The VEGF angiogenic switch of. broblasts is regulated by MMP-7 from cancer cells
The VEGF angiogenic switch of. broblasts is regulated by MMP-7 from cancer cells
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DOI：
10.1038/sj.onc.1210535
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发表时间：
2007-11-08
期刊：
影响因子：
8
通讯作者：
Ochiai, A.
中科院分区：
文献类型：
--
作者：
Ito, T-K;Ishii, G.;Ochiai, A.
间质成纤维细胞产生的血管内皮生长因子(VEGF)在肿瘤血管生成中起重要作用。然而，正常组织成纤维细胞也表达血管内皮生长因子，这就提出了成纤维细胞的血管内皮生长因子活性是如何调节的问题。在此，我们报道了成纤维细胞潜在的血管生成活性被癌细胞激活，导致成纤维细胞来源的血管内皮生长因子的肿瘤选择性利用。人VA-13成纤维细胞通过产生血管内皮生长因子促进人胰腺癌Capan-1移植瘤的血管生成和生长，而单独的VA-13成纤维细胞不显示明显的血管生成。用基质金属蛋白酶-7(一种癌细胞特有的胞外蛋白水解酶)处理VA-13成纤维细胞上清液，可诱导内皮管形成。这一作用被抗血管内皮生长因子抗体或结缔组织生长因子(CTGF)所消除，此前有报道称，结缔组织生长因子可以隔离血管内皮生长因子，并被基质金属蛋白酶-7降解。抑制CAPAN-1细胞中的基质金属蛋白酶-7可取消VA-13成纤维细胞的肿瘤血管生成活性，这种活性可通过抑制VA-13成纤维细胞中的CTGF来恢复。我们进一步证明，这些触发血管生成的分子机制在人类原代成纤维细胞和人类大肠组织中是有效的。这些数据表明，成纤维细胞可能在细胞外环境中以潜伏状态储存血管内皮生长因子，以便紧急用于血管生成。
Vascular endothelial growth factor (VEGF) production by stromal fibroblasts plays an important role in tumor angiogenesis. However, VEGF is also expressed by normal tissue fibroblasts, raising the question of how the VEGF activity of fibroblasts is regulated. Here we report that the latent VEGF angiogenic activity of fibroblasts is activated by cancer cells, resulting in tumor-selective utilization of fibroblast-derived VEGF. Through the production of VEGF, human VA-13 fibroblasts promote angiogenesis in and growth of human pancreas cancer Capan-1 xenograft tumors, whereas VA-13 fibroblasts alone do not show significant angiogenesis. Treatment of VA-13 fibroblast supernatant with matrix metalloproteinase-7 (MMP- 7), an extracellular proteinase characteristically expressed by cancer cells, elicits endothelial tube formation. This effect is abrogated by anti-VEGF antibody or connective tissue growth factor (CTGF), which was previously reported to sequester VEGF and be degraded by MMP-7. Suppression of MMP-7 in Capan-1 cells abrogates the tumor angiogenic activity of VA-13 fibroblasts, which is restored by suppression of CTGF in VA-13 fibroblasts. We further show that these molecular mechanisms that trigger angiogenesis are effective in human primary fibroblasts and human colorectal tissue. These data suggest that fibroblasts may store VEGF in a latent state in the extracellular environment for urgent use in angiogenesis.