Abstract
BackgroundCell proliferation in all rapidly renewing mammalian tissues follows a circadian rhythm that is often disrupted in advanced-stage tumors. Epidemiologic studies have revealed a clear link between disruption of circadian rhythms and cancer development in humans. Mice lacking the circadian genes Period1 and 2 (Per) or Cryptochrome1 and 2 (Cry) are deficient in cell cycle regulation and Per2 mutant mice are cancer-prone. However, it remains unclear how circadian rhythm in cell proliferation is generated in vivo and why disruption of circadian rhythm may lead to tumorigenesis.Methodology/Principal FindingsMice lacking Per1 and 2, Cry1 and 2, or one copy of Bmal1, all show increased spontaneous and radiation-induced tumor development. The neoplastic growth of Per-mutant somatic cells is not controlled cell-autonomously but is dependent upon extracellular mitogenic signals. Among the circadian output pathways, the rhythmic sympathetic signaling plays a key role in the central-peripheral timing mechanism that simultaneously activates the cell cycle clock via AP1-controlled Myc induction and p53 via peripheral clock-controlled ATM activation. Jet-lag promptly desynchronizes the central clock-SNS-peripheral clock axis, abolishes the peripheral clock-dependent ATM activation, and activates myc oncogenic potential, leading to tumor development in the same organ systems in wild-type and circadian gene-mutant mice.Conclusions/SignificanceTumor suppression in vivo is a clock-controlled physiological function. The central circadian clock paces extracellular mitogenic signals that drive peripheral clock-controlled expression of key cell cycle and tumor suppressor genes to generate a circadian rhythm in cell proliferation. Frequent disruption of circadian rhythm is an important tumor promoting factor.
Highlights
Disruption of circadian rhythm increases spontaneous and carcinogen-induced mammary tumors in rodents [1,2,3,4,5,6]
We found that when kept in 24 hour alternating light-dark conditions (24hr LD cycles), mice deficient in Bmal1 (Bmal1+/2), Cry1 and Cry2 (Cry12/2;Cry22/2), Per1 and Per2 (Per12/2;Per2m/m) or Per2 alone (Per22/2) were all cancer-prone
Bmal1+/2, Cryptochrome1 and 2 (Cry)- and Period1 and 2 (Per)-mutant mice all showed increased risk of ulcerative dermatitis and hyperplasia in the salivary gland, preputial gland, liver and uterus as well as spontaneous lymphoma, liver and ovarian tumor development, spontaneous tumors in Cry-mutants were mostly identified after 50 weeks of age, later than that of Per12/2; Per2m/m and Per22/2 mice (Fig. 1a, Table 1, Fig. S1a and data not shown)
Summary
Disruption of circadian rhythm increases spontaneous and carcinogen-induced mammary tumors in rodents [1,2,3,4,5,6]. Loss of circadian rhythm is associated with accelerated tumor growth in both rodents and human cancer patients [13,14,15]. The SCN clock responds to external cues and drives peripheral clocks via circadian output pathways Both the central and peripheral clocks are operated by feedback loops of circadian genes, including Bmal, Clock, Period (Per1-3) and Cryptochrome (Cry and 2). Mice lacking the circadian genes Period and 2 (Per) or Cryptochrome and 2 (Cry) are deficient in cell cycle regulation and Per mutant mice are cancer-prone. It remains unclear how circadian rhythm in cell proliferation is generated in vivo and why disruption of circadian rhythm may lead to tumorigenesis
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