Gene Targeting Therapy against tumor endothelial cells

肿瘤是一种遗传性疾病，针对癌细胞的基因靶向治疗已经开展。然而，肿瘤基因的异常是复杂的，针对单基因产物的肿瘤治疗效率很难提高。另一方面，由于肿瘤间质新生血管对肿瘤的生存和生长至关重要，干扰新生血管的治疗在癌症治疗中将是有效的。有报道称，通过从口腔癌口腔移植模型中分离出肿瘤内皮细胞，肿瘤内皮细胞与正常内皮细胞相比具有不同的遗传特性。这些细胞表达CD34和CD131，经证实为内皮细胞。提取RNA，进行DNA微阵列，共鉴定出70个在肿瘤内皮细胞中上调的基因。用实时荧光定量RT-PCR、Western blotting和免疫组织化学方法证实了这些基因产物的表达。通过将siRNA导入肿瘤内皮细胞，抑制了细胞的增殖。此外，我们还发现COX-2抑制剂选择性地降低了肿瘤内皮细胞的运动和增殖活性，这些结果提示靶向肿瘤内皮细胞对肿瘤的有利治疗具有重要意义。

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.