高压氧联合尼莫司汀靶向人脑胶质瘤干细胞模型的实验研究  

Experimental study on hyperbaric oxygen combined with nimustine in targeting human glioma stem cells model

作　　者：席宇君 马加威 薛彦平[1] 蔡洪华 盛余敬[2] 陈延明[1] 陆朝晖[1] 刘兵[1] 戴纯刚[1] 黄强[1] 董军[1] Xi Yujun Ma Jiawei Xue Yanping Cai Honghua Sheng Yujing Chen Yanming Lu Zhaohui Liu Bing Dai Cungang Huang Qiang Dong Jun(Neurosurgery Department, Second Hospital Affiliated to Suzhou University, Suzhou 215004, China)

机构地区：[1]苏州大学附属第二医院神经外科,江苏215004 [2]苏州大学附属第二医院影像科

出　　处：《中华航海医学与高气压医学杂志》2017年第2期103-109,共7页Chinese Journal of Nautical Medicine and Hyperbaric Medicine

基　　金：国家自然科学基金项目（81472739,81602183）;江苏省自然科学基金项目（BK20151214）;中国抗癌协会神经肿瘤研究项目（CSND-2014-MSD09）

摘　　要：目的探索高压氧（HBO）治疗联合尼莫司汀（ACNU）作用对人脑胶质瘤干细胞模型的影响，并初步分析其相关机制。方法人脑胶质瘤干细胞系SU3接种于Balb/c裸小鼠皮下，待肿瘤生长至40 mm3后，随机分为ACNU组、HBO组、ACNU＋HBO组及空白对照组，每组5只。实验期间定期测量荷瘤鼠体质量及肿瘤体积，微电极测量瘤内氧含量变化，治疗结束后取皮下肿瘤称重，观察移植瘤组织形态，并分析乏氧、坏死及血管生成等相关分子表达情况。结果HBO治疗后荷瘤鼠肿瘤组织内氧含量明显升高（P〈0.01），瘤内坏死出血较对照组明显减少。ACNU＋HBO组肿瘤质量最小（1.43±0.38）g，与其他3组差异存在统计学意义（P〈0.05），ACNU＋HBO、ACNU、HBO组的抑瘤率分别为76.29%、43.79%和31.51%。肿瘤坏死因子-α（TNF-α）、缺氧诱导因子-1α（HIF-1α）、血管内皮生长因子（VEGF）和核因子-κB（NF-κB）表达水平和炎细胞浸润光密度值与肿瘤抑制率呈负相关。结论HBO处理可改变肿瘤干细胞赖以生存的乏氧微环境，在一定程度上抑制胶质瘤干细胞启动的肿瘤增殖和肿瘤相关炎细胞浸润，与ACNU联合治疗可提高后者疗效，相关机制与HBO处理逆转肿瘤干细胞巢乏氧、并调控HIF-1α、TNF-α、VEGF和NF-κB表达下降相关。ObjectiveTo explore therapeutic effects of hyperbaric oxygen（HBO） combined with nimustine（ACNU）on human glioma stem cells model, and analyze the related mechanism involved.MethodsBalb/c nude mice were inoculated subcutaneously with human glioma stem cell line SU3, then were divided randomly into 4 groups, i. e., the ACNU group, the HBO group, the ACNU＋ HBO group and the blank control group. The body weight and tumor volume of the tumor-bearing mice were measured regularly during the experiment. Unisense microelectrode was applied to detect oxygen level in tumor-bearing mice after HBO treatment. Upon completion of treatment, the tumor-bearing mice were sacrificed and tumors were weighed. Histomorphological analyses of the transplanted tumors were also performed to analyze hypoxia, necrosis and expression levels of angiogenic related factors.ResultsFollowing HBO therapy, the oxygen level in the tumor tissue of the tumor-bearing mice was significantly increased（P〈0.01）, and necrotic hemorrhage experienced a sharp decrease, when compared with the control group. The tumor weight of the ACNU＋ HBO group was the lowest（1.43±0.38）g, and statistical differences could be seen, when compared with those of the other 3 groups（P〈0.05）. Tumor inhibition rates of the ACNU＋ HBO group, the ACNU group and the HBO group were respectively 76.29%, 43.79% and 31.51%. The expression levels of TNF-α, HIF-1α, NF-κB and VEGF and the density of inflammatory cell infiltration were negatively correlated with tumor inhibition rate.ConclusionsHBO therapy could alter the hypoxic microenvironment in which tumor stem cells survive, and could also inhibit tumor cell proliferation and tumor-related inflammatory cell infiltration triggered by glioma stem cells to a certain extent. Besides, combined HBO therapy could improve the curative effect of ACNU, and reverse the hypoxia micro-environment of tumor stem cell niche via negative regulation on the expressions of NF-κB, HIF-1α, TNF-α and VEGF.

关 键 词：胶质瘤干细胞 高压氧 尼莫司汀 免疫炎症反应 小鼠 

分 类 号：R739.41[医药卫生—肿瘤]