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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

BMC Cancer 1/2017

Circadian disruption promotes tumor growth by anabolic host metabolism; experimental evidence in a rat model

Zeitschrift:
BMC Cancer > Ausgabe 1/2017
Autoren:
Natalí N. Guerrero-Vargas, Raful Navarro-Espíndola, Mara A. Guzmán-Ruíz, María del Carmen Basualdo, Estefania Espitia-Bautista, Ana López-Bago, Ricardo Lascurain, Cinthya Córdoba-Manilla, Ruud M. Buijs, Carolina Escobar
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12885-017-3636-3) contains supplementary material, which is available to authorized users.

Abstract

Background

Light 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.

Methods

Male 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.

Results

We 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.

Conclusions

Data indicates that circadian disruption by LL provides a favorable condition for tumor growth by promoting an anabolic metabolism in the host.
Zusatzmaterial
Additional file 3: High sugar diet (HS) induces a suitable metabolic environment for tumor growth. (A) HS rats (white circles) gained more body weight along the 4-week protocol as compared with chow diet rats (grey circles). Data are the mean ± SEM (n = 7/group). The repeated-measures two-way ANOVA indicated significant effects for condition versus time, interaction p = 0.0014. The Bonferroni test ***p < 0.001 indicated statistical difference from chow diet. (B) HS rats ingest more Kcal in 24 h. Data are the mean ± SEM (n = 7/group). ** p < 0.01 indicates statistical difference from chow diet; unpaired t test. (C) Basal plasma triglycerides (TG) and glucose levels (D) under ad libitum conditions were significantly increased in HS rats. Data are the mean ± SEM (n = 6–7/group), **p < 0.01, ***p < 0.001 indicates statistical difference from chow diet; unpaired t test. (E) Glucose tolerance test (GTT, 0–120 min) following i.p. administration of 1 g of glucose/kg. Values are expressed as mean ± SEM (n = 7/group). The repeated-measures two-way ANOVA indicated significant effects for condition versus time interaction p = 0.016. The Bonferroni test **p < 0.01 indicated statistical difference from chow diet. (F) Tumor volume along 13 days after subcutaneous C6 cells inoculation. The repeated-measures two-way ANOVA indicated a significant interaction for condition versus time, p = 0.0032. Data are expressed as mean ± SEM (n = 4-7group). The Bonferroni test indicated **p < 0.01 statistical difference from chow diet. (PDF 328 kb)
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