神经母细胞瘤细胞系原位荷瘤及转移瘤荷瘤鼠模型的建立及基因芯片差异表达的实验研究
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摘要
目的：用新鲜肿瘤组织，建立神经母细胞瘤体外细胞系，通过建立神经母细胞瘤荷瘤鼠原位荷瘤与转移瘤模型，比较二者差异，从而证明肿瘤异质性理论并进一步探讨神经母细胞瘤转移机制。
方法：分2批建立神经母细胞瘤荷瘤鼠模型，先利用从术中新鲜肿瘤标本建立人体外神经母细胞瘤细胞系，制备单细胞悬液，通过Typlan细胞计数法，调整细胞浓度为2.5×10~7／ml。接种于裸鼠(N=11)和SCID小鼠(N=3)皮下，建立荷瘤鼠原位荷瘤与转移瘤模型，再利用荷瘤鼠模型建立的鼠原位瘤体外细胞系及我们自建的人体外细胞系，再次接种于裸鼠(N=20)皮下(人细胞系N=8；鼠细胞系N=6)及腹腔(人细胞系N=6)，观察并比较致瘤情况。接种浓度均为2.5×10~7／ml的单细胞悬液0.5ml。
结果：裸鼠2批共接种34只，第一批接种14只，致瘤7只，其中单侧皮下致瘤3只，双侧腹膜后致瘤1只，全身转移有明显恶液质体征的裸鼠1只(有明显的肝脏转移和恶液质体征)，SCID鼠2只致瘤，其中1只单侧皮下致瘤，1只腹膜后双侧致瘤。即裸鼠(5／11)和SCID小鼠(N=2／3)荷瘤成功。以上均经过体格检查及CT和核磁共振病理检查证实。裸鼠致瘤率为45.5％，SCID鼠致瘤率为66.7％。致瘤时间最短4周，最长18周，平均9.5周；第二批接种20只，全部致瘤，其中鼠原位瘤体外细胞系皮下接种组6只仅接种局部致瘤，人体外细胞系皮下注射组则5只发生注射原位局部致瘤，3只发生肝脏或腹腔转移，腹腔接种6只均出现腹部脏器转移。所有转移瘤模型均有肝脏转移，均经病理证实。致瘤率为100％。致瘤时间最短4周，最长10周，平均7周。
结论：我们两次均成功建立神经母细胞瘤荷瘤鼠皮下原位荷瘤及转移瘤模型，同时转移瘤模型均有肝脏受累，证实我们自己建立的神经母细胞瘤细胞系具有局部致瘤及转移特性，并且转移具有器官特异性的特点，说明细胞系中存在具有转移潜性的细胞亚群，而此类细胞亚群正是肿瘤转移的细胞生物学基础，从而证明肿瘤异质性理论，为进一步探讨神经母细胞瘤转移机制奠定基础，并为下一步通过基因芯片寻找神经母细胞瘤转移相关基因创造了良好的开端。
目的：比较神经母细胞瘤荷瘤鼠模型原位瘤和转移瘤基因表达谱，寻找与神经母细胞瘤转移相关基因改变，深入探讨神经母细胞瘤的转移机制。
方法：采用SuperArray系列Oligo Tumor Metastasis Microarray基因芯片4张分3组对同一细胞系建立的荷瘤鼠模型原位瘤及转移瘤组织进行芯片杂交，检测发光信号，通过对图像和数据分析比较原位瘤与转移瘤的共同差异表达基因。
结果：在113个候选转移相关基因中，筛选出25个显著差异表达基因。功能涉及介导细胞黏附、凋亡及基质金属蛋白酶、细胞因子、细胞转录、细胞周期调节、细胞生长与增殖、凋亡诱导等方面。
结论：同一细胞系建立的荷瘤鼠模型转移瘤与原位瘤基因表达谱存在差异，提示这些基因可能与神经母细胞瘤转移特性密切相关，这些基因有可能成为神经母细胞瘤转移潜在的代表基因而值得进一步关注和深入研究。
Objective: By establishing the bear-tumor nude mice model of transplanted tumor in situ and metastatic tumor, heterogenicity of tumor theory is proved, and so, we can discuss the metastasis mechanism of neuroblastuma deeply.
Methods: Took the fresh tumor tissue from the patient under the sterilizing: situation during the operation, used the enzyme digestion method to establish the in vitro cell line. We inoculated the single cell suspension by the mode of hypodermic injection for 11 SPF nude mice and 3 SCID mice, established the bear-tumor nude mice model of local tumor in situ and metastatic tumor, then use the in vitro cell line of the bear-tumer nude mice model of local tumor in situ and the human in vitro cell line we had established to inoculate the single cell suspension by the mode of hypodermic injection for 14 nude mice and the mode of celiac injection for 6 nude mice. The injected dose is 0.5 ml in the consistence of 2.5×10~7/ml.
Results: We obtained the bear-cancer nude mice models (5/14) and the SCID mice models (2/3). There are two nude mice with metastasis all over the body, the others obtain the tumor at inoculated site. The second time all the nude mice totally bear tumor. In the human in vitro cell line hypodermic injection group, there are 5 nude mice wita metastasis, the others obtain the tumor at inoculated site; In the mouse in vitro cell line hypodermic injection group, all the 6 mice bear the tumor at inoculated site; in the human in vitro cell line celiac injection group , all the 6 nude mice are with metastasis in abdominal viscera. All were testified by pathology.
Conclusions: we successfully establish the bear-tumor mice model of local tumor in situ and metastatic tumor twice. It proved that our human in vitro cell line we had established has local oncogenesis and metastasis character, and metastasis is organ specific. So heterogenicity of tumor theory is proved. Our experiments can supply a very important basis for the further research to the metastasis mechanism of neuroblastuma.
Objective: By comparing gene expressions of the local tumor in situ with metastatic tumor of bear-tumor nude mice model, search the related metastatic gene.
Methods: 4 SuperArray series Oligo Tumor Metastasis Microarray were divided 3 group, hybridize the local tumor in situ and metastatic tumor of bear-tumor nude mice model, detect photogenesis signal, by analyzing image and data ,find the differential gene between the local tumor in situ and metastatic tumor.
Results: In 113 candidate gene, we screen 25 signifcant different expression genes between local tumor in situ and metastatic tumor of neuroblastoma, including Cell adhesion genes ;Apoptosis genes ;Cell cycle genes; Matrix metalloproteinases; Cell growth and proliferation genes; Apoptosis genes.
Conclusions: It exists significant difference in gene expression between local turnoi in situ and metastatic tumor of neuroblastoma that were established by the same cell line. these genes maybe closely correlate with neuroblastoma metastasis. These genes may be characteristic matastasis genes of neuroblatoma, so it's worth to advanced study.
方法：分2批建立神经母细胞瘤荷瘤鼠模型，先利用从术中新鲜肿瘤标本建立人体外神经母细胞瘤细胞系，制备单细胞悬液，通过Typlan细胞计数法，调整细胞浓度为2.5×10~7／ml。接种于裸鼠(N=11)和SCID小鼠(N=3)皮下，建立荷瘤鼠原位荷瘤与转移瘤模型，再利用荷瘤鼠模型建立的鼠原位瘤体外细胞系及我们自建的人体外细胞系，再次接种于裸鼠(N=20)皮下(人细胞系N=8；鼠细胞系N=6)及腹腔(人细胞系N=6)，观察并比较致瘤情况。接种浓度均为2.5×10~7／ml的单细胞悬液0.5ml。
结果：裸鼠2批共接种34只，第一批接种14只，致瘤7只，其中单侧皮下致瘤3只，双侧腹膜后致瘤1只，全身转移有明显恶液质体征的裸鼠1只(有明显的肝脏转移和恶液质体征)，SCID鼠2只致瘤，其中1只单侧皮下致瘤，1只腹膜后双侧致瘤。即裸鼠(5／11)和SCID小鼠(N=2／3)荷瘤成功。以上均经过体格检查及CT和核磁共振病理检查证实。裸鼠致瘤率为45.5％，SCID鼠致瘤率为66.7％。致瘤时间最短4周，最长18周，平均9.5周；第二批接种20只，全部致瘤，其中鼠原位瘤体外细胞系皮下接种组6只仅接种局部致瘤，人体外细胞系皮下注射组则5只发生注射原位局部致瘤，3只发生肝脏或腹腔转移，腹腔接种6只均出现腹部脏器转移。所有转移瘤模型均有肝脏转移，均经病理证实。致瘤率为100％。致瘤时间最短4周，最长10周，平均7周。
结论：我们两次均成功建立神经母细胞瘤荷瘤鼠皮下原位荷瘤及转移瘤模型，同时转移瘤模型均有肝脏受累，证实我们自己建立的神经母细胞瘤细胞系具有局部致瘤及转移特性，并且转移具有器官特异性的特点，说明细胞系中存在具有转移潜性的细胞亚群，而此类细胞亚群正是肿瘤转移的细胞生物学基础，从而证明肿瘤异质性理论，为进一步探讨神经母细胞瘤转移机制奠定基础，并为下一步通过基因芯片寻找神经母细胞瘤转移相关基因创造了良好的开端。
目的：比较神经母细胞瘤荷瘤鼠模型原位瘤和转移瘤基因表达谱，寻找与神经母细胞瘤转移相关基因改变，深入探讨神经母细胞瘤的转移机制。
方法：采用SuperArray系列Oligo Tumor Metastasis Microarray基因芯片4张分3组对同一细胞系建立的荷瘤鼠模型原位瘤及转移瘤组织进行芯片杂交，检测发光信号，通过对图像和数据分析比较原位瘤与转移瘤的共同差异表达基因。
结果：在113个候选转移相关基因中，筛选出25个显著差异表达基因。功能涉及介导细胞黏附、凋亡及基质金属蛋白酶、细胞因子、细胞转录、细胞周期调节、细胞生长与增殖、凋亡诱导等方面。
结论：同一细胞系建立的荷瘤鼠模型转移瘤与原位瘤基因表达谱存在差异，提示这些基因可能与神经母细胞瘤转移特性密切相关，这些基因有可能成为神经母细胞瘤转移潜在的代表基因而值得进一步关注和深入研究。
Objective: By establishing the bear-tumor nude mice model of transplanted tumor in situ and metastatic tumor, heterogenicity of tumor theory is proved, and so, we can discuss the metastasis mechanism of neuroblastuma deeply.
Methods: Took the fresh tumor tissue from the patient under the sterilizing: situation during the operation, used the enzyme digestion method to establish the in vitro cell line. We inoculated the single cell suspension by the mode of hypodermic injection for 11 SPF nude mice and 3 SCID mice, established the bear-tumor nude mice model of local tumor in situ and metastatic tumor, then use the in vitro cell line of the bear-tumer nude mice model of local tumor in situ and the human in vitro cell line we had established to inoculate the single cell suspension by the mode of hypodermic injection for 14 nude mice and the mode of celiac injection for 6 nude mice. The injected dose is 0.5 ml in the consistence of 2.5×10~7/ml.
Results: We obtained the bear-cancer nude mice models (5/14) and the SCID mice models (2/3). There are two nude mice with metastasis all over the body, the others obtain the tumor at inoculated site. The second time all the nude mice totally bear tumor. In the human in vitro cell line hypodermic injection group, there are 5 nude mice wita metastasis, the others obtain the tumor at inoculated site; In the mouse in vitro cell line hypodermic injection group, all the 6 mice bear the tumor at inoculated site; in the human in vitro cell line celiac injection group , all the 6 nude mice are with metastasis in abdominal viscera. All were testified by pathology.
Conclusions: we successfully establish the bear-tumor mice model of local tumor in situ and metastatic tumor twice. It proved that our human in vitro cell line we had established has local oncogenesis and metastasis character, and metastasis is organ specific. So heterogenicity of tumor theory is proved. Our experiments can supply a very important basis for the further research to the metastasis mechanism of neuroblastuma.
Objective: By comparing gene expressions of the local tumor in situ with metastatic tumor of bear-tumor nude mice model, search the related metastatic gene.
Methods: 4 SuperArray series Oligo Tumor Metastasis Microarray were divided 3 group, hybridize the local tumor in situ and metastatic tumor of bear-tumor nude mice model, detect photogenesis signal, by analyzing image and data ,find the differential gene between the local tumor in situ and metastatic tumor.
Results: In 113 candidate gene, we screen 25 signifcant different expression genes between local tumor in situ and metastatic tumor of neuroblastoma, including Cell adhesion genes ;Apoptosis genes ;Cell cycle genes; Matrix metalloproteinases; Cell growth and proliferation genes; Apoptosis genes.
Conclusions: It exists significant difference in gene expression between local turnoi in situ and metastatic tumor of neuroblastoma that were established by the same cell line. these genes maybe closely correlate with neuroblastoma metastasis. These genes may be characteristic matastasis genes of neuroblatoma, so it's worth to advanced study.
引文
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