Ito T-K, Ishii G, Chiba H, Ochiai A
Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa-City, Chiba, Japan.
Oncogene. 2007 Nov 8;26(51):7194-203. doi: 10.1038/sj.onc.1210535. Epub 2007 May 21.
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.
基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VEGF，这就引发了成纤维细胞的VEGF活性如何被调节的问题。在此我们报告，成纤维细胞潜在的VEGF血管生成活性被癌细胞激活，导致肿瘤选择性利用成纤维细胞衍生的VEGF。通过产生VEGF，人VA - 13成纤维细胞促进人胰腺癌Capan - 1异种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（MMP - 7，一种癌细胞特征性表达的细胞外蛋白酶）处理VA - 13成纤维细胞的上清液，可引发内皮管形成。抗VEGF抗体或结缔组织生长因子（CTGF，先前报道其可螯合VEGF并被MMP - 7降解）可消除这种作用。抑制Capan - 1细胞中的MMP - 7可消除VA - 13成纤维细胞的肿瘤血管生成活性，而抑制VA - 13成纤维细胞中的CTGF可恢复该活性。我们进一步表明，这些触发血管生成的分子机制在人原代成纤维细胞和人大肠组织中有效。这些数据表明，成纤维细胞可能在细胞外环境中将VEGF以潜伏状态储存起来，以备血管生成时紧急使用。
