Circadian Disruption Accelerates Tumor Growth and Angio/Stromagenesis through a Wnt Signaling Pathway

Abstract

Epidemiologic studies show a high incidence of cancer in shift workers, suggesting a possible relationship between circadian rhythms and tumorigenesis. However, the precise molecular mechanism played by circadian rhythms in tumor progression is not known. To identify the possible mechanisms underlying tumor progression related to circadian rhythms, we set up nude mouse xenograft models. HeLa cells were injected in nude mice and nude mice were moved to two different cases, one case is exposed to a 24-hour light cycle (L/L), the other is a more “normal” 12-hour light/dark cycle (L/D). We found a significant increase in tumor volume in the L/L group compared with the L/D group. In addition, tumor microvessels and stroma were strongly increased in L/L mice. Although there was a hypervascularization in L/L tumors, there was no associated increase in the production of vascular endothelial cell growth factor (VEGF). DNA microarray analysis showed enhanced expression of WNT10A, and our subsequent study revealed that WNT10A stimulates the growth of both microvascular endothelial cells and fibroblasts in tumors from light-stressed mice, along with marked increases in angio/stromagenesis. Only the tumor stroma stained positive for WNT10A and WNT10A is also highly expressed in keloid dermal fibroblasts but not in normal dermal fibroblasts indicated that WNT10A may be a novel angio/stromagenic growth factor. These findings suggest that circadian disruption induces the progression of malignant tumors via a Wnt signaling pathway.

The Circadian Clock in Cancer Development and Therapy

“…These studies demonstrate that disruption of circadian endocrine rhythms either by constant light exposure or pinealectomy increases spontaneous and carcinogen-induced mammary gland and hepatocellular carcinogenesis in rodents 114–116 . Similar experiments conducted in recent years have also shown that disruption of circadian homeostasis by a short period of back-and-forth or consecutive phase advance shifts of environmental light cues, or by constant light exposure significantly accelerate tumor growth in animals 117–121 . Compared to sham-operated animals, mice lacking a central clock due to surgical ablation of the SCN were unable to maintain circadian rhythmicity in locomotor activity, body temperature and immune function.…”

Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow

“…Stress induces hypothalamic signaling which activates the sympathetic nervous system, ultimately resulting in the systemic release of norepinephrine/epinephrine. Stress may also be an important factor that influences activation of dormant DTCs after long periods of time in marrow through immune system suppression (11), activating release of pro-inflammatory mediators (12,13), and activation of neurotransmitters from adrenergic neurons (14,15). Growing evidence supports the observation that β-adrenergic receptor antagonists, which interfere with norepinephrine ( NE ) signaling, may reduce cancer relapse or slow disease progression (16–19).…”

Melatonin and Circadian Rhythm: Aging, Cancer, and Mechanism

“…The disturbances occur in both sleep initiation and sleep maintenance. Epidemiologic studies show high incidence of cancer in shift workers [36]. The finding suggests that circadian disruption induces the progression of malignant tumors via a Wnt signaling pathway.…”