Circadian disruption in experimental cancer processes.
The circadian timing system (CTS) coordinated by the suprachiasmatic nuclei (SCN) of the hypothalamus regulates daily rhythms of behavior, physiology, as well as cellular metabolism and proliferation. Altered circadian rhythms predict for poor survival in cancer patients. An increased incidence of several cancers has been reported in flight attendants and in shift workers. To explore the contribution of the CTS to tumor growth, we developed experimental models of disrupted or enhanced circadian coordination through stereotaxic destruction of the SCN, modifications of photoperiodic or feeding synchronizers and/or the administration of pharmacologic agents. SCN ablation or exposure to experimental chronic jetlag (CJL, consisting of an 8-hour advance of the light-dark cycle every 2 days) caused alterations in circadian physiology and significantly accelerated tumor growth. CJL suppressed or altered the rhythms of clock gene and cell cycle gene expression in mouse liver. It increased p53 and decreased c-Myc expression, a result in line with the promotion of diethylnitrosamine -initiated hepatocarcinogenesis in jet-lagged mice. The accelerating effect of CJL on tumor growth was counterbalanced by the regular timing of food access over the 24-h. Meal timing prevented the circadian disruption produced by CJL and slowed down tumor growth. In synchronized mice, meal timing reinforced host circadian coordination, phase-shifted the transcriptional rhythms of clock genes in the liver of tumor-bearing mice and slowed down cancer progression. These results support the role of the CTS in cancer progression and call for the development of therapeutic strategies aimed at preventing or treating circadian clock dysfunctions.
Filipski
Elisabeth
E
Hôpital Paul Brousse, Villejuif, France. elisabeth.filipski@inserm.fr
Lévi
Francis
F
D000818:Animals; D002908:Chronic Disease; D002940:Circadian Rhythm / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005502:Food; D020179:Jet Lag Syndrome / Q000150:complications* / Q000503:physiopathology; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D017440:Photoperiod; D013493:Suprachiasmatic Nucleus / Q000503:physiopathology