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Inhibition of tumor angiogenesis through chondromodulin-I gene transfer

通过软骨调节蛋白-I 基因转移抑制肿瘤血管生成

基本信息

批准号：
16591295
负责人：
OHTSUKA Masayuki
金额：
$ 2.18万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591295/
关键词：
chondromodulin-I angiogenesis gene transfer mTOR rapamycin lymphangiogenesis

项目摘要

In our first study, we examined whether insertion of chondoromodulin-I gene into the cancer tissue could inhibit tumor growth through the prevention of tumor angiogenesis. Chondoromodulin-I was identified as an angiogenesis inhibitor derived from extracts of fetal epiphyseal cartilage, which is normally devoided of capillary network. At present, although chondoromodulin-I protein was detected in vitro after transfection, the efficiency was not high after chondormodulin-I gene transfer with several vectors, especially in vivo. Therefore, inhibition of tumor growth and reduction of microvessel density were not significant. We are now developing a new vector to provide for efficient gene transfer.In our second study, we investigated the effect of rapamycin (inhibitor of mammalian target of rapamycin (mTOR)) on the proliferation activity of several cell lines including cancer cells and the expression of angiogenesis-related molecules such as vascular endothelial growth factor (VEGF) family, angiopoietin family. Tumor growth was also evaluated in vivo after administration of rapamycin. In vitro, the levels of VEGF-A mRNA and protein expressions were significantly decreased after treatment of rapamycin with even relatively low dose. In addition, the expression level of VEGF-C, which is a strong promoter of lymphangiogenesis, was also found to be down-regulated. In vivo, tumor growth was significantly inhibited. These results suggest that rapamycin could inhibit not only angiogenesis but also lymphangiogenesis. Based on these results, we are now investigating whether rapamycin could prevent lymph node metastasis by inhibiting cancer lymphangiogenesis.

在我们的第一项研究中，我们研究了在肿瘤组织中插入软骨调节蛋白-I基因是否可以通过阻止肿瘤血管生成来抑制肿瘤生长。软骨调节蛋白-I是从正常情况下不存在毛细血管网络的胎儿骨骺软骨中提取的一种血管生成抑制因子。目前，虽然在体外可以检测到软骨调节蛋白-I蛋白的表达，但通过几种载体转导软骨调节蛋白-I基因的效率并不高，尤其是在体内。因此，对肿瘤生长的抑制和微血管密度的降低并不明显。我们正在开发一种新的载体来提供有效的基因转移。在我们的第二项研究中，我们研究了雷帕霉素(雷帕霉素的哺乳动物靶点(MTOR)的抑制剂)对包括癌细胞在内的几种细胞株的增殖活性以及血管生成相关分子如血管内皮生长因子(VEGF)家族、血管生成素家族的表达的影响。给予雷帕霉素后，还评估了体内肿瘤生长情况。在体外，即使是相对较低剂量的雷帕霉素也能显著降低血管内皮生长因子-A的mRNA和蛋白表达水平。此外，作为淋巴管生成强促进剂的血管内皮生长因子-C的表达水平也下调。在体内，肿瘤生长受到明显抑制。提示雷帕霉素不仅能抑制血管生成，还能抑制淋巴管生成。基于这些结果，我们现在正在研究雷帕霉素是否可以通过抑制肿瘤淋巴管生成来防止淋巴转移。