Filipski Elisabeth, King Verdun M, Li XiaoMei, Granda Teresa G, Mormont Marie-Christine, Liu XuHui, Claustrat Bruno, Hastings Michael H, Lévi Francis
Institut National de la Santé et de la Recherche Médicale, Equipe Propre INSERM 0118 Cancer chronotherapeutics, Université Paris XI, Paul Brousse Hospital, Villejuif, France.
J Natl Cancer Inst. 2002 May 1;94(9):690-7. doi: 10.1093/jnci/94.9.690.
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.
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.
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).
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.
由下丘脑视交叉上核（SCN）控制的昼夜节律系统调节运动活动和肾上腺皮质分泌的每日节律。这些节律的改变与转移性结直肠癌或乳腺癌患者的不良生存相关。我们建立了一个小鼠模型来研究严重昼夜节律功能障碍对肿瘤生长的影响。
通过双侧电解损伤破坏小鼠的SCN，并通过植入腹腔的无线电发射器记录身体活动和体温。测量血浆皮质酮水平和循环淋巴细胞计数（SCN损伤组n = 75，假手术组n = 64）。死后确定SCN是否完全破坏。给小鼠接种格拉斯哥骨肉瘤（SCN损伤组n = 16，假手术组n = 12）或胰腺腺癌（SCN损伤组n = 13，假手术组n = 13）肿瘤植入物，以确定昼夜节律改变对肿瘤进展的影响。通过频谱分析和余弦分析对体温和静息-活动模式的时间序列进行分析。参数数据通过方差分析（ANOVA）和对数秩检验的生存曲线进行比较。所有统计检验均为双侧检验。
与64只假手术小鼠相比，75只SCN完全破坏的小鼠的24小时静息-活动周期被消除，血清皮质酮水平和淋巴细胞计数的每日节律明显改变（皮质酮的双向ANOVA：采样时间效应P<.001，损伤效应P =.001，时间x损伤交互作用P<.001；淋巴细胞分别为P =.001、.002和.002）。75只SCN损伤小鼠中有60只的体温节律受到抑制（P<.001）。两种类型的肿瘤在SCN损伤小鼠中的生长速度比假手术小鼠快两到三倍（双向ANOVA：损伤和肿瘤效应P<.001；损伤x肿瘤效应交互作用P =.21）。与假手术小鼠相比，SCN损伤小鼠的生存期在统计学上显著缩短（对数秩P =.0062）。
小鼠昼夜节律的破坏与两种类型恶性肿瘤的加速生长相关，提示宿主昼夜节律钟可能在内源性肿瘤进展控制中起重要作用。
