Disruption of circadian coordination and malignant growth.
Altered circadian rhythms predicted for poor survival in patients with metastatic colorectal or breast cancer. An increased incidence of cancers has been reported in flying attendants and in women working predominantly at night. To explore the contribution of circadian structure to tumor growth we ablated the 24-h rest-activity cycle and markedly altered the rhythms in body temperature, serum corticosterone and lymphocyte count in mice by complete stereotaxic destruction of the suprachiasmatic nuclei (SCN) or by subjecting the mice to experimental chronic jet-lag. Such disruption of circadian coordination significantly accelerated malignant growth in two transplantable tumor models, Glasgow osteosarcoma and Pancreatic adenocarcinoma. The mRNA expression of clock genes per2 and reverb-alpha in controls displayed significant circadian rhythms in the liver (Cosinor, p=0.006 and p=0.003, respectively) and in the tumor (p=0.04 and p<0.001, respectively). Both rhythms were suppressed in the liver and in the tumor of jet lagged mice. This functional disturbance of molecular clock resulted in down regulation of p53 and overexpression of c-Myc, two effects which may favor cancer growth.


CONCLUSIONS
These results indicate that circadian system could play an important role in malignant growth control. This should be taken into consideration in cancer prevention and therapy.
Filipski
Elizabeth
E
INSERM E 354 Cancer Chronotherapeutics, Hôpital Paul Brousse, Villejuif, France. filipski@vjf.inserm.fr
Li
Xiaoi Mei
XM
Lévi
Francis
F
D000818:Animals; D001683:Biological Clocks; D001831:Body Temperature; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D021081:Chronobiology Disorders / Q000150:complications* / Q000503:physiopathology; D002940:Circadian Rhythm; D003345:Corticosterone / Q000097:blood; D004268:DNA-Binding Proteins / Q000378:metabolism; D020179:Jet Lag Syndrome / Q000150:complications / Q000503:physiopathology; D018655:Lymphocyte Count; D051379:Mice; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D012516:Osteosarcoma / Q000473:pathology* / Q000503:physiopathology; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D056950:Period Circadian Proteins; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000503:physiopathology; D014157:Transcription Factors / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C498262:Nr1d1 protein, mouse; D009687:Nuclear Proteins; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D003345:Corticosterone