睡眠质量差加速癌细胞生长

　　

生物通报道：科学家们发现，睡眠质量差会加速癌细胞的生长，提高肿瘤的侵袭能力，抑制免疫系统控制和清除早期癌细胞的能力。文章于一月二十一日发表在Cancer Research杂志上。

这是首次在动物模型中展示，片断化睡眠对肿瘤生长和侵袭能力的影响。此外，研究还为人们提供了这种影响背后的生物学机制，鉴定了癌症治疗的潜在靶标。

 “片断化的睡眠改变了免疫系统应对癌症的方式，令癌细胞更具侵袭性。”文章的通讯作者，Chicago大学的David Gozal说。

“所幸的是，我们也找到了潜在的药物靶标，”他说。“研究显示，控制先天免疫系统活化的Toll样受体4，是睡眠匮乏促进癌症的关键。如果小鼠缺乏这一蛋白，片断化睡眠就无法起到促进癌症的作用。”

研究人员将小鼠分组进行睡眠干扰，并在七天后分别为它们注射两种肿瘤细胞（TC-1或3LLC）。在9到12天内，所有的小鼠都长出了明显的肿瘤。研究人员在接种四周后，对肿瘤进行了检测。

他们发现，在片断化睡眠的小鼠体内，肿瘤是正常睡眠小鼠的两倍，而且这些肿瘤更有侵袭性，进入了肿瘤周围的组织。

研究显示，上述差异是由免疫系统的细胞促成的，即肿瘤相关巨噬细胞（TAM）。TAM是免疫系统应答癌症的标志，会聚集在肿瘤发生的地方，尤其是在肿瘤边缘。这样的应答有多种途径，取决于TAM收到的信号。例如，M1型巨噬细胞能够启动强免疫应答，对肿瘤细胞进行清除。而M2却型巨噬细胞却抑制免疫应答，促进新血管生长，为肿瘤生长提供帮助。

研究人员指出，在正常休息的小鼠体内，肿瘤处聚集的主要是M1型TAM。而片断化睡眠的小鼠，主要拥有M2型TAM。此外，睡眠受到干扰的小鼠拥有高水平的Toll样受体4（TLR4）。

M2型巨嗜细胞的出现，取决于三个关键分子：TLR4、MYD88和TRIF。研究人员分别构建了缺乏这三种蛋白的小鼠，为其注射肿瘤细胞，并扰乱小鼠的睡眠。他们发现，如果小鼠缺乏MYD88或TRIF，肿瘤生长只是稍微减少。而在缺乏TLR4的小鼠中，肿瘤生长受到了很大抑制，回到了正常睡眠组的水平。

“在缺乏TLR4的小鼠中”Gozal说。“正常睡眠和片断化睡眠并没有什么差别。”越来越多的证据显示，睡眠障碍与癌症有某种关联，而这项研究解析了这一现象背后的分子机制。下一步，他们将研究睡眠是否也影响了癌细胞对化疗的抗性。

 

生物通编辑：叶予

生物通推荐原文摘要：

Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling.

Fragmented sleep (SF) is a highly prevalent condition and a hallmark of sleep apnea, a condition that has been associated with increased cancer incidence and mortality. In this study, we examined the hypothesis that SF promotes tumor growth and progression through pro-inflammatory TLR4 signaling. In the design, we compared mice that were exposed to SF one week before engraftment of syngeneic TC1 or LL3 tumor cells and tumor analysis three weeks later. We also compared host contributions through the use of mice genetically deficient in TLR4 or its effector molecules MYD88 or TRIF. We found that SF enhanced tumor size and weight compared to control mice. Increased invasiveness was apparent in SF tumors, which penetrated the tumor capsule into surrounding tissues including adjacent muscle. Tumor-associated macrophages (TAM) were more numerous in SF tumors where they were distributed in a relatively closer proximity to the tumor capsule, compared to control mice. Although tumors were generally smaller in both MYD88-/- and TRIF-/- hosts, the more aggressive features produced by SF persisted. In contrast, these more aggressive features produced by SF were abolished completely in TLR4-/- mice. Our findings offer mechanistic insights into how sleep perturbations can accelerate tumor growth and invasiveness through TAM recruitment and TLR4 signaling pathways.