
Droin
Nathalie
N
Cathelin
Dominique
D
Bouyer
Florence
F
Favier
Laure
L
Ghiringhelli
François
F
Kroemer
Guido
G
Solary
Eric
E
Martin
François
F
Chauffert
Bruno
B
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000473:pathology*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004171:Diploidy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D020440:Gene Duplication / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects; D010641:Phenotype; D011123:Polyploidy; D051381:Rats; D013997:Time Factors; D019139:Tumor Escape / Q000187:drug effects*
D004273:DNA, Neoplasm; D001973:Bromodeoxyuridine; D002945:Cisplatin