索拉菲尼诱导大鼠肝细胞癌形成过程中巨噬细胞和自然杀伤细胞的聚集  

Sorafenib induces aggregation of macrophages and natural killer cells in hepatocellular carcinoma rats

作　　者：许文[1] 王阁[1] 陈川[1] 张志敏[1] 李琼[1] 雒喜忠[1] 郑继军[1] 胡庆[1] 王东[1] 李增鹏[1] 

机构地区：[1]第三军医大学大坪医院野战外科研究所肿瘤中心,重庆400042

出　　处：《第三军医大学学报》2009年第11期1009-1012,共4页Journal of Third Military Medical University

基　　金：国家自然科学基金(30370341;30570410);教育部高等学校全国优秀博士学位论文作者专项基金(200261)~~

摘　　要：目的探讨多分子靶点药物索拉菲尼(Sorafenib)对肝细胞癌(hepatocellular carcinoma,HCC)形成过程中巨噬细胞标记物CD68和自然杀伤细胞标记物CD57的分布、表达情况的影响。方法改良法建立HCC模型,设立正常对照组(A组)、单纯模型组(B组)、早期单倍组(C组)、早期双倍组(D组)、晚期单倍组(E组)、晚期双倍组(F组),在HCC形成早期和晚期应用单、双倍剂量的索拉菲尼对C～F组进行干预,用免疫组织化学方法动态观察HCC组织中CD57、CD68和CD34的变化。结果B组CD57、CD68阳性细胞的数目逐渐增加,各个实验组(C～F组)分别在第12、14周时出现峰值后不同程度的减少,而D、F组在第18周后两者数目减少不明显,其中第20、22周时D、F组分别与B组相比均显著增加(P<0.05),同时D组比C组,F组比E组以及D组比F组亦显著增加(P<0.01,P<0.05),其余各组之间比较差异无统计学意义(P>0.05)。B组CD34阳性细胞数目逐渐增加,各个实验组(B～F组)在第16周后随诱癌时间延长有不同程度的减少,D组与C、E、F组相比亦显著减少(P<0.05)。结论索拉菲尼不仅可以抑制HCC组织的血管生成,还可以诱导HCC组织中的巨噬细胞和自然杀伤细胞的聚集,以早期双倍剂量组更明显,提示索拉菲尼治疗HCC的分子机制可能存在一种新的免疫调节机制,并呈剂量依赖性。Objective To study the effects of Sorafenib, a kind of multiple targeted agent, on the distribution and expression of CD68 and CD57, the markers of macrophages and natural killer cell during the course of hepatocellular carcinoma （HCC）. Methods HCC model was established using improved method. The subjects were divided into six groups ： blank control （ group A）, HCC model without intervention （ group B）, early stage HCC model with single dose of Sorafenib （ group C） , early stage HCC model with double dose of Sorafenib （group D） , advanced stage with single dose （group E） and advanced stage with double dose （group F）. The dynamic changes in CD57, CD68 and CD34 expressions from HCC tissues were detected immunohistochemically. Results Count of CD57 and CD68 positive cells in group B increased gradually, but the count of these cells in groups C, D, E and F decreased at different degrees after the occurrence of the peak value at 12 and 14 weeks. No obvious change in the count of CD57 and CD68 positive cells was found in groups D and F at 18th week. At 20th and 22nd weeks, CD57 and CD68 positive cells in group D and F increased significantly as compared with those in group B （P 〈 0.05） , and the same result was found between groups D and C, groups F and E, and groups D and F （P 〈0. 01, P 〈0. 05）. No significant difference was found between other groups. CD34 positive cells in group B increased gradually, but these cells in groups B, C, D, E and F decreased at 16th week in a time-dependent manner. Significant difference was found between group D and groups C, E and F （ P 〈 0. 05）. Conclusion Sorafenib can not only inhibit angiogenesis of HCC, but also induce the aggregation of macrophages and natural killer cells in HCC tissues, suggesting there might be a novel dose-dependent immuno- regulatory mechanism in the molecular targeted therapy of HCC treatment with Sorafenib.

关 键 词：索拉菲尼 肝细胞癌 CD68 CD57 CD34 巨噬细胞 自然杀伤细胞 

分 类 号：R73-36[医药卫生—肿瘤] R735.7[医药卫生—临床医学]