Development of iPS cells-derived vector cells for antiangiogenic gene therapy for hepatocellular carcinoma.

开发 iPS 细胞衍生的载体细胞，用于肝细胞癌的抗血管生成基因治疗。

基本信息

批准号：
22590752
负责人：
TORIMURA Takuji
金额：
$ 2.91万
依托单位：
Kurume University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

项目摘要

In the present study, we investigated the anti-tumor effects of anti-angiogenic gene therapy with iPS cell-derived vector cells transfected soluble VEGF receptor-1 and 2 cDNAs. At first, we tried to develop the vector cells from mouse iPS cells. However, mouse iPS cell-derived smooth cells showed less proliferative activity and less homing to tumor tissues than we had expected. So, we changed to construct mesenchymal stem cells from human iPS cells. After constructing mesenchymal stem cells, we transferred CXCR4 cDNA to mesenchymal stem cells to up-regulate the ability of homing to tumor tissues. As vector cells might produce several kinds of growth factors through the activation of HIF signaling under hypoxic condition in tumor tissues, we reduced the expression of HIF1-?? with siRNA technique. Then, we transferred soluble VEGFreceptor-1 and 2 cDNAs with adenovirus vector and injected the vector cells (1x106/week for4 weeks) to tumor-bearing mice of hepatoma cells through the til vein. After 4 weeks of initial treatment, tumor growth was suppressed comparing with non-treated control mice. Injected vector cells mainly located in the stroma of tumor tissues. Some of vector cellsdifferentiated to endothelial cells and smooth muscle cells in tumor tissues. The microvascular density in tumor tissues was decreased comparing with control group. The homing of vector cells to non-cancerous tissues was rarely detected. Severe adverse events such as bone marrow suppression or abnormality of liver function test were not observed.

在本研究中，我们研究了IPS细胞衍生的载体细胞转染的可溶性VEGF受体1和2 cDNA的抗血管生成基因治疗的抗肿瘤作用。首先，我们尝试从小鼠IPS细胞开发载体细胞。然而，小鼠IPS细胞衍生的光滑细胞的增殖活性较小，对肿瘤组织的归巢比我们预期的要少。因此，我们更改为构建人IPS细胞的间充质干细胞。构建间充质干细胞后，我们将CXCR4 cDNA转移到间充质干细胞上，以上调节饲养肿瘤组织的能力。由于载体细胞可能通过在肿瘤组织缺氧条件下激活HIF信号传导产生几种生长因子，因此我们降低了HIF1-的表达。使用siRNA技术。然后，我们用腺病毒载体将可溶性蔬菜受体1和2 cDNA转移，并通过TIL静脉将载体细胞（1x106/周）注射到肝癌细胞的肿瘤小鼠。初次治疗4周后，与未处理的对照小鼠相比，抑制了肿瘤生长。注射的载体细胞主要位于肿瘤组织的基质中。一些载体细胞分化为肿瘤组织中的内皮细胞和平滑肌细胞。与对照组相比，肿瘤组织中的微血管密度降低。很少检测到载体细胞向非癌组织的归纳。未观察到严重的不良事件，例如骨髓抑制或肝功能测试异常。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Antiangiogenic mechanisms of aflibercept in mouse hepatoma model

阿柏西普在小鼠肝癌模型中的抗血管生成机制

DOI：
发表时间：
2011
期刊：
影响因子：
0
作者：
Nobuhiro Aizawa;Hirayuki Enomoto;Yuji Iimuro;Jiro Fujimoto;Shuhei Nishiguch;Nakano M Takahashi Het al.(他6名);新関敬;會澤信弘;Torimura Takuji;Nakamura M;會澤信弘;Takuji Torimura
通讯作者：
Takuji Torimura

肝細胞癌を用いた作用機序の異なる血管新生阻害療法の比較:メトロノミックケモラピーとVEGFR-2リン酸化阻害剤の比較.

不同作用机制的抗血管生成疗法治疗肝细胞癌的比较：节拍化疗与 VEGFR-2 磷酸化抑制剂的比较。