间充质干细胞携带选择复制性腺病毒靶向肿瘤治疗的研究
摘要
研究背景和目的以腺病毒介导的基因治疗在肿瘤疾病治疗中取得了较大进展。既往,国内外学者通过对病毒结构的改造,如Fiber区,E1A区pRb结合位点,E1B区p53结合位点以及外原性增加特异性启动子等,使其获得了一定的选择感染性,选择复制性或者选择表达性。其目的在于仅杀伤肿瘤细胞,而对正常细胞无毒性作用。尽管如此,选择复制性腺病毒的应用和发展仍存在的一定局限性,主要表现在：(1)其在体内全身分布存在“器官隔绝”效应的“肝嗜性”；(2)宿主对其产生中和抗体而导致其被快速免疫清除。这些障碍导致了腺病毒的应用途径仅停留在局部注射阶段。静脉注射或其它全身给药方式导致绝大部分腺病毒要么被机体免疫系统清除,要么被滞留于肝脏。到达病灶局部的病毒量几乎微乎其微。治愈肿瘤性疾病不仅依赖于原位病灶的清除,更依赖于宿主全身无法通过局部给药方式清除的转移性病灶。
间充质干细胞(MSC)的研究已成为近年来一个热点。其在造血干细胞移植,移植物抗宿主免疫排斥反应(GVHD),组织损伤与修复,炎症反应,心肌梗死,神经细胞再生中发挥了重要作用。更为重要的是,其与肿瘤关系密切。肿瘤病灶由肿瘤实质与间质组成。有学者报道,其可归巢于肿瘤局部,作为肿瘤间质的前体细胞,参与肿瘤的组成。本研究旨在探索和研究间充质干细胞装载选择复制性腺病毒靶向归巢于肿瘤局部并发挥杀伤效应治疗肿瘤性疾病的思路和方式。为肿瘤性疾病病毒介导的基因治疗提供新的方向。
方法
1间充质干细胞平台的建立以及其携带与释放病毒的能力(1)密度梯度离心法联合贴壁剔除法自健康成人骨髓中分离获得间充质干细胞并行体外传代培养；(2)流式细胞技术及免疫荧光激光共聚焦显微镜鉴定其分子表面标记物表达情况；(3)应用条件培养基诱导细胞分化,阿辛蓝、茜素红及油红染色验证多向分化潜能；(4)流式细胞仪检测病毒转染能力,透射电镜观测细胞内病毒颗粒；(5)结晶紫染色检测病毒释放的时间依赖性与剂量依赖性关系；(6)50%组织培养感染剂量法(TCID50)检测释放病毒的滴度；(7)实时定量PCR检测病毒复制能力；(8)G显带技术分析转染选择复制性腺病毒后的MSCs染色体核型。
2体外验证MSC携带选择复制性腺病毒后对肿瘤细胞及正常细胞的杀伤能力(1)相差显微镜观察携带有选择复制性腺病毒的MSC对肿瘤细胞(MDA-MB-231, MDA-MB-435)及正常血管内皮细胞(HUVEC)产生细胞病变反应能力(CPE效应)：(2)原位杂交验证病毒在细胞中复制情况；(3)流式细胞仪检测MSC携带病毒引起的细胞凋亡分析；(4)免疫蛋白印迹技术(Western blot方法)检测靶细胞中Stat3及其下游通路信号分子的变化情况。
3体内验证间充质干细胞归巢能力(1)苏木素伊红染色验证裸鼠原位乳腺癌模型；(2)体外验证超顺磁性三氧化二铁颗粒(SPIO)对间充质干细胞标记浓度及效率(3)冰冻切片普鲁士蓝染色验证间充质干细胞体内归巢能力；(4)流式细胞仪检测细胞示踪剂(Cell tracker Red)对间充质干细胞的标记浓度及效率；(5)激光共聚焦显微镜观测携带选择复制性腺病毒后的间充质干细胞的归巢能力。
4体内验证间充质干细胞携带选择复制性腺病毒对肿瘤的靶向杀伤效应(1)定期测量各治疗组瘤体长径和短径,计算其瘤体大小；(2)免疫组织化学检测各组肿瘤组织Ki67及Cleaved Caspase3表达情况；(3)免疫蛋白印迹技术(Western blot方法)检测Stat3分子及下游分子的变化情况；(4)随访各治疗组老鼠生存预后情况。
结果
1.成功分离并培养人骨髓来源间充质干细胞；其阳性表面标记物CD44、CD90及CD105均有高于95%以上的表达,其阴性表面标记物CD34、CD45及CD19表达均低于5%；分离获得的间充质干细胞具有成骨、成脂以及成软骨等多向分化潜能；在高于500MOI滴度下,间充质干细胞具有高于90%以上的病毒转染效率；选择复制性腺病毒可在间充质干细胞中进行有效指数倍数扩增,并在96小时后完全释放。
2.经过间充质干细胞复制后释放出来病毒可在肿瘤细胞中复制,对肿瘤细胞产生明显细胞病变效应(CPE效应),并产生的一定诱导凋亡作用,且其凋亡率显著高于直接用相同初始病毒剂量产生的杀伤作用；这种杀伤作用与间充质干细胞和肿瘤细胞共培养的比例成正相关；与对照组相比,间充质干细胞携带病毒组对肿瘤细胞中Stat3、p-stat3及下游Survivin、Bcl-xl、C-myc分子均有明显下调作用。
3.间充质干细胞具有显著归巢于肿瘤组织的能力,24小时后主要分布于肿瘤组织边缘,72小时后主要分布于肿瘤实体内部。携带选择复制性腺病毒Adv-stat3(-)后的间充质干细胞仍具归巢能力,24小时,间充质干细胞主要分布于血流丰富的器官如肝、脾、肺。24小时后,肝、脾、肺组织中的间充质干细胞逐渐减少,而肿瘤组织中间充质干细胞数量明显增多。
4.与单独腺病毒组、MSC组及PBS组相比,间充质干细胞携带选择复制性腺病毒Adv-stat3(-)可通过在肿瘤局部抑制Ki67表达,增强Cleaved Caspase3,从而抑制肿瘤生长,诱导肿瘤细胞凋亡,明显提高小鼠生存时间。
结论间充质干细胞不仅可携带选择复制性腺病毒靶向肿瘤局部,并作为其复制扩增场所,抑制肿瘤细胞增殖,诱导肿瘤细胞凋亡。
Adenovirus-based gene therapy represented a promising treatment alternative for patients with malignant tumors. However, the treatment was temporarily abandoned due to toxicity of wild type adenovirus itself. With the discovery of recombinant DNA technology, it became possible to genetically engineer viruses, including E1A pRb binding region, E1B p53 binding region and fiber region to enhance its selective antitumoral potency. Even though, the replication-selective adenovirus was still hampered by the following reasons: first, intravenous and intraperitoneal injection results in considerable uptake of adenoviral vectors and gene expression in the liver; Second, rapid clearance of viruses by neutralizing antibody and complement occurred when systematically injected, all of which lead to minimal doses of adenovirus arriving at tumor mass or even metastasis.
Mesenchymal stem cell (MSC) is an attractive novel candidate in the present study which participates in nearly all of human diseases including hemopoietic stem cell (HSC) transplantation, acute graft-versus-host disease, tissue injury and recovery, inflammation and myocardial infarction. Recently, it was reported that MSC had the tropism of homing to tumor site and could selectively proliferate to tumors and contribute to the formation of tumor-associated stroma. In this study, we aimed to examine the feasibility of using human mesenchymal stem cells (MSC) to deliver a replication-competent oncolytic adenovirus (Adv-stat3 antisense) in a model of breast cancer.
We showed that MSC were efficiently infected with adenovirus type 5 at the concentration of above 500MOI. In addition, replication-selective adenovirus adv-stat3(-) could replicate more steadily than wild type adenovirus in the carrier cells of MSC and eventually release from it after 96 hours. MSC loaded with adv-stat3(-) caused significant tumor cell killing when cocultured with breast cancer cell lines of MDA-MB-231 and MDA-MB-435. Our study verifies the preferential tumor homing of MSC in an animal model of breast orthotopic tumor. In the first 24 hours after tail-vein injection, MSC was mainly distributed in liver, lung, spleen and the margin of tumor. After 48 hours, MSC could be mostly detected in the tumor parenchyma, especially nearly vasculature. The existence of MSC in liver, lung and spleen were found to decrease to a relative low level after 72 hours, while the amount of MSC in tumor parenchyma reached to a maximal level. In vivo study showed MSC-based delivery of the Adv-stat3(-) dramatically inhibited tumor growth compared with direct viral group, MSC group and PBS group. Follow-up observation demonstrated that injection of MSC loading with Adv-stat3(-) could increase survival rate of tumor-bearing mice compared to control groups. Taken together, these data indicates that MSC can serve as not only a cell carrier but also as a proliferating site for replicative-adenoviruses and suggests that the natural homing property of specific cell type can be used for targeted delivery of virus.
间充质干细胞(MSC)的研究已成为近年来一个热点。其在造血干细胞移植,移植物抗宿主免疫排斥反应(GVHD),组织损伤与修复,炎症反应,心肌梗死,神经细胞再生中发挥了重要作用。更为重要的是,其与肿瘤关系密切。肿瘤病灶由肿瘤实质与间质组成。有学者报道,其可归巢于肿瘤局部,作为肿瘤间质的前体细胞,参与肿瘤的组成。本研究旨在探索和研究间充质干细胞装载选择复制性腺病毒靶向归巢于肿瘤局部并发挥杀伤效应治疗肿瘤性疾病的思路和方式。为肿瘤性疾病病毒介导的基因治疗提供新的方向。
方法
1间充质干细胞平台的建立以及其携带与释放病毒的能力(1)密度梯度离心法联合贴壁剔除法自健康成人骨髓中分离获得间充质干细胞并行体外传代培养；(2)流式细胞技术及免疫荧光激光共聚焦显微镜鉴定其分子表面标记物表达情况；(3)应用条件培养基诱导细胞分化,阿辛蓝、茜素红及油红染色验证多向分化潜能；(4)流式细胞仪检测病毒转染能力,透射电镜观测细胞内病毒颗粒；(5)结晶紫染色检测病毒释放的时间依赖性与剂量依赖性关系；(6)50%组织培养感染剂量法(TCID50)检测释放病毒的滴度；(7)实时定量PCR检测病毒复制能力；(8)G显带技术分析转染选择复制性腺病毒后的MSCs染色体核型。
2体外验证MSC携带选择复制性腺病毒后对肿瘤细胞及正常细胞的杀伤能力(1)相差显微镜观察携带有选择复制性腺病毒的MSC对肿瘤细胞(MDA-MB-231, MDA-MB-435)及正常血管内皮细胞(HUVEC)产生细胞病变反应能力(CPE效应)：(2)原位杂交验证病毒在细胞中复制情况；(3)流式细胞仪检测MSC携带病毒引起的细胞凋亡分析；(4)免疫蛋白印迹技术(Western blot方法)检测靶细胞中Stat3及其下游通路信号分子的变化情况。
3体内验证间充质干细胞归巢能力(1)苏木素伊红染色验证裸鼠原位乳腺癌模型；(2)体外验证超顺磁性三氧化二铁颗粒(SPIO)对间充质干细胞标记浓度及效率(3)冰冻切片普鲁士蓝染色验证间充质干细胞体内归巢能力；(4)流式细胞仪检测细胞示踪剂(Cell tracker Red)对间充质干细胞的标记浓度及效率；(5)激光共聚焦显微镜观测携带选择复制性腺病毒后的间充质干细胞的归巢能力。
4体内验证间充质干细胞携带选择复制性腺病毒对肿瘤的靶向杀伤效应(1)定期测量各治疗组瘤体长径和短径,计算其瘤体大小；(2)免疫组织化学检测各组肿瘤组织Ki67及Cleaved Caspase3表达情况；(3)免疫蛋白印迹技术(Western blot方法)检测Stat3分子及下游分子的变化情况；(4)随访各治疗组老鼠生存预后情况。
结果
1.成功分离并培养人骨髓来源间充质干细胞；其阳性表面标记物CD44、CD90及CD105均有高于95%以上的表达,其阴性表面标记物CD34、CD45及CD19表达均低于5%；分离获得的间充质干细胞具有成骨、成脂以及成软骨等多向分化潜能；在高于500MOI滴度下,间充质干细胞具有高于90%以上的病毒转染效率；选择复制性腺病毒可在间充质干细胞中进行有效指数倍数扩增,并在96小时后完全释放。
2.经过间充质干细胞复制后释放出来病毒可在肿瘤细胞中复制,对肿瘤细胞产生明显细胞病变效应(CPE效应),并产生的一定诱导凋亡作用,且其凋亡率显著高于直接用相同初始病毒剂量产生的杀伤作用；这种杀伤作用与间充质干细胞和肿瘤细胞共培养的比例成正相关；与对照组相比,间充质干细胞携带病毒组对肿瘤细胞中Stat3、p-stat3及下游Survivin、Bcl-xl、C-myc分子均有明显下调作用。
3.间充质干细胞具有显著归巢于肿瘤组织的能力,24小时后主要分布于肿瘤组织边缘,72小时后主要分布于肿瘤实体内部。携带选择复制性腺病毒Adv-stat3(-)后的间充质干细胞仍具归巢能力,24小时,间充质干细胞主要分布于血流丰富的器官如肝、脾、肺。24小时后,肝、脾、肺组织中的间充质干细胞逐渐减少,而肿瘤组织中间充质干细胞数量明显增多。
4.与单独腺病毒组、MSC组及PBS组相比,间充质干细胞携带选择复制性腺病毒Adv-stat3(-)可通过在肿瘤局部抑制Ki67表达,增强Cleaved Caspase3,从而抑制肿瘤生长,诱导肿瘤细胞凋亡,明显提高小鼠生存时间。
结论间充质干细胞不仅可携带选择复制性腺病毒靶向肿瘤局部,并作为其复制扩增场所,抑制肿瘤细胞增殖,诱导肿瘤细胞凋亡。
Adenovirus-based gene therapy represented a promising treatment alternative for patients with malignant tumors. However, the treatment was temporarily abandoned due to toxicity of wild type adenovirus itself. With the discovery of recombinant DNA technology, it became possible to genetically engineer viruses, including E1A pRb binding region, E1B p53 binding region and fiber region to enhance its selective antitumoral potency. Even though, the replication-selective adenovirus was still hampered by the following reasons: first, intravenous and intraperitoneal injection results in considerable uptake of adenoviral vectors and gene expression in the liver; Second, rapid clearance of viruses by neutralizing antibody and complement occurred when systematically injected, all of which lead to minimal doses of adenovirus arriving at tumor mass or even metastasis.
Mesenchymal stem cell (MSC) is an attractive novel candidate in the present study which participates in nearly all of human diseases including hemopoietic stem cell (HSC) transplantation, acute graft-versus-host disease, tissue injury and recovery, inflammation and myocardial infarction. Recently, it was reported that MSC had the tropism of homing to tumor site and could selectively proliferate to tumors and contribute to the formation of tumor-associated stroma. In this study, we aimed to examine the feasibility of using human mesenchymal stem cells (MSC) to deliver a replication-competent oncolytic adenovirus (Adv-stat3 antisense) in a model of breast cancer.
We showed that MSC were efficiently infected with adenovirus type 5 at the concentration of above 500MOI. In addition, replication-selective adenovirus adv-stat3(-) could replicate more steadily than wild type adenovirus in the carrier cells of MSC and eventually release from it after 96 hours. MSC loaded with adv-stat3(-) caused significant tumor cell killing when cocultured with breast cancer cell lines of MDA-MB-231 and MDA-MB-435. Our study verifies the preferential tumor homing of MSC in an animal model of breast orthotopic tumor. In the first 24 hours after tail-vein injection, MSC was mainly distributed in liver, lung, spleen and the margin of tumor. After 48 hours, MSC could be mostly detected in the tumor parenchyma, especially nearly vasculature. The existence of MSC in liver, lung and spleen were found to decrease to a relative low level after 72 hours, while the amount of MSC in tumor parenchyma reached to a maximal level. In vivo study showed MSC-based delivery of the Adv-stat3(-) dramatically inhibited tumor growth compared with direct viral group, MSC group and PBS group. Follow-up observation demonstrated that injection of MSC loading with Adv-stat3(-) could increase survival rate of tumor-bearing mice compared to control groups. Taken together, these data indicates that MSC can serve as not only a cell carrier but also as a proliferating site for replicative-adenoviruses and suggests that the natural homing property of specific cell type can be used for targeted delivery of virus.
引文
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