HSP70介导RFA联合TAE治疗肝癌中T细胞免疫的实验研究
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摘要
第一部分射频消融联合肝动脉化疗栓塞对兔肝VX2肿瘤消融疗效的影响
目的：通过观察肝动脉化疗栓塞(TACE)联合射频消融(RFA)、肝动脉化疗栓塞(TAE)联合RFA、RFA和TACE治疗兔VX2肝肿瘤的疗效及病理学改变，研究TACE和TAE增强RFA疗效的机制及病理学特点。
材料与方法：24只荷瘤日本大耳白兔随机平均分为4组，每组6只：TACE+RFA组，TACE后15分钟行RFA治疗；TAE+RFA组，采用PVA(polyvinylalcoholparticles)TAE后15分钟行RFA治疗；RFA组，单独行射频消融；TACE组，单独行TACE。术后7天处死实验兔，比较肿瘤区凝固性坏死区或出血性梗死性区的最大切面积。对比典型的病理切片。
结果：21只实验兔全部存活，实验成功率为87.5%(21/24)，其中死亡3只。TAE+RFA组中一只实验兔死于介入术中腹腔出血，RFA组中一只死于术中气胸；术后2天TACE+RFA组中一只实验兔死于肝叶坏死。TACE+RFA组中的凝固性坏死最大面积与TAE+RFA组、RFA组和TACE组相比均有统计学差异。TAE+RFA组与RFA组坏死最大面积相比，具有统计学差异(P<0.05)。病理分析显示在TACE+RFA组和其他组相比具有更多的血管栓塞及坏死区、较少的岛屿状存活肿瘤细胞群。
结论：TACE+RFA组取得最大治疗截面积为局部化疗效果、高热、减少肿瘤供血和它们之间的协同效应的结果。TACE+RFA治疗法能够比TAE+RFA、单独使用RFA和TACE治疗更能达到毁损肿瘤的目的。
第二部分热休克蛋白70在射频消融联合TAE治疗兔VX2肿瘤后表达的实验研究
目的：应用RFA联合TAE建立局部缺氧及高热条件，制作不同程度的HSP70高表达水平的动物肝癌模型。
材料与方法：75只荷瘤日本大耳朵白兔随机平均分为5组，每组15只：TAE+RFA组TAE后15分钟行RFA治疗；RFA组，单独行射频消融；TAE组，单独行TAE；Sham组，采用射频消融针穿刺入肿瘤中心，打开多极针延伸至1cm，半分钟后收回多极针，主针撤出肝组织，采用明胶海绵条填塞穿刺道；Control组，不做治疗。各组分别于术后1、3、7天处死5只。采用免疫组化和Westernblot分析法测定HSP70表达；采用实时定量PCR测量HSP70mRNA。
结果：TAE+RFA组中HSP70的表达在术后1天、3天、7天，消融区周边的残存肿瘤组织和肝组织的明显分别高于对应时间点其他组中两组织的HSP70的表达。TAE+RFA组中HSP70的表达术后3天的明显高于术后1天和7天的表达。TAE组肝组织及肿瘤组织内HSP70的表达术后1天分别高于对照组和假手术组中的表达。TAE、RFA和TAE+RFA组中，HSP70mRNA在消融区周边的残存肿瘤组织和肝组织内的表达，术后1天达到峰值，术后3天降低，7天恢复到基线水平。术后1天，HSP70mRNA在TAE+RFA、RFA组两组织内的表达要高于分别高于其他组的两组织内的表达。
结论：TAE、RFA和TAE+RFA组中，残存肿瘤周边和消融区周边的肝组织HSP70的表达在术后1天明显增加，术后3天达到峰值，术后7天降低。TAE引起的缺氧能够增加HSP70在残存肿瘤组织内的表达。TAE联合RFA能够协同促进HSP70的表达。
第三部分射频消融联合肝动脉栓塞治疗VX2兔肝肿瘤后激活CD8+T细胞肿瘤免疫的研究
目的：TAE联合RFA治疗兔VX2肝肿瘤模型后，研究肿瘤周边和外周血中HSP70浓度与肿瘤周边浸润和外周血中CD8+T细胞数量之间的关系。探索RFA联合TAE治疗肝癌后HSP70介导的特异性抗肿瘤免疫的作用机制。
材料与方法：54只荷瘤日本大耳白兔采用随机数字法被分为3组，每组18只：TAE+RFA组TAE后15分钟行RFA治疗；RFA组，单独行射频消融；Control组，不做治疗。分别于术后1、3、7天处死。采用免疫组化法检测残存肿瘤周边的HSP70表达和CD8+T细胞的浸润；采用免疫酶联反应检测外周血中的HSP70和采用流式细胞仪检测CD8+T细胞在淋巴细胞中的百分比。
结果：术后1天、3天、7天TAE+RFA组中HSP70的表达明显分别高于对应时间点其他组中的表达；RFA组中HSP70的表达明显分别高于对应时间点Control组中的表达。TAE+RFA、RFA组中HSP70的表达术后3天的明显高于术后1天和7天的表达。术后1天、3天、7天残存肿瘤周边CD8+T细胞浸润数量，TAE+RFA组明显高于RFA组和Control组；RFA组高于Control组。TAE+RFA、RFA组残存肿瘤周边CD8+T细胞浸润数量中术后7天与术后1、3天相比，具有统计学差异。术后7天为TAE+RFA组和RFA组CD8+T细胞浸润数量的峰值期。RFA和TAE+RFA组外周血中的HSP70值在术后1天达到峰值，与此同时的是外周血中的CD8+T细胞百分比也达到峰值。
结论：残存肿瘤周边HSP70的表达与周围CD8+T细胞的浸润数量呈正相关。血清中的HSP70诱导的抗肿瘤免疫随着血清中HSP70的降低而减弱。在兔VX2肝癌模型中TAE+RFA治疗法能够通过缺氧联合高热刺激HSP70高表达，继而产生更强的抗肿瘤免疫反应。
Purpose:To investigate the effect and histopathologic characteristics of radiofrequency ablation (RFA) combined with transcatheter arterial chemoembolization (TACE) and RFA combined with transcatheter arterial embolization (TAE) for rabbit VX2hepatic tumors.
Materials and Methods:Twenty four Japanese White rabbits with VX2hepatic tumors were randomly divided into four treatment groups:TACE+RFA, RFA followed15min later by TACE (n=6); TAE+RFA, RFA followed15min later by transcatheter arterial embolization (TAE) with poly vinyl alcohol particles (PVA)(n=6); RFA, RFA alone (n=6); and the TACE group, TACE alone (n=6).
Results:The maximum diameters of the coagulation or infarcted zones in the gross specimens were compared. A rabbit in TAE-RFA group died of intraperitoneal bleeding and a rabbit in RFA group died of pneumothorax in the procedure and a rabbit in TACE+RFA group died of hepatic necrosis2days after the procedure. The procedures were successfully performed in the remaining animals (21/24;87.5%). Significantly larger areas of coagulation and infarction were observed in the TACE+RFA group compared with the TAE+RFA (P<0.05), RFA (P<0.05) and TACE groups (P<0.05). The TAE-RFA group showed larger treatment areas compared to the RFA group (P<0.05). Histopathological analysis revealed greater vascular thrombosis and necrosis and fewer islands of viable tumor cells in the TACE+RFA group compared with the other groups.
Conclusions:The largest treatment dimensions were produced in the TACE+RFA group by the synergistic effect of local chemotherapy, hyperthermia and reduction of the blood flow feeding the tumors. TACE+RFA are more effective for achieving tumor destruction than TAE+RFA, RFA or TACE performed alone.
Purpose:To establish over-expression HSP70model in a rabbit model of VX2hepatic tumors by TAE combined with RFA treatments.
Materials and Methods:Japanese White rabbits (75animals) with VX2liver tumors were randomly divided into five groups:TAE+RFA, RFA followed15min later by transcatheter arterial embolization (TAE) with polyvinyl alcohol particles (PVA)(n=15); RFA, RFA alone (n=15); TAE group, TAE alone (n=15); Sham group, received sham procedure without radiofrequency ablation; Control group, received no procedure until sample collection time (n=15). Five rabbits in each group were sacrificed on day1,3,7after procedures, respectively. HSP70expression was detected by immunohistochemistry staining and Western blot analysis; HSP70mRNA expression was by RT-PCR.
Results:HSP70expression in the liver and residual tumor in TAE+RFA group were significantly greater than others groups on dayl,3and7, respectively. HSP70expression in the liver and residual tumor in TAE+RFA group on day3had statistically significant compared with on day1,7respectively. TAE induced greater HSP70expression than control group and sham group in residual tumor on dayl. In TAE, RFA and TAE+RFA groups, HSP70mRNA expressed in the both tissues peaked on day1, dropped on day3and dropped to base line on day7after treatment. TAE+RFA and RFA groups showed a stronger HSP70mRNA expression compared with others groups in both tissues on day1.
Conclusions:The expression of HSP70was noted in residual tumors and liver tissue in the marginal area of necrosis area due to different treatments, increased on day1, peaked on day3and dropped on day7after treatment in TAE, RFA and TAE+RFA groups. Hypoxia caused by TAE can enhance HSP70expression in residual tumor. RFA combined with TAE showed the synergistic effect on HSP70expression.
Purpose:To explore the relationship between the expression of HSP70surrounding residual tumor and in peripheral blood and CD8+T cells surrounding the residual tumors and in peripheral blood in a rabbit model of VX2hepatic tumor after TAE+RF A treatment.
Materials and Methods:Japanese White rabbits (54animals) with VX2liver tumors were randomly divided into three groups:TAE+RFA, RFA followed15min later by TAE (n=18); RFA, RFA alone (n=18); Control group, received no procedure until sample collection time (n=18). Six rabbits in each group were sacrificed on day1,3,7after procedures, respectively. HSP70expression and infiltration of CD8+T cells surrounding the residual tumors were detected by immunohistochemistry staining; HSP70expression and the positive percentage of CD8+T cells in lymphocyte in the peripheral blood was detected by ELISA Kit and measured by flow cytometry, respectively.
Results:HSP70expression in the residual tumors in TAE+RFA group was significantly greater than others groups on day1,3and7, respectively; RFA group was significantly greater than Control group on day1,3and7, respectively. HSP70expression in the residual tumors in TAE+RFA, RFA groups on day3had statistically significant compared with on day1,7respectively. The number of infiltration of CD8+T cells surrounding the residual tumors in TAE+RFA group was significantly greater than others groups on day1,3and7, respectively; RFA group was significantly greater than Control group on day1,3and7. The number of infiltration of CD8+T cells surrounding the residual tumors TAE+RFA and RFA groups on day3had statistically significant compared with on day1,7, respectively. The serum HSP70levels were on peak in RFA and TAE+RFA groups on day1and the peak levels of CD8+T cells in RFA and TAE+RFA groups in peripheral blood at same time.
Conclusions:There were positive correlations between HSP70expression levels and infiltration of CD8+T levels surrounding the residual tumors and in RFA, TAE+RFA groups. The ability of serum HSP70initiating of antitumor immunity may reduce with serum HSP70decreasing. TAE+RFA treatment can activate the strongest antitumor immunity by hyperpyrexia and hypoxia induction of the most significant HSP70proteins expression from residual tumors cells in rabbit VX2hepatic tumors.
目的：通过观察肝动脉化疗栓塞(TACE)联合射频消融(RFA)、肝动脉化疗栓塞(TAE)联合RFA、RFA和TACE治疗兔VX2肝肿瘤的疗效及病理学改变，研究TACE和TAE增强RFA疗效的机制及病理学特点。
材料与方法：24只荷瘤日本大耳白兔随机平均分为4组，每组6只：TACE+RFA组，TACE后15分钟行RFA治疗；TAE+RFA组，采用PVA(polyvinylalcoholparticles)TAE后15分钟行RFA治疗；RFA组，单独行射频消融；TACE组，单独行TACE。术后7天处死实验兔，比较肿瘤区凝固性坏死区或出血性梗死性区的最大切面积。对比典型的病理切片。
结果：21只实验兔全部存活，实验成功率为87.5%(21/24)，其中死亡3只。TAE+RFA组中一只实验兔死于介入术中腹腔出血，RFA组中一只死于术中气胸；术后2天TACE+RFA组中一只实验兔死于肝叶坏死。TACE+RFA组中的凝固性坏死最大面积与TAE+RFA组、RFA组和TACE组相比均有统计学差异。TAE+RFA组与RFA组坏死最大面积相比，具有统计学差异(P<0.05)。病理分析显示在TACE+RFA组和其他组相比具有更多的血管栓塞及坏死区、较少的岛屿状存活肿瘤细胞群。
结论：TACE+RFA组取得最大治疗截面积为局部化疗效果、高热、减少肿瘤供血和它们之间的协同效应的结果。TACE+RFA治疗法能够比TAE+RFA、单独使用RFA和TACE治疗更能达到毁损肿瘤的目的。
第二部分热休克蛋白70在射频消融联合TAE治疗兔VX2肿瘤后表达的实验研究
目的：应用RFA联合TAE建立局部缺氧及高热条件，制作不同程度的HSP70高表达水平的动物肝癌模型。
材料与方法：75只荷瘤日本大耳朵白兔随机平均分为5组，每组15只：TAE+RFA组TAE后15分钟行RFA治疗；RFA组，单独行射频消融；TAE组，单独行TAE；Sham组，采用射频消融针穿刺入肿瘤中心，打开多极针延伸至1cm，半分钟后收回多极针，主针撤出肝组织，采用明胶海绵条填塞穿刺道；Control组，不做治疗。各组分别于术后1、3、7天处死5只。采用免疫组化和Westernblot分析法测定HSP70表达；采用实时定量PCR测量HSP70mRNA。
结果：TAE+RFA组中HSP70的表达在术后1天、3天、7天，消融区周边的残存肿瘤组织和肝组织的明显分别高于对应时间点其他组中两组织的HSP70的表达。TAE+RFA组中HSP70的表达术后3天的明显高于术后1天和7天的表达。TAE组肝组织及肿瘤组织内HSP70的表达术后1天分别高于对照组和假手术组中的表达。TAE、RFA和TAE+RFA组中，HSP70mRNA在消融区周边的残存肿瘤组织和肝组织内的表达，术后1天达到峰值，术后3天降低，7天恢复到基线水平。术后1天，HSP70mRNA在TAE+RFA、RFA组两组织内的表达要高于分别高于其他组的两组织内的表达。
结论：TAE、RFA和TAE+RFA组中，残存肿瘤周边和消融区周边的肝组织HSP70的表达在术后1天明显增加，术后3天达到峰值，术后7天降低。TAE引起的缺氧能够增加HSP70在残存肿瘤组织内的表达。TAE联合RFA能够协同促进HSP70的表达。
第三部分射频消融联合肝动脉栓塞治疗VX2兔肝肿瘤后激活CD8+T细胞肿瘤免疫的研究
目的：TAE联合RFA治疗兔VX2肝肿瘤模型后，研究肿瘤周边和外周血中HSP70浓度与肿瘤周边浸润和外周血中CD8+T细胞数量之间的关系。探索RFA联合TAE治疗肝癌后HSP70介导的特异性抗肿瘤免疫的作用机制。
材料与方法：54只荷瘤日本大耳白兔采用随机数字法被分为3组，每组18只：TAE+RFA组TAE后15分钟行RFA治疗；RFA组，单独行射频消融；Control组，不做治疗。分别于术后1、3、7天处死。采用免疫组化法检测残存肿瘤周边的HSP70表达和CD8+T细胞的浸润；采用免疫酶联反应检测外周血中的HSP70和采用流式细胞仪检测CD8+T细胞在淋巴细胞中的百分比。
结果：术后1天、3天、7天TAE+RFA组中HSP70的表达明显分别高于对应时间点其他组中的表达；RFA组中HSP70的表达明显分别高于对应时间点Control组中的表达。TAE+RFA、RFA组中HSP70的表达术后3天的明显高于术后1天和7天的表达。术后1天、3天、7天残存肿瘤周边CD8+T细胞浸润数量，TAE+RFA组明显高于RFA组和Control组；RFA组高于Control组。TAE+RFA、RFA组残存肿瘤周边CD8+T细胞浸润数量中术后7天与术后1、3天相比，具有统计学差异。术后7天为TAE+RFA组和RFA组CD8+T细胞浸润数量的峰值期。RFA和TAE+RFA组外周血中的HSP70值在术后1天达到峰值，与此同时的是外周血中的CD8+T细胞百分比也达到峰值。
结论：残存肿瘤周边HSP70的表达与周围CD8+T细胞的浸润数量呈正相关。血清中的HSP70诱导的抗肿瘤免疫随着血清中HSP70的降低而减弱。在兔VX2肝癌模型中TAE+RFA治疗法能够通过缺氧联合高热刺激HSP70高表达，继而产生更强的抗肿瘤免疫反应。
Purpose:To investigate the effect and histopathologic characteristics of radiofrequency ablation (RFA) combined with transcatheter arterial chemoembolization (TACE) and RFA combined with transcatheter arterial embolization (TAE) for rabbit VX2hepatic tumors.
Materials and Methods:Twenty four Japanese White rabbits with VX2hepatic tumors were randomly divided into four treatment groups:TACE+RFA, RFA followed15min later by TACE (n=6); TAE+RFA, RFA followed15min later by transcatheter arterial embolization (TAE) with poly vinyl alcohol particles (PVA)(n=6); RFA, RFA alone (n=6); and the TACE group, TACE alone (n=6).
Results:The maximum diameters of the coagulation or infarcted zones in the gross specimens were compared. A rabbit in TAE-RFA group died of intraperitoneal bleeding and a rabbit in RFA group died of pneumothorax in the procedure and a rabbit in TACE+RFA group died of hepatic necrosis2days after the procedure. The procedures were successfully performed in the remaining animals (21/24;87.5%). Significantly larger areas of coagulation and infarction were observed in the TACE+RFA group compared with the TAE+RFA (P<0.05), RFA (P<0.05) and TACE groups (P<0.05). The TAE-RFA group showed larger treatment areas compared to the RFA group (P<0.05). Histopathological analysis revealed greater vascular thrombosis and necrosis and fewer islands of viable tumor cells in the TACE+RFA group compared with the other groups.
Conclusions:The largest treatment dimensions were produced in the TACE+RFA group by the synergistic effect of local chemotherapy, hyperthermia and reduction of the blood flow feeding the tumors. TACE+RFA are more effective for achieving tumor destruction than TAE+RFA, RFA or TACE performed alone.
Purpose:To establish over-expression HSP70model in a rabbit model of VX2hepatic tumors by TAE combined with RFA treatments.
Materials and Methods:Japanese White rabbits (75animals) with VX2liver tumors were randomly divided into five groups:TAE+RFA, RFA followed15min later by transcatheter arterial embolization (TAE) with polyvinyl alcohol particles (PVA)(n=15); RFA, RFA alone (n=15); TAE group, TAE alone (n=15); Sham group, received sham procedure without radiofrequency ablation; Control group, received no procedure until sample collection time (n=15). Five rabbits in each group were sacrificed on day1,3,7after procedures, respectively. HSP70expression was detected by immunohistochemistry staining and Western blot analysis; HSP70mRNA expression was by RT-PCR.
Results:HSP70expression in the liver and residual tumor in TAE+RFA group were significantly greater than others groups on dayl,3and7, respectively. HSP70expression in the liver and residual tumor in TAE+RFA group on day3had statistically significant compared with on day1,7respectively. TAE induced greater HSP70expression than control group and sham group in residual tumor on dayl. In TAE, RFA and TAE+RFA groups, HSP70mRNA expressed in the both tissues peaked on day1, dropped on day3and dropped to base line on day7after treatment. TAE+RFA and RFA groups showed a stronger HSP70mRNA expression compared with others groups in both tissues on day1.
Conclusions:The expression of HSP70was noted in residual tumors and liver tissue in the marginal area of necrosis area due to different treatments, increased on day1, peaked on day3and dropped on day7after treatment in TAE, RFA and TAE+RFA groups. Hypoxia caused by TAE can enhance HSP70expression in residual tumor. RFA combined with TAE showed the synergistic effect on HSP70expression.
Purpose:To explore the relationship between the expression of HSP70surrounding residual tumor and in peripheral blood and CD8+T cells surrounding the residual tumors and in peripheral blood in a rabbit model of VX2hepatic tumor after TAE+RF A treatment.
Materials and Methods:Japanese White rabbits (54animals) with VX2liver tumors were randomly divided into three groups:TAE+RFA, RFA followed15min later by TAE (n=18); RFA, RFA alone (n=18); Control group, received no procedure until sample collection time (n=18). Six rabbits in each group were sacrificed on day1,3,7after procedures, respectively. HSP70expression and infiltration of CD8+T cells surrounding the residual tumors were detected by immunohistochemistry staining; HSP70expression and the positive percentage of CD8+T cells in lymphocyte in the peripheral blood was detected by ELISA Kit and measured by flow cytometry, respectively.
Results:HSP70expression in the residual tumors in TAE+RFA group was significantly greater than others groups on day1,3and7, respectively; RFA group was significantly greater than Control group on day1,3and7, respectively. HSP70expression in the residual tumors in TAE+RFA, RFA groups on day3had statistically significant compared with on day1,7respectively. The number of infiltration of CD8+T cells surrounding the residual tumors in TAE+RFA group was significantly greater than others groups on day1,3and7, respectively; RFA group was significantly greater than Control group on day1,3and7. The number of infiltration of CD8+T cells surrounding the residual tumors TAE+RFA and RFA groups on day3had statistically significant compared with on day1,7, respectively. The serum HSP70levels were on peak in RFA and TAE+RFA groups on day1and the peak levels of CD8+T cells in RFA and TAE+RFA groups in peripheral blood at same time.
Conclusions:There were positive correlations between HSP70expression levels and infiltration of CD8+T levels surrounding the residual tumors and in RFA, TAE+RFA groups. The ability of serum HSP70initiating of antitumor immunity may reduce with serum HSP70decreasing. TAE+RFA treatment can activate the strongest antitumor immunity by hyperpyrexia and hypoxia induction of the most significant HSP70proteins expression from residual tumors cells in rabbit VX2hepatic tumors.
引文
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