Abstract
BackgroundLight at night creates a conflicting signal to the biological clock and disrupts circadian physiology. In rodents, light at night increases the risk to develop mood disorders, overweight, disrupted energy metabolism, immune dysfunction and cancer. We hypothesized that constant light (LL) in rats may facilitate tumor growth via disrupted metabolism and increased inflammatory response in the host, inducing a propitious microenvironment for tumor cells.MethodsMale Wistar rats were exposed to LL or a regular light-dark cycle (LD) for 5 weeks. Body weight gain, food consumption, triglycerides and glucose blood levels were evaluated; a glucose tolerance test was also performed. Inflammation and sickness behavior were evaluated after the administration of intravenous lipopolysaccharide. Tumors were induced by subcutaneous inoculation of glioma cells (C6). In tumor-bearing rats, the metabolic state and immune cells infiltration to the tumor was investigated by using immunohistochemistry and flow cytometry. The mRNA expression of genes involved metabolic, growth, angiogenes and inflammatory pathways was measured in the tumor microenvironment by qPCR. Tumor growth was also evaluated in animals fed with a high sugar diet.ResultsWe found that LL induced overweight, high plasma triglycerides and glucose levels as well as reduced glucose clearance. In response to an LPS challenge, LL rats responded with higher pro-inflammatory cytokines and exacerbated sickness behavior. Tumor cell inoculation resulted in increased tumor volume in LL as compared with LD rats, associated with high blood glucose levels and decreased triglycerides levels in the host. More macrophages were recruited in the LL tumor and the microenvironment was characterized by upregulation of genes involved in lipogenesis (Acaca, Fasn, and Pparγ), glucose uptake (Glut-1), and tumor growth (Vegfα, Myc, Ir) suggesting that LL tumors rely on these processes in order to support their enhanced growth. Genes related with the inflammatory state in the tumor microenvironment were not different between LL and LD conditions. In rats fed a high caloric diet tumor growth was similar to LL conditions.ConclusionsData indicates that circadian disruption by LL provides a favorable condition for tumor growth by promoting an anabolic metabolism in the host.
Highlights
Light at night creates a conflicting signal to the biological clock and disrupts circadian physiology
We have previously demonstrated that circadian disruption induces a increased inflammatory response [8] and promotes metabolic disturbances, including, dyslipidemia, insulin insensitivity and increased adipose mass [5], all of them leading to an obesogenic environment, which is an additional factor that could provide a favorable internal environment for tumor growth [19]
The obesogenic metabolism observed in LD; 2. Constant light (LL) hosts associated to an altered immune response may have favored a propitious internal tumor environment
Summary
Light at night creates a conflicting signal to the biological clock and disrupts circadian physiology. Light at night increases the risk to develop mood disorders, overweight, disrupted energy metabolism, immune dysfunction and cancer. Light at night increases the growth rate of mammary adenocarcinomas [11], chemical induced hepatocarcinogenesis [12], and accelerates aging and tumorigenesis in young rats [13]. These studies have related the increased tumor growth to the decreased nocturnal production of melatonin and its reduced blood concentration due to light at night. In addition to melatonin suppression, other deleterious changes triggered by constant illumination conditions (LL), may favor the process of tumor development
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