Vascular endothelial growth factor stimulates organ-specific host matrix metalloproteinase-9 expression and ovarian cancer invasion
Vascular endothelial growth factor stimulates organ-specific host matrix metalloproteinase-9 expression and ovarian cancer invasion
复制标题
DOI：
10.1158/1541-7786.mcr-07-0366
复制
发表时间：
2008-04-01
影响因子：
5.2
通讯作者：
Tarabolettl, Giulia
中科院分区：
文献类型：
--
作者：
Belotti, Dorina;Calcagno, Catia;Tarabolettl, Giulia
血管内皮生长因子(VEGF)和基质金属蛋白酶(MMPs)相互调节，促进肿瘤的发展。我们以前曾报道过MMP9诱导肿瘤血管内皮生长因子的释放，促进人卵巢癌移植瘤腹水的形成。本研究的目的是探讨肿瘤来源的血管内皮生长因子是否通过基质调节明胶酶的表达，从而影响卵巢肿瘤的侵袭性。使用来源于1A9人卵巢癌的肿瘤变异体，稳定表达VEGF(121)的正义(1A9-vs-1)和反义定向(1A9-VAS-3)。在体内，对1A9-VS-1裸鼠腹膜移植瘤的酶谱分析显示，明胶酶水平较高，尤其是小鼠MMP9，表明血管内皮生长因子刺激宿主表达基质降解酶。小鼠MMP9在携带1A9-VS-1肿瘤的小鼠卵巢中的表达也很高。对宿主MMP9活性的影响是器官特异性的。卵巢中宿主原-MMP9水平与血浆肿瘤血管内皮生长因子水平及卵巢的选择性侵袭有关。宿主MMP9在肿瘤和卵巢中的表达诱导与肿瘤生长部位无关，这在携带腹膜内和皮下肿瘤的小鼠中可以看到。抗血管内皮生长因子抗体贝伐单抗(阿瓦斯丁)抑制MMP9在荷瘤小鼠卵巢中的表达和肿瘤侵袭。这些发现表明，在卵巢肿瘤的发展过程中，血管内皮生长因子和基质金属蛋白酶之间存在复杂的相互作用，并提示使用血管内皮生长因子抑制剂来影响依赖基质金属蛋白酶的肿瘤侵袭的可能性。
Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP) regulate each other, contributing to tumor progression. We have previously reported that MMP9 induces the release of tumor VEGF, promoting ascites formation in human ovarian carcinoma xenografts. The aim of this study was to investigate whether tumor-derived VEGF regulated the expression of gelatinase by the stroma, influencing the invasive properties of ovarian tumors. Tumor variants derived from 1A9 human ovarian carcinoma, stably expressing VEGF(121) in the sense (1A9-VS-1) and antisense orientations (1A9-VAS-3), were used. In vivo, zymographic analysis of tumors from 1A9-VS-1 implanted in the peritoneal cavity of nude mice showed higher levels of gelatinases, particularly murine MMP9, indicating that VEGF stimulates host expression of the matrix-degrading enzyme. Murine MMP9 expression was also high in the ovaries of mice bearing 1A9-VS-1 tumors. The effect on host MMP9 activity was organ-specific. The levels of host pro-MMP9 in ovaries correlated with the plasma levels of tumor VEGF and with the selective invasion of the ovaries. Induction of host MMP9 expression in tumors and ovaries was independent of the site of tumor growth as it was seen in mice carrying both intraperitoneal and subcutaneous tumors. The anti-VEGF antibody bevacizumab (Avastin) inhibited MMP9 expression and tumor invasion in the ovaries of mice bearing 1A9-VS-1 tumors. These findings point to a complex cross-talk between VEGF and MMPs in the progression of ovarian tumor and suggest the possibility of using VEGF inhibitors to affect MMP-dependent tumor invasion.