Extracellular matrix metalloproteinase inducer stimulates tumor angiogenesis by elevating vascular endothelial cell growth factor and matrix metal loproteinases
Extracellular matrix metalloproteinase inducer stimulates tumor angiogenesis by elevating vascular endothelial cell growth factor and matrix metal loproteinases
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DOI：
10.1158/0008-5472.can-04-3605
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发表时间：
2005-04-15
期刊：
影响因子：
11.2
通讯作者：
Yan, L
中科院分区：
文献类型：
--
作者：
Tang, Y;Nakada, MT;Yan, L
基质金属蛋白酶（MMP）是内肽酶，在促进肿瘤疾病进展（包括肿瘤血管生成）中发挥关键作用。在许多实体瘤中，MMP 表达可归因于肿瘤基质细胞，并且通过肿瘤细胞相关的细胞外基质金属蛋白酶诱导物 (EMMPRIN) 部分受到肿瘤-基质相互作用的调节。通过使用重组DNA工程和中和抗体调节EMMPRIN表达和活性，探索了EMMPRIN在肿瘤血管生成和生长过程中的作用。在人类乳腺癌细胞中，EMMPRIN 表达的变化影响了 RNA 和蛋白质水平上血管内皮生长因子 (VEGF) 的产生。在模拟肿瘤-基质相互作用的肿瘤细胞和成纤维细胞的共培养中，VEGF 表达以 EMMPRIN 和 MMP 依赖性方式诱导，并通过过度表达 EMMPRIN 进一步增强。相反，通过抑制肿瘤细胞中的EMMPRIN表达、中和EMMPRIN活性或通过抑制MMP来抑制VEGF表达。在体内，EMMPRIN 过度表达刺激肿瘤血管生成和生长；两者均受到 EMMPRIN 反义抑制的显着抑制。分别源自肿瘤细胞和宿主细胞的人和小鼠 VEGF 和 MMP 的表达均受 EMMPRIN 调节。这些结果表明了一种新的肿瘤血管生成机制，其中肿瘤相关EMMPRIN功能性介导肿瘤-基质相互作用，并通过刺激VEGF和MMP表达直接促进肿瘤血管生成和生长。
Matrix metalloproteinases (MMPs) are endopeptidases that play pivotal roles in promoting tumor disease progression, including tumor angiogenesis. In many solid tumors, MMP expression could be attributed to tumor stromal cells and is partially regulated by tumor-stroma interactions via tumor cell-associated extracellular matrix metalloproteinase inducer (EMMPRIN). The role of EMMPRIN during tumor angiogenesis and growth was explored by modulating EMMPRIN expression and activity using recombinant DNA engineering and neutralizing antibodies. In human breast cancer cells, changes in EMMPRIN expression influenced vascular endothelial growth factor (VEGF) production at both RNA and protein levels. In coculture of tumor cells and fibroblasts mimicking tumor-stroma interactions, VEGF expression was induced in an EMMPRIN- and MMP-dependent fashion, and was further enhanced by over-expressing EMMPRIN. Conversely, VEGF expression was inhibited by suppressing EMMPRIN expression in tumor cells, by neutralizing EMMPRIN activity, or by inhibiting MMPs. In vivo, EMMPRIN overexpression stimulated tumor angiogenesis and growth; both were significantly inhibited by antisense suppression of EMMPRIN. Expression of both human and mouse VEGF and MMP, derived from tumor and host cells, respectively, was regulated by EMMPRIN. These results suggest a novel tumor angiogenesis mechanism in which tumor-associated EMMPRIN functionally mediates tumor-stroma interactions and directly contributes to tumor angiogenesis and growth by stimulating VEGF and MMP expression.