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Gene Targeting Therapy against tumor endothelial cells

针对肿瘤内皮细胞的基因靶向治疗

基本信息

批准号：
18390530
负责人：
TOTSUKA Yasunori
金额：
$ 10.71万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390530/
关键词：
tumor endothelial cell human oral carcinoma human ranal carcinoma human lung carcinoma DNA microarray ヒト口腔癌

项目摘要

Tumor is a genetic disorder, and gene targeting therapy for cancer cells has been conducted. However, tumor gene abnormalities arre complicated, and it is quite difficult to improve efficiency of cancer treatment targeting single gene product.On the other hand, since neovasculization in tumor stroma is essential for tumor survival and Growth, therapy for disturbing neovasculaizaion would be effective in cancer therapy.It has been considered that the blood vessels in tumor stroma was composed of normal endothelial cells; however, Hida et al. have reported that tumor endothelial cells have genetically varied character compared to the normal endothelial cells by isolation of tumor endothelial cells from mouth xenograft models of human cancers.We established human tumor endothelial cells by using magnetic beads method from the operation materials of oral carcinoma, renal carcinoma and lung carcinoma. These cells express CD34 and CD131, and confirmed as endothelial cells. RNA was extracted and DNA microarray has been carried out, and we have identified 70 genes that were upregulated in tumor endothelial cells. We confirmed the expression of these gene product by real-time RT-PCR, Western blotting and immunohistochemisty. Proliferation of tumor endothelial cells was decreased by introducing siRNA into the cells. In addition, we found that motility and proliferative activity of tumor endothelial cells were selectively decreased by Cox-2 inhibitor treatment.These results imply the significance of targeting tumor endothelial cells for favorable cancer therapy.

肿瘤是一种遗传性疾病，针对肿瘤细胞的基因靶向治疗已经开展。然而，肿瘤基因异常复杂，针对单基因产物提高肿瘤治疗效率相当困难。另一方面，由于肿瘤基质的新生血管形成对肿瘤的生存和生长至关重要，因此干扰新生血管形成的治疗在癌症治疗中是有效的。一直认为肿瘤基质中的血管是由正常的内皮细胞组成的；然而，Hida等人通过从人类癌症口腔异种移植模型中分离肿瘤内皮细胞报道，与正常内皮细胞相比，肿瘤内皮细胞具有遗传变异特征。我们采用磁珠法从口腔癌、肾癌和肺癌的手术材料中建立人肿瘤内皮细胞。这些细胞表达CD34和CD131，证实为内皮细胞。提取RNA，进行DNA微阵列，鉴定出70个肿瘤内皮细胞中上调的基因。通过实时RT-PCR、Western blotting和免疫组织化学等方法证实了这些基因产物的表达。引入siRNA后，肿瘤内皮细胞的增殖能力下降。此外，我们发现Cox-2抑制剂可选择性地降低肿瘤内皮细胞的运动性和增殖活性。这些结果暗示了靶向肿瘤内皮细胞对肿瘤治疗的重要意义。