Departamento de Anatomía, Facultad de Medicina, UNAM, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510, México City, Mexico.
Departamento de Medicina experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico.
BMC Cancer. 2017 Sep 6;17(1):625. doi: 10.1186/s12885-017-3636-3.
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.
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.
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.
Data indicates that circadian disruption by LL provides a favorable condition for tumor growth by promoting an anabolic metabolism in the host.
夜间的光线向生物钟发出了相互矛盾的信号，扰乱了昼夜生理节律。在啮齿动物中，夜间的光线会增加其患上情绪障碍、超重、能量代谢紊乱、免疫功能障碍和癌症的风险。我们假设，大鼠持续光照（LL）可能会通过扰乱宿主的代谢和增加炎症反应来促进肿瘤生长，从而为肿瘤细胞创造有利的微环境。
雄性 Wistar 大鼠接受 LL 或常规明暗循环（LD）照射 5 周。评估体重增加、食物消耗、甘油三酯和血糖水平；还进行了葡萄糖耐量试验。在静脉注射脂多糖后评估炎症和疾病行为。通过皮下接种神经胶质瘤细胞（C6）诱导肿瘤。在荷瘤大鼠中，通过免疫组织化学和流式细胞术研究肿瘤的代谢状态和免疫细胞浸润。通过 qPCR 测量肿瘤微环境中参与代谢、生长、血管生成和炎症途径的基因的 mRNA 表达。还在喂食高糖饮食的动物中评估了肿瘤生长情况。
我们发现，LL 导致超重、血浆甘油三酯和血糖水平升高，以及葡萄糖清除率降低。在 LPS 挑战下，LL 大鼠表现出更高的促炎细胞因子和更严重的疾病行为。与 LD 大鼠相比，LL 大鼠的肿瘤细胞接种导致肿瘤体积增加，同时宿主的血糖水平升高，甘油三酯水平降低。更多的巨噬细胞被募集到 LL 肿瘤中，并且微环境的特点是上调了参与脂肪生成（Acaca、Fasn 和 Pparγ）、葡萄糖摄取（Glut-1）和肿瘤生长（Vegfα、Myc、Ir）的基因，这表明 LL 肿瘤依赖这些过程来支持其增强的生长。肿瘤微环境中与炎症状态相关的基因在 LL 和 LD 条件下没有差异。在喂食高热量饮食的大鼠中，肿瘤生长与 LL 条件相似。
数据表明，LL 通过促进宿主的合成代谢，为肿瘤生长提供了有利条件，从而破坏了昼夜节律。
