Host circadian clock as a control point in tumor progression.
BACKGROUND
The circadian timing system controlled by the suprachiasmatic nuclei (SCN) of the hypothalamus regulates daily rhythms of motor activity and adrenocortical secretion. An alteration in these rhythms is associated with poor survival of patients with metastatic colorectal or breast cancer. We developed a mouse model to investigate the consequences of severe circadian dysfunction upon tumor growth.


METHODS
The SCN of mice were destroyed by bilateral electrolytic lesions, and body activity and body temperature were recorded with a radio transmitter implanted into the peritoneal cavity. Plasma corticosterone levels and circulating lymphocyte counts were measured (n = 75 with SCN lesions, n = 64 sham-operated). Complete SCN destruction was ascertained postmortem. Mice were inoculated with implants of Glasgow osteosarcoma (n = 16 with SCN lesions, n = 12 sham-operated) or pancreatic adenocarcinoma (n = 13 with SCN lesions, n = 13 sham-operated) tumors to determine the effects of altered circadian rhythms on tumor progression. Time series for body temperature and rest-activity patterns were analyzed by spectral analysis and cosinor analysis. Parametric data were compared by the use of analysis of variance (ANOVA) and survival curves with the log-rank test. All statistical tests were two-sided.


RESULTS
The 24-hour rest-activity cycle was ablated and the daily rhythms of serum corticosterone level and lymphocyte count were markedly altered in 75 mice with complete SCN destruction as compared with 64 sham-operated mice (two-way ANOVA for corticosterone: sampling time effect P<.001, lesion effect P =.001, and time x lesion interaction P<.001; for lymphocytes P =.001,.002, and.002 respectively). Body temperature rhythm was suppressed in 60 of the 75 mice with SCN lesions (P<.001). Both types of tumors grew two to three times faster in mice with SCN lesions than in sham-operated mice (two-way ANOVA: P<.001 for lesion and for tumor effects; P =.21 for lesion x tumor effect interaction). Survival of mice with SCN lesions was statistically significantly shorter compared with that of sham-operated mice (log-rank P =.0062).


CONCLUSIONS
Disruption of circadian rhythms in mice was associated with accelerated growth of malignant tumors of two types, suggesting that the host circadian clock may play an important role in endogenous control of tumor progression.
Filipski
Elisabeth
E
Institut National de la Santé et de la Recherche Médicale, Equipe Propre INSERM 0118 Cancer chronotherapeutics, Université Paris XI, Paul Brousse Hospital, Villejuif, France.
King
Verdun M
VM
Li
XiaoMei
X
Granda
Teresa G
TG
Mormont
Marie-Christine
MC
Liu
XuHui
X
Claustrat
Bruno
B
Hastings
Michael H
MH
Lévi
Francis
F
D000230:Adenocarcinoma / Q000503:physiopathology*; D000818:Animals; D001831:Body Temperature; D001835:Body Weight; D002940:Circadian Rhythm / Q000502:physiology*; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D012516:Osteosarcoma / Q000503:physiopathology*; D012878:Skin Neoplasms / Q000503:physiopathology*; D013493:Suprachiasmatic Nucleus / Q000502:physiology / Q000601:surgery
D003345:Corticosterone