Filipski Elizabeth, Li Xiaoi Mei, Lévi Francis
INSERM E 354 Cancer Chronotherapeutics, Hôpital Paul Brousse, Villejuif, France.
Cancer Causes Control. 2006 May;17(4):509-14. doi: 10.1007/s10552-005-9007-4.
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.
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.
昼夜节律改变预示着转移性结直肠癌或乳腺癌患者的预后不良。据报道，空乘人员以及主要在夜间工作的女性患癌症的几率增加。为了探究昼夜节律结构对肿瘤生长的影响，我们通过完全立体定向破坏视交叉上核（SCN）或使小鼠经历实验性慢性时差反应，消除了小鼠24小时的休息-活动周期，并显著改变了其体温、血清皮质酮和淋巴细胞计数的节律。昼夜协调的这种破坏在两种可移植肿瘤模型，即格拉斯哥骨肉瘤和胰腺腺癌中显著加速了恶性肿瘤的生长。对照小鼠肝脏中生物钟基因per2和reverb-α的mRNA表达呈现出显著的昼夜节律（分别为余弦分析，p = 0.006和p = 0.003），肿瘤中也有显著节律（分别为p = 0.04和p < 0.001）。在经历时差反应的小鼠的肝脏和肿瘤中，这两种节律均受到抑制。分子生物钟的这种功能紊乱导致p53下调和c-Myc过表达，这两种效应可能有利于癌症生长。
这些结果表明昼夜节律系统可能在恶性肿瘤生长控制中发挥重要作用。在癌症预防和治疗中应考虑到这一点。
