Daily timed meals dissociate circadian rhythms in hepatoma and healthy host liver

Abstract

Dividing cells, including human cancers, organize processes necessary for their duplication according to circadian time. Recent evidence has shown that disruption of central regulation of circadian rhythms can increase the rate at which a variety of cancers develop in rodents. To study circadian rhythms in liver tumors, we have chemically induced hepatocellular carcinoma in transgenic rats bearing a luciferase reporter gene attached to the promoter of a core circadian clock gene (Period 1). We explanted normal liver cells and hepatomas, placed them into short‐term culture, and precisely measured their molecular clock function by recording light output. Results show that isolated hepatocellular carcinoma is capable of generating circadian rhythms in vitro. Temporally restricting food availability to either day or night altered the phase of the rhythms in both healthy and malignant tissue. However, the hepatomas were much less sensitive to this signal resulting in markedly different phase relationships between host and tumor tissue as a function of mealtime. These data support the conclusion that hepatoma is differentially sensitive to circadian timing signals, although it maintains the circadian organization of the nonmalignant cells from which it arose. Because circadian clocks are known to modulate the sensitivity of many therapeutic cytotoxic targets, controlling mealtiming might be used to increase the efficacy of treatment. Specifically, meal and treatment schedules could be designed that take advantage of coincident times of greatest tumor sensitivity and lowest sensitivity of host tissue to damage. © 2005 Wiley‐Liss, Inc.

Improved Tumor Control through Circadian Clock Induction by Seliciclib, a Cyclin-Dependent Kinase Inhibitor

“…Even dividing fibroblasts passed information on their own circadian phase to their daughter cells (40). Thus, daily Seliciclib could reset the clocks of malignant cells, an effect also achieved with glucocorticoids and meal timing (11,39,41). However, Seliciclib also significantly modified the 24-hour mean expression of Rev-erba and Bmal1 in opposite directions without affecting that of Per2, a finding consistent with the down-regulation of Bmal1 by Rev-erba (6,8,9).…”

Circadian clocks: regulators of endocrine and metabolic rhythms

“…Critically, the cycle of cell division is highly circadian in proliferating tissues such as oral mucosa and skin (Bjarnason et al 2001), and by restricting when competent cells might divide to a narrow temporal window, the circadian timing system has potentially oncostatic effects. This becomes particularly relevant with the discovery that tumour cells also possess a functional clockwork (Filipski et al 2004, Davidson et al 2006b) that is entrained to factors within the host. Consequently, a disrupted host clock may open this gate within the tumour, thereby allowing increased proliferation.…”

Cross-talks between Circadian Timing System and Cell Division Cycle Determine Cancer Biology and Therapeutics

“…In a mouse breast cancer model at a more advanced stage of growth (early to late), Per1 and Per2 mRNAs lacked any circadian periodicity, whereas Bmal1 mRNA remained rhythmic, yet with a 13-fold reduction in circadian amplitude (You et al 2005). An elegant study performed in rats with diethylnitrosamine-induced hepatocarcinoma, a very slow growing tumor, further shows that the entrainment properties of Per1 in cancerous liver tissue differ from those of the healthy liver tissue it originates from (Davidson et al 2006).…”