大肠癌细胞系SW620的肿瘤干细胞研究及原代大肠肿瘤的靶向性促凋亡基因治疗研究
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摘要
第一部分摘要：研究表明,CD133在许多肿瘤(包括大肠癌肿瘤)中都被证实为肿瘤干细胞的标记,O'Brien和Ricci等人通过原代大肠癌的肿瘤研究证实大肠癌的肿瘤起始细胞为CD133阳性标记群体,CD133阳性细胞最终决定了肿瘤的生长、复发、转移及耐药。然而,通过使用LacZ基因敲除小鼠模型,Shmelkov等人对这种被日益接受的观点提出了质疑。Shmelkov等人主要提出两个不同观点：首先,他们认为CD133广泛表达于人或老鼠的大肠癌细胞群体内,而非仅限于一小部分所谓的干细胞群体内。第二,CD133阴性肿瘤细胞也能在裸鼠体内诱发肿瘤,并且其具有更加强大的远处转移能力。基于以上两个相互背离的观点,我们认为,CD133在肿瘤细胞内的表达与干细胞特性之间可能存在定量关系而非绝对单一的定性关系。定量分析CD133在肿瘤细胞内的表达也许会更好的揭示CD133与肿瘤干细胞之间的关系。为了证实这种关系的存在,我们选择大肠癌细胞系SW620进行培养并用免疫磁珠分选的技术方法将其分为CD133高表达(CD133Hi),CD133中表达(CD133Mid)及CD133低表达(CD133Low)三组并进行体内接种及体外培养研究。研究结果显示CD133高表达组的肿瘤细胞在体内外的生长活性更加强大旺盛,证实肿瘤干细胞(肿瘤起始细胞)与CD133的表达强度存在正相关关系。CD133的高表达也许可以作为筛选肿瘤干细胞的指标之一
第二部分摘要：肿瘤坏死因子相关凋亡诱导配体(TRAIL)是肿瘤坏死因子(tumor necrosis factor,TNF)家族成员,很多研究发现体外实验及静脉注射重组TRAIL蛋白能够诱导肿瘤细胞凋亡,抑制肿瘤增殖,提高荷瘤动物的生存率而不引起毒性反应。同时,其对体内正常组织却不产生或仅产生微弱的毒副作用。之后很多研究者以腺病毒作为载体,将TRAIL基因直接转染到肿瘤细胞中,发现这种基因治疗方法同样可以诱导肿瘤细胞凋亡,抑制肿瘤的生长。目前认为TRAIL诱导凋亡机制主要是与死亡受体DR4或DR5结合并活化死亡受体,激活Caspase-8引发和传导凋亡信号,再进一步激活Caspase-3蛋白酶级联反应诱发TRAIL诱导的凋亡。但已有文献报导,一些细胞系对单独TRAIL的治疗已经产生抗药性,而与化疗药联合应用可以一定程度地降低耐药性的发生。为了观察靶向基因药物TRAIL与化疗药联合应用提高肿瘤细胞敏感性,降低耐药性的的可行性,本研究探讨了重组腺病毒载体介导的TRAIL基因制剂Ad/gTRAIL)与化疗药物Taxol、5-Fu等联合应用对原代大肠癌细胞的作用,同时还探讨了该种治疗模式在原代大肠癌裸鼠荷瘤模型中的联合治疗效应。通过检测不同处理组内肿瘤细胞TRAIL, DR4,Caspase-3,Caspase-8及凋亡发生率来验证可能的TRAIL抑制肿瘤细胞生长的机制。本研究的结果显示,经Ad/TRAIL药物治疗后单药组及联合用药组肿瘤细胞内TRAIL蛋白相对于其他对照组表达增高从而发挥抗肿瘤作用。组化结果显示各处理组肿瘤组织中处于TRAIL凋亡通路最下游的Caspase-3均有表达,而以含TRAIL药物组癌组织中Caspase-3表达明显增高,反映出在相应药物处理作用下,癌细胞Caspase凋亡通路受到激活,促凋亡产物得以明显提升。凋亡染色结果说明,通过瘤内注射Ad/TRAIL时,致使Ad/TRAIL接触到的肿瘤腺体发生Ad/TRAIL感染及旁观者效应导致肿瘤腺体的彻底崩解,使肿瘤得到有效杀伤。通过裸鼠体内瘤体接种实验及生存率曲线分析显示,药物处理组的裸鼠平均瘤体生长较慢,裸鼠生存率较长,从体外实验角度支持TRAIL药物的抗肿瘤活性。各实验组裸鼠重要脏器均未见明显异常,显示TRAIL的药物毒性并不明显。本研究的结果阐明了由hTERT启动子驱动的TRAIL基因产物对直接取自肿瘤患者的原代培养肿瘤细胞的药理学和毒性作用,更加完善了Ad/hTERT-gTRAIL作为新型基因治疗药物在直接应用于患者身体前的适用性的理论体系,为临床应用TRAIL基因治疗肿瘤提供了模拟临床的抗肿瘤理论和科学依据。
Part 1:CD133 is regarded as one marker of tumor initiating cells in many tumors including colorectal cancer. O'Brien and Ricci et al. have proved in primary colorectal tumors that there being colorectal tumor stem cells (initiating cells) which are marked by CD 133 antigen, and the tumor initiating cells are responsible for tumor proliferation, recurrence, metastasis and drug resistance. Using a genetic knockin lacZ reporter mouse model, Shmelkov et al. challenged this increasingly influential viewpoint and drew two important conclusions oppugning the former opinions. First, CD133 is widely distributed throughout the full range of tumor epithelial cells in colon other than limited in a few cells. Second, CD 133 negative cells of colon tumors are also tumorigenic and are more inclined to metastasize. Based on the two distinct opinions, we assume that the expression of CD133 is different among the tumor cells and the quantitative but not qualitative analyses of CD 133 abundance are necessary to determine the relationship between CD133 expression and tumor stem cell characteristics. To verify this hypothesis, colorectal cancer cell line SW620 was cultured and sorted into CD133Hi, CD133Mid and CD133Low subgroups using magnetic microbeads to compare their xenograft biological characteristics. The results showed that the CD133Hi subgroup of SW620 is more close to the tumor initiating cells in biological characteristics than CD133Mid and CD133low subgroups, but the CD133low subgroup still keep the ability of tumorigenicity. It supported that tumor initiating cells are more correlated to the abundance of CD 133.
Part 2:Tumour necrosis factor-related apoptosis-inducing ligand or Apo2 ligand (TRAIL/Apo2L) is a member of the tumour necrosis factor (TNF) superfamily of cytokines that induces apoptosis upon binding to its death domain-containing transmembrane receptors, death receptors 4 and 5 (DR4, DR5), and then activate caspase-8 by death domain to induce apoptosis in tumor cells. In the meantime, TRAIL preferentially induces apoptosis in cancer cells while exhibiting little or no toxicity in normal cells. Many researches demonstrated that TRAIL delivered by adenovirus can induce apoptosis and suppress growth in a wide range of tumor cell lines in in vivo and in vitro circumstances. But recent findings report TRAIL resistance in some cell lines requiring combined treatments with sensitizing agents as standard chemotherapeutics can enhance tumor cells sensitivity to TRAIL. To assess whether combination of targeted gene agent TRAIL with chemo agent (5-Fu and TAXOL) can enhance the sensitivity of tumor cells to TRAIL as well as decrease TRAIL resistance, we detect the treatment of recombinant adenoviral vector expressing the TRAIL protein(Ad/TRAIL) in combination with chemotherapeutic drug 5-Fu or TAXOL to primary colorectal cancer tumors ex vivo an in vivo, and the Synergetic effects in nude mice tumor xenograft model. By detecting the expression of TRAIL, DR4, caspase-3, caspase-8 and tumor apoptosis rate, we can realize the possible anti-cancer mechanism of TRAIL. The immunohistochemical results show high expression of TRAIL protein and high expression of caspase-3 in the end pathway of TRAIL induced apoptosis in subgroups containing Ad/TRAIL. It reflects that caspase related apoptosis pathway is activated by TRAIL which led to increase of apoptosis product. The TUNUL staining show us that tumor cells infected with Ad/TRAIL collapse or fall in apoptosis by direct infection or by bystander effect. The in vivo experiments indicate that tumor grows slowly in treatment groups than in control groups and the tumor-bearing mice in treatment groups suvive longer than in control groups. The combination of Ad/TRAIL and chemotherapeutics will significantly increased survival rate compared to the control mice or mice receiving Ad-/TRAIL alone. All the results abovementioned support the anti-tumor characters of Ad/TRAIL agent. No obvious side effects were found showing mild damage to normal cells of the body. Our findings demonstrate that Ad/TRAIL gene products activated by promoter hTERT exert effective therapeutic and toxic effects to primary colorectal tumor cells and will exhibit robust tumoricidal activity against human primary tumors in clinical practice with minimal toxic side effects.
第二部分摘要：肿瘤坏死因子相关凋亡诱导配体(TRAIL)是肿瘤坏死因子(tumor necrosis factor,TNF)家族成员,很多研究发现体外实验及静脉注射重组TRAIL蛋白能够诱导肿瘤细胞凋亡,抑制肿瘤增殖,提高荷瘤动物的生存率而不引起毒性反应。同时,其对体内正常组织却不产生或仅产生微弱的毒副作用。之后很多研究者以腺病毒作为载体,将TRAIL基因直接转染到肿瘤细胞中,发现这种基因治疗方法同样可以诱导肿瘤细胞凋亡,抑制肿瘤的生长。目前认为TRAIL诱导凋亡机制主要是与死亡受体DR4或DR5结合并活化死亡受体,激活Caspase-8引发和传导凋亡信号,再进一步激活Caspase-3蛋白酶级联反应诱发TRAIL诱导的凋亡。但已有文献报导,一些细胞系对单独TRAIL的治疗已经产生抗药性,而与化疗药联合应用可以一定程度地降低耐药性的发生。为了观察靶向基因药物TRAIL与化疗药联合应用提高肿瘤细胞敏感性,降低耐药性的的可行性,本研究探讨了重组腺病毒载体介导的TRAIL基因制剂Ad/gTRAIL)与化疗药物Taxol、5-Fu等联合应用对原代大肠癌细胞的作用,同时还探讨了该种治疗模式在原代大肠癌裸鼠荷瘤模型中的联合治疗效应。通过检测不同处理组内肿瘤细胞TRAIL, DR4,Caspase-3,Caspase-8及凋亡发生率来验证可能的TRAIL抑制肿瘤细胞生长的机制。本研究的结果显示,经Ad/TRAIL药物治疗后单药组及联合用药组肿瘤细胞内TRAIL蛋白相对于其他对照组表达增高从而发挥抗肿瘤作用。组化结果显示各处理组肿瘤组织中处于TRAIL凋亡通路最下游的Caspase-3均有表达,而以含TRAIL药物组癌组织中Caspase-3表达明显增高,反映出在相应药物处理作用下,癌细胞Caspase凋亡通路受到激活,促凋亡产物得以明显提升。凋亡染色结果说明,通过瘤内注射Ad/TRAIL时,致使Ad/TRAIL接触到的肿瘤腺体发生Ad/TRAIL感染及旁观者效应导致肿瘤腺体的彻底崩解,使肿瘤得到有效杀伤。通过裸鼠体内瘤体接种实验及生存率曲线分析显示,药物处理组的裸鼠平均瘤体生长较慢,裸鼠生存率较长,从体外实验角度支持TRAIL药物的抗肿瘤活性。各实验组裸鼠重要脏器均未见明显异常,显示TRAIL的药物毒性并不明显。本研究的结果阐明了由hTERT启动子驱动的TRAIL基因产物对直接取自肿瘤患者的原代培养肿瘤细胞的药理学和毒性作用,更加完善了Ad/hTERT-gTRAIL作为新型基因治疗药物在直接应用于患者身体前的适用性的理论体系,为临床应用TRAIL基因治疗肿瘤提供了模拟临床的抗肿瘤理论和科学依据。
Part 1:CD133 is regarded as one marker of tumor initiating cells in many tumors including colorectal cancer. O'Brien and Ricci et al. have proved in primary colorectal tumors that there being colorectal tumor stem cells (initiating cells) which are marked by CD 133 antigen, and the tumor initiating cells are responsible for tumor proliferation, recurrence, metastasis and drug resistance. Using a genetic knockin lacZ reporter mouse model, Shmelkov et al. challenged this increasingly influential viewpoint and drew two important conclusions oppugning the former opinions. First, CD133 is widely distributed throughout the full range of tumor epithelial cells in colon other than limited in a few cells. Second, CD 133 negative cells of colon tumors are also tumorigenic and are more inclined to metastasize. Based on the two distinct opinions, we assume that the expression of CD133 is different among the tumor cells and the quantitative but not qualitative analyses of CD 133 abundance are necessary to determine the relationship between CD133 expression and tumor stem cell characteristics. To verify this hypothesis, colorectal cancer cell line SW620 was cultured and sorted into CD133Hi, CD133Mid and CD133Low subgroups using magnetic microbeads to compare their xenograft biological characteristics. The results showed that the CD133Hi subgroup of SW620 is more close to the tumor initiating cells in biological characteristics than CD133Mid and CD133low subgroups, but the CD133low subgroup still keep the ability of tumorigenicity. It supported that tumor initiating cells are more correlated to the abundance of CD 133.
Part 2:Tumour necrosis factor-related apoptosis-inducing ligand or Apo2 ligand (TRAIL/Apo2L) is a member of the tumour necrosis factor (TNF) superfamily of cytokines that induces apoptosis upon binding to its death domain-containing transmembrane receptors, death receptors 4 and 5 (DR4, DR5), and then activate caspase-8 by death domain to induce apoptosis in tumor cells. In the meantime, TRAIL preferentially induces apoptosis in cancer cells while exhibiting little or no toxicity in normal cells. Many researches demonstrated that TRAIL delivered by adenovirus can induce apoptosis and suppress growth in a wide range of tumor cell lines in in vivo and in vitro circumstances. But recent findings report TRAIL resistance in some cell lines requiring combined treatments with sensitizing agents as standard chemotherapeutics can enhance tumor cells sensitivity to TRAIL. To assess whether combination of targeted gene agent TRAIL with chemo agent (5-Fu and TAXOL) can enhance the sensitivity of tumor cells to TRAIL as well as decrease TRAIL resistance, we detect the treatment of recombinant adenoviral vector expressing the TRAIL protein(Ad/TRAIL) in combination with chemotherapeutic drug 5-Fu or TAXOL to primary colorectal cancer tumors ex vivo an in vivo, and the Synergetic effects in nude mice tumor xenograft model. By detecting the expression of TRAIL, DR4, caspase-3, caspase-8 and tumor apoptosis rate, we can realize the possible anti-cancer mechanism of TRAIL. The immunohistochemical results show high expression of TRAIL protein and high expression of caspase-3 in the end pathway of TRAIL induced apoptosis in subgroups containing Ad/TRAIL. It reflects that caspase related apoptosis pathway is activated by TRAIL which led to increase of apoptosis product. The TUNUL staining show us that tumor cells infected with Ad/TRAIL collapse or fall in apoptosis by direct infection or by bystander effect. The in vivo experiments indicate that tumor grows slowly in treatment groups than in control groups and the tumor-bearing mice in treatment groups suvive longer than in control groups. The combination of Ad/TRAIL and chemotherapeutics will significantly increased survival rate compared to the control mice or mice receiving Ad-/TRAIL alone. All the results abovementioned support the anti-tumor characters of Ad/TRAIL agent. No obvious side effects were found showing mild damage to normal cells of the body. Our findings demonstrate that Ad/TRAIL gene products activated by promoter hTERT exert effective therapeutic and toxic effects to primary colorectal tumor cells and will exhibit robust tumoricidal activity against human primary tumors in clinical practice with minimal toxic side effects.
引文
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