Lee Do-Hun, Ahn Yong, Kim Seung U, Wang Kyu-Chang, Cho Byung-Kyu, Phi Ji Hoon, Park In Ho, Black Peter M, Carroll Rona S, Lee Joonyub, Kim Seung-Ki
Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, Korea.
Clin Cancer Res. 2009 Aug 1;15(15):4925-34. doi: 10.1158/1078-0432.CCR-08-3076. Epub 2009 Jul 28.
Brainstem gliomas are usually inoperable and have a dismal prognosis. Based on the robust tropisms of neural stem cells (NSC) and mesenchymal stem cells (MSC) to brain tumors, we compared the tumor-tropic migratory capacities of these stem cells and evaluated the therapeutic potential of genetically engineered human NSCs encoding cytosine deaminase (CD) and IFNbeta against brainstem gliomas.
The directed migratory capacities of NSCs and MSCs to brainstem glioma (F98) were evaluated both in vitro and in vivo. The human NSCs (HB1.F3) and various human MSCs, such as bone marrow-derived MSCs (HM3.B10), adipose tissue-derived MSCs, and umbilical cord blood-derived MSCs, were tested. Human fibroblast cells (HFF-1) were used as the negative control. As a proof of concept, the bioactivity of HB1.F3-CD-IFNbeta was analyzed with a cell viability assay, and animals with brainstem gliomas were injected with HB1.F3-CD-IFNbeta cells followed by systemic 5-fluorocytosine treatment.
In an in vitro modified Transwell migration assay and in vivo stem cell injection into established brainstem gliomas in rats, all the stem cells showed a significant migratory capacity compared with that of the control (P < 0.01). Histologic analysis showed a 59% reduction in tumor volume in the HB1.F3-CD-IFNbeta-treated group (P < 0.05). Apoptotic cells were increased 2.33-fold in animals treated with HB1.F3-CD-IFNbeta compared with the respective control groups (P < 0.01).
The brainstem glioma-tropic migratory capacities of MSCs from various sources were similar to those of NSCs. Genetically engineered NSCs show therapeutic efficacy against brainstem gliomas.
脑干胶质瘤通常无法进行手术切除，预后较差。基于神经干细胞（NSC）和间充质干细胞（MSC）对脑肿瘤强大的趋向性，我们比较了这些干细胞的肿瘤趋向性迁移能力，并评估了编码胞嘧啶脱氨酶（CD）和干扰素β（IFNβ）的基因工程化人神经干细胞对脑干胶质瘤的治疗潜力。
在体外和体内评估神经干细胞和间充质干细胞对脑干胶质瘤（F98）的定向迁移能力。测试了人神经干细胞（HB1.F3）和各种人源间充质干细胞，如骨髓来源的间充质干细胞（HM3.B10）、脂肪组织来源的间充质干细胞和脐带血来源的间充质干细胞。人成纤维细胞（HFF-1）用作阴性对照。作为概念验证，通过细胞活力测定分析了HB1.F3-CD-IFNβ的生物活性，并对患有脑干胶质瘤的动物注射HB1.F3-CD-IFNβ细胞，随后进行全身性5-氟胞嘧啶治疗。
在体外改良的Transwell迁移试验以及将干细胞注射到大鼠已形成的脑干胶质瘤体内的实验中，与对照组相比，所有干细胞均显示出显著的迁移能力（P < 0.01）。组织学分析显示，HB1.F3-CD-IFNβ治疗组的肿瘤体积减少了59%（P < 0.05）。与各自的对照组相比，接受HB1.F3-CD-IFNβ治疗的动物体内凋亡细胞增加了2.33倍（P < 0.01）。
各种来源的间充质干细胞对脑干胶质瘤的趋向性迁移能力与神经干细胞相似。基因工程化神经干细胞对脑干胶质瘤显示出治疗效果。
