MMP13 as a stromal mediator in controlling persistent angiogenesis in skin carcinoma
MMP13 as a stromal mediator in controlling persistent angiogenesis in skin carcinoma
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DOI：
10.1093/carcin/bgp248
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发表时间：
2010-07-01
期刊：
影响因子：
4.7
通讯作者：
Mueller, Margareta M.
中科院分区：
文献类型：
--
作者：
Lederle, Wiltrud;Hartenstein, Bettina;Mueller, Margareta M.
基质金属蛋白酶（MMP）如MMP 13通过介导细胞外基质（ECM）重组和调节细胞因子的生物活性来促进肿瘤生长和进展。使用Mmp 13-/-小鼠，我们证明了这种单一的胶原酶在皮肤鳞状细胞癌（SCC）的高度恶性和侵袭性生长中的重要作用。宿主MMP 13的缺乏强烈损害了恶性SCC细胞的肿瘤生长，导致小的，主要是无血管的囊肿。虽然Mmp 13 +/+和Mmp 13-/-动物的肿瘤移植物中的初始基质活化是相似的，但MMP 13对于维持血管生成和侵袭是必不可少的。MMP 13在侵袭开始时在野生型动物的成纤维细胞中诱导，并且与血管内皮生长因子（VEGF）蛋白的强烈增加及其与侵袭区域中内皮细胞上的血管内皮生长因子受体2的关联相关。相比之下，基质中的VEGF蛋白几乎检测不到，尽管VEGF信使RNA表达持续，但Mmp 13-/-动物的肿瘤侵袭下调。结合显示MMP 13表达成纤维细胞从ECM释放VEGF的体外数据，这些数据强烈表明MMP 13在通过从ECM释放VEGF促进血管生成中的关键作用，从而允许SCC细胞的侵入性生长。
Matrix metalloproteinases (MMPs) such as MMP13 promote tumour growth and progression by mediating extracellular matrix (ECM) reorganization and regulating the biological activity of cytokines. Using Mmp13-/- mice, we demonstrate an essential role of this single collagenase for highly malignant and invasive growth in skin squamous cell carcinoma (SCC). Lack of host MMP13 strongly impaired tumour growth of malignant SCC cells, leading to small, mostly avascular cysts. While initial stromal activation in tumour transplants of Mmp13+/+ and Mmp13-/- animals was similar, MMP13 was essential for maintenance of angiogenesis and for invasion. MMP13 was induced in fibroblasts of the wild-type animals at the onset of invasion and correlated with a strong increase in vascular endothelial growth factor (VEGF) protein and its association with vascular endothelial growth factor receptor-2 on endothelial cells in invasive areas. In contrast, VEGF protein in the stroma was barely detectable and tumour invasion was downregulated in Mmp13-/- animals, despite ongoing VEGF messenger RNA expression. Taken together with in vitro data showing the release of VEGF from the ECM by MMP13 expressing fibroblasts, these data strongly suggest a crucial role of MMP13 in promoting angiogenesis via releasing VEGF from the ECM and thus allowing the invasive growth of the SCC cells.