Tumor-stromal cell contact promotes invasion of human uterine cervical carcinoma cells by augmenting the expression and activation of stromal matrix metalloproteinases
Tumor-stromal cell contact promotes invasion of human uterine cervical carcinoma cells by augmenting the expression and activation of stromal matrix metalloproteinases
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DOI：
10.1016/j.ygyno.2003.09.012
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发表时间：
2004-01-01
影响因子：
4.7
通讯作者：
Ito, A
中科院分区：
文献类型：
--
作者：
Sato, T;Sakai, T;Ito, A
Objective.基质金属蛋白酶（MMPs）的表达和活化与肿瘤的侵袭和转移有关。此外，肿瘤间质细胞接触提供了一个重要的信号，调节细胞周围的蛋白水解肿瘤侵袭的进展。本研究在人宫颈癌细胞和人宫颈成纤维细胞的体外共培养模型中评估了肿瘤-基质细胞接触对MMPs和金属蛋白酶组织抑制剂（TIMP）表达和激活的调节。方法。当人宫颈癌SKG-II细胞与人宫颈成纤维细胞（HUCF）共培养时，使用Matrigel的体外侵袭测定来分析SKG-II细胞的侵袭活性。采用Western blot、北方印迹和明胶酶谱分析检测MMP和TIMP的产生、mRNA表达和活化。SKG-11细胞，组成性地产生膜I型MMP（MT 1-MMP）和痕量的proMMP-2，但既不TIMP-1也不TIMP-2，在体外表现出较差的侵袭性。在与HUCFs共培养后，发现SKG-11细胞通过增强肿瘤MT 1-MMP的产生和mRNA表达而转化为侵袭性表型。此外，观察到成纤维细胞proMMP-2的活化的连续增加，沿着在肿瘤细胞表面形成MT 1-MMP-TIMP-2-proMMP-2复合物。此外，在共培养条件下，成纤维细胞proMMP-1和proMMP-3的产生和基因表达增加，而proMMP-2，TIMP-1和TIMP-2的mRNA表达不变。此外，我们证明了肿瘤细胞衍生的可溶性因子在HUCF中proMMP-1和proMMP-3的产生增加中的部分参与。然而，抗整合素I和β 3抗体未能消除共培养中成纤维细胞proMMP-3产生和proMMP-2活化的增加。宫颈癌细胞与外周间质成纤维细胞之间的细胞-细胞接触增加了MMPs的产生和激活，因此MMPs和TIMP之间的失衡可能导致宫颈癌细胞体内侵袭性的进展。(C)2003年爱思唯尔公司All rights reserved.
Objective. The augmentation of the expression and activation of matrix metalloproteinases (MMPs) is associated with tumor invasion and metastasis. In addition, tumor-stromal cell contact provides a crucial signal for regulating the pericellular proteolysis for the progression of tumor invasiveness. The present study evaluates the regulation of the expression and activation of MMPs and tissue inhibitors of metalloproteinases (TIMPs) by tumor-stromal cell contact in an in vitro co-culture model of human uterine cervical carcinoma cells and human uterine cervical fibroblasts.Methods. When human uterine cervical carcinoma SKG-II cells were co-cultured with human uterine cervical fibroblasts (HUCFs), the invasive activity of SKG-II cells was analyzed using an in vitro invasion assay using Matrigel. The production, mRNA expression and activation of MMPs and TIMPs were monitored by Western blot and Northern blot analyses and gelatin zymography.Results. SKG-11 cells, which constitutively produced membrane-type I MMP (MT1-MMP) and a trace of proMMP-2 but neither TIMP-1 nor TIMP-2, showed poor invasiveness in vitro. Upon co-culturing with HUCFs, SKG-11 cells were found to transform to the invasive phenotype by enhancing the production and mRNA expression of tumoral MT1-MMP. In addition, a sequential increase in the activation of fibroblast proMMP-2 was observed along with the fort-nation of an MT1-MMP-TIMP-2-proMMP-2 complex on the tumor cell surface. Furthermore, the production and gene expression of fibroblast proMMP-1 and proMMP-3 were augmented under co-culture conditions, whereas mRNA expression of proMMP-2, TIMP-1 and TIMP-2 was unchanged. Moreover, we demonstrated the partial involvement of tumor-cell-derived soluble factors in the augmentation of the production of proMMP-1 and proMMP-3 in HUCFs. However, anti-integrin I and beta3 antibodies failed to abolish the augmentation of fibroblast proMMP-3 production and proMMP-2 activation in the co-culture.Conclusion. Cell-cell contact between cervical carcinoma cells and peripheral stromal fibroblasts augments the production and activation of MMPs, and therefore the subsequent imbalance between MMPs and TIMPs may result in the progression of invasiveness of cervical carcinoma cells in vivo. (C) 2003 Elsevier Inc. All rights reserved.