Gastroenterology:高胆固醇水平可增加自然杀伤细胞的抗肿瘤功能并减少肿瘤的生长

2020-05-04 MedSci原创 MedSci原创

血清胆固醇水平与肝细胞癌(HCC)发展之间的关系尚不清楚。本项研究调查了血清胆固醇水平对小鼠肝肿瘤发展的影响。

背景和目标: 血清胆固醇水平与肝细胞癌(HCC)发展之间的关系尚不清楚。本项研究调查了血清胆固醇水平对小鼠肝肿瘤发展的影响。

方法:  研究人员对C57BL/6J小鼠,以及低密度脂蛋白受体基因受到破坏的小鼠(Ldlr-/-小鼠)和有条件删除自然杀伤(NK)细胞的小鼠(NKdele小鼠)进行了研究。给一些C57BL/6J和NKdele小鼠注射二乙基initrosamine诱导肝肿瘤形成。将小鼠置于正常饮食(ND)或高胆固醇饮食(HCD)上以诱导高血清胆固醇水平。研究人员还研究了纯合破坏ApoE的小鼠(ApoE-/-小鼠),它们自发形成高血清胆固醇。C57BL/6J和NKdele在ND或HCD上的小鼠植入Hep1-6(小鼠肝癌)细胞,并监测异种移植肿瘤的生长和肺转移。从小鼠采集血样,并通过生物化学和流式细胞仪进行分析;收集肝脏和肿瘤组织,并通过组织学,免疫组织化学和RNA序列分析进行分析。从小鼠中分离出NK细胞,并分析其胆固醇含量,脂质筏形成,免疫信号传导和功能变化。同时,研究人员从30例HCC患者中获得了匹配的肿瘤组织和血液样本,并从40名健康志愿者中获得了血液样本,测量胆固醇水平和NK细胞的细胞毒性。

结果: HCD和ApoE-/-小鼠中具有高血清胆固醇水平的C57BL/6J小鼠注射二乙基己胺胺或植入Hep1-6细胞后,其肝脏肿瘤和肺转移的发生率要少于ND小鼠。与来自ND喂养的小鼠的肿瘤相比,来自HCD喂养的小鼠和ApoE-/-小鼠的肝肿瘤的NK细胞数量增加。NKDele小鼠或以抗体为基础的NK细胞耗竭的小鼠在注射二乙基己内酰胺或植入Hep1-6细胞后,ND和HCD组的肿瘤数目和大小相似。从用HCD喂养的C57BL/6J小鼠中分离出的NK细胞表达增强的NK细胞激活受体,效应子功能标记(粒酶B和穿孔素)以及细胞因子和趋化因子与ND小鼠的NK细胞相比;这些NK细胞还具有增强的针对小鼠肝癌细胞的细胞毒性活性,胆固醇积累,脂质筏形成增加和免疫信号激活。血清胆固醇水平与从人肝癌分离的NK细胞的数量和活性有关。

结论: 注射肝癌细胞或化学致癌物后,由于HCD或ApoE基因破坏而使血清中胆固醇水平升高的小鼠,肿瘤的数量越来越少,胆固醇在NK细胞中蓄积并激活其针对肝癌细胞的效应功能。

原始出处:

Wen-Hao Qin. Et al. High Serum Levels of Cholesterol Increase Antitumor Functions of Nature Killer Cells and Reduce Growth of Liver Tumors in Mice. Gastroenterology.2020.

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    2021-03-15 许安
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