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Suppression of tumor growth and metastasis via apoptosis induced specifically in endothelial cells by caspin/PEDF/EPC-1

Caspin/PEDF/EPC-1 通过特异性诱导内皮细胞凋亡来抑制肿瘤生长和转移

基本信息

批准号：
11670228
负责人：
SAGA Shinsuke
金额：
$ 2.5万
依托单位：
Aichi Medical University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670228/
关键词：
caspin PEDF EPC-1 apaptosis endothelial cell angiogenesis tumor growth tumor metastasis collagen 血管新生 deletion mutants 抗ヒトcaspin抗体

项目摘要

We investigated the physiological and pathophysiological roles of caspin/PEDF/EPC-1 in tumor growth and metastasis as an inhibitor of angiogenesis. Overexpression of caspin in murine and human cancer cell lines with a high capability of lung metastasis did not affect the cell growth in vitro, but did significantly suppress both tumor growth in vivo and lung metastasis. The density of microvessels was significantly reduced in tumors formed by s.c. inoculation of cancer cells when caspin was overexpressed, indicating that caspin can cause the inhibition of tumor angiogenesis. In addition, supplement of recombinant caspin in the cultures evidently inhibited ex vivo outgrowth of microvessels from excised rat aorta and in vitro growth of cultured endothelial cells in a dose-dependent manner. Furthermore, we found that caspin can induce apoptosis specifically in endothelial cells, but not in any other type of cultured cells. These findings suggest that caspin/PEDF/EPC-1 regulates angiogenesis by inducing apoptosis of endothelial cells. Thus, this protein might play a crucial role in important biological events, in which tissue reconstruction with prominent angiogenesis is essentially required, such as embryogenesis, wound healing, and the formation of granulation tissue as well as tumor growth and metastasis.

我们研究了Caspin/PEDF/EPC-1作为血管生成抑制剂在肿瘤生长和转移中的生理和病理生理作用。Caspin在小鼠和人肺癌细胞系中的过表达具有高的肺转移能力，在体外不影响细胞生长，但在体内显著抑制肿瘤生长和肺转移。微血管密度在s.c.形成的肿瘤中显著降低。接种癌细胞时，Caspin过表达，表明Caspin可引起肿瘤血管生成的抑制。此外，在培养物中添加重组半胱天冬肽明显抑制离体大鼠主动脉微血管的生长和培养的内皮细胞的体外生长，并呈剂量依赖性。此外，我们发现，半胱天冬肽可以诱导凋亡，特别是在内皮细胞，而不是在任何其他类型的培养细胞。这些结果表明，Caspin/PEDF/EPC-1通过诱导内皮细胞凋亡来调节血管生成。因此，这种蛋白质可能在重要的生物学事件中发挥至关重要的作用，其中基本上需要具有显著血管生成的组织重建，例如胚胎发生、伤口愈合和肉芽组织的形成以及肿瘤生长和转移。