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Transcatheter Arterial Embolization Containing Donafenib Induces Anti-Angiogenesis and Tumoricidal CD8+ T-Cell Infiltration in Rabbit VX2 Liver Tumor
Cancer Management and Research ( IF 3.3 ) Pub Date : 2021-09-07 , DOI: 10.2147/cmar.s328294 Qin Shi 1, 2 , Tongqiang Li 1, 2 , Songjiang Huang 1, 2 , Yaowei Bai 1, 2 , Yingliang Wang 1, 2 , Jiacheng Liu 1, 2 , Chen Zhou 1, 2 , Yang Chen 1, 2 , Bin Xiong 1, 2
Cancer Management and Research ( IF 3.3 ) Pub Date : 2021-09-07 , DOI: 10.2147/cmar.s328294 Qin Shi 1, 2 , Tongqiang Li 1, 2 , Songjiang Huang 1, 2 , Yaowei Bai 1, 2 , Yingliang Wang 1, 2 , Jiacheng Liu 1, 2 , Chen Zhou 1, 2 , Yang Chen 1, 2 , Bin Xiong 1, 2
Affiliation
Purpose: To evaluate the effect and immune response of transcatheter arterial embolization (TAE) combined with donafenib in rabbit VX2 liver tumor model.
Materials and Methods: Thirty-six New Zealand white rabbits with VX2 liver tumor were randomly divided into three groups. The LD group was treated with the emulsion of 0.5 mL lipiodol and 4 mg donafenib via hepatic arterial administration. The LE group was treated with the emulsion of 0.5 mL lipiodol and 4 mg epirubicin. The control group was treated with the equal volume of saline. Four rabbits were euthanized in each group on day 1, 3 and 7 after treatment. The tumor growth, histological markers associated with angiogenesis and immune response were assessed by imaging and histopathology. In addition, immune modulatory cytokines included interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and biochemical hepatorenal function were measured.
Results: Compared to other groups, LD group achieved lower tumor growth rate, fewer metastatic lesions, and higher tumor necrosis rate on day 7 after treatment. The percentage of CD31-positive area in the LD group was significantly lower than that in the LE group on day 3 and 7 after treatment. In addition, CD8+ lymphocytes infiltration was more pronounced in LD group than in LE group on day 7 after treatment, regardless of in the tumor or adjacent liver tissue. Serum cytokines including IL-6, TNF-α and IFN-γ were strongly upregulated in the LD group on day 1 after treatment. And there was no significant difference in the hepatorenal function between LD group and LE group after treatment.
Conclusion: The combination of TAE and angiogenesis inhibitor donafenib resulted in a potentiated tumoricidal effect, anti-angiogenesis and antitumour T cell response in rabbit VX2 liver tumor model. This may provide a potential basis for exploring the immune-related mechanisms of embolization in liver cancer.
Keywords: liver cancer, transcatheter arterial embolization, donafenib, tumor angiogenesis, immune response
中文翻译：
含有多纳非尼的经导管动脉栓塞诱导兔 VX2 肝肿瘤中的抗血管生成和杀肿瘤 CD8+ T 细胞浸润
目的：评价经导管动脉栓塞术（TAE）联合多纳非尼对兔VX2肝肿瘤模型的疗效及免疫反应。
材料和方法：将36只患有VX2肝肿瘤的新西兰大白兔随机分为三组。LD组采用0.5 mL碘油和4 mg多那非尼乳剂经肝动脉给药治疗。LE组用0.5mL碘油和4mg表柔比星乳剂治疗。对照组给予等体积生理盐水。治疗后第1、3、7天各组4只兔实施安乐死。通过成像和组织病理学评估肿瘤生长、与血管生成和免疫反应相关的组织学标志物。此外，还检测了免疫调节细胞因子包括白细胞介素（IL）-6、肿瘤坏死因子（TNF）-α、干扰素（IFN）-γ，并测定了生化肝肾功能。
结果：与其他组相比，LD组在治疗后第7天肿瘤生长率较低，转移灶较少，肿瘤坏死率较高。LD组CD31阳性面积百分比在治疗后第3天和第7天明显低于LE组。此外，在治疗后第7天，LD组CD8 +淋巴细胞浸润比LE组更明显，无论是肿瘤还是邻近肝组织。在治疗后第 1 天，LD 组的血清细胞因子（包括 IL-6、TNF-α 和 IFN-γ）强烈上调。LD组与LE组治疗后肝肾功能差异无统计学意义。
结论：在兔 VX2 肝肿瘤模型中，TAE 和血管生成抑制剂多纳非尼的组合导致了增强的肿瘤杀伤作用、抗血管生成和抗肿瘤 T 细胞反应。这可能为探索肝癌栓塞的免疫相关机制提供潜在的基础。
关键词：肝癌，经导管动脉栓塞，多纳非尼，肿瘤血管生成，免疫反应
更新日期：2021-09-06
Materials and Methods: Thirty-six New Zealand white rabbits with VX2 liver tumor were randomly divided into three groups. The LD group was treated with the emulsion of 0.5 mL lipiodol and 4 mg donafenib via hepatic arterial administration. The LE group was treated with the emulsion of 0.5 mL lipiodol and 4 mg epirubicin. The control group was treated with the equal volume of saline. Four rabbits were euthanized in each group on day 1, 3 and 7 after treatment. The tumor growth, histological markers associated with angiogenesis and immune response were assessed by imaging and histopathology. In addition, immune modulatory cytokines included interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and biochemical hepatorenal function were measured.
Results: Compared to other groups, LD group achieved lower tumor growth rate, fewer metastatic lesions, and higher tumor necrosis rate on day 7 after treatment. The percentage of CD31-positive area in the LD group was significantly lower than that in the LE group on day 3 and 7 after treatment. In addition, CD8+ lymphocytes infiltration was more pronounced in LD group than in LE group on day 7 after treatment, regardless of in the tumor or adjacent liver tissue. Serum cytokines including IL-6, TNF-α and IFN-γ were strongly upregulated in the LD group on day 1 after treatment. And there was no significant difference in the hepatorenal function between LD group and LE group after treatment.
Conclusion: The combination of TAE and angiogenesis inhibitor donafenib resulted in a potentiated tumoricidal effect, anti-angiogenesis and antitumour T cell response in rabbit VX2 liver tumor model. This may provide a potential basis for exploring the immune-related mechanisms of embolization in liver cancer.
Keywords: liver cancer, transcatheter arterial embolization, donafenib, tumor angiogenesis, immune response
中文翻译：
含有多纳非尼的经导管动脉栓塞诱导兔 VX2 肝肿瘤中的抗血管生成和杀肿瘤 CD8+ T 细胞浸润
目的：评价经导管动脉栓塞术（TAE）联合多纳非尼对兔VX2肝肿瘤模型的疗效及免疫反应。
材料和方法：将36只患有VX2肝肿瘤的新西兰大白兔随机分为三组。LD组采用0.5 mL碘油和4 mg多那非尼乳剂经肝动脉给药治疗。LE组用0.5mL碘油和4mg表柔比星乳剂治疗。对照组给予等体积生理盐水。治疗后第1、3、7天各组4只兔实施安乐死。通过成像和组织病理学评估肿瘤生长、与血管生成和免疫反应相关的组织学标志物。此外，还检测了免疫调节细胞因子包括白细胞介素（IL）-6、肿瘤坏死因子（TNF）-α、干扰素（IFN）-γ，并测定了生化肝肾功能。
结果：与其他组相比，LD组在治疗后第7天肿瘤生长率较低，转移灶较少，肿瘤坏死率较高。LD组CD31阳性面积百分比在治疗后第3天和第7天明显低于LE组。此外，在治疗后第7天，LD组CD8 +淋巴细胞浸润比LE组更明显，无论是肿瘤还是邻近肝组织。在治疗后第 1 天，LD 组的血清细胞因子（包括 IL-6、TNF-α 和 IFN-γ）强烈上调。LD组与LE组治疗后肝肾功能差异无统计学意义。
结论：在兔 VX2 肝肿瘤模型中，TAE 和血管生成抑制剂多纳非尼的组合导致了增强的肿瘤杀伤作用、抗血管生成和抗肿瘤 T 细胞反应。这可能为探索肝癌栓塞的免疫相关机制提供潜在的基础。
关键词：肝癌，经导管动脉栓塞，多纳非尼，肿瘤血管生成，免疫反应
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