Tumor cell and carcinoma-associated fibroblast interaction regulates matrix metalloproteinases and their inhibitors in oral squamous cell carcinoma.
Tumor cell and carcinoma-associated fibroblast interaction regulates matrix metalloproteinases and their inhibitors in oral squamous cell carcinoma.
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DOI：
10.1016/j.yexcr.2012.03.023
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发表时间：
2012-08-01
影响因子：
3.7
通讯作者：
Dudas, Jozsef
中科院分区：
文献类型：
--
作者：
Fullar, Alexandra;Kovalszky, Ilona;Bitsche, Mario;Romani, Angela;Schartinger, Volker Hans;Sprinzl, Georg Mathias;Riechelmann, Herbert;Dudas, Jozsef
牙周膜（PDL）成纤维细胞和SCC-25口腔鳞状细胞癌细胞（OSCC）的共培养，导致PDL转化为癌相关成纤维细胞（CAF）。假设CAFs和OSCC细胞之间的旁分泌回路调节共培养中基质重塑酶的基因表达，共培养7天，然后分析金属蛋白酶（MMPs）、其组织抑制剂（TIMPs）和其他相关基因的mRNA/蛋白表达和活性。白细胞介素1-β、转化生长因子-β1、纤维连接蛋白和αvβ6整合素参与了CAFs和肿瘤细胞共培养中MMP和TIMP基因表达的调节。此外，这些细胞还协同激活MMP前酶。特别令人感兴趣的是，成纤维细胞产生的无活性MMP-2已被肿瘤细胞产生的膜1型基质金属蛋白酶（MT 1-MMP）激活。癌细胞和周围成纤维基质细胞之间的串扰对于癌细胞侵袭力的微调是必不可少的。SCC-25细胞和成纤维细胞间旁分泌相互作用中MMPs和TIMPs调节机制的建议总结。MMP-9表现出肿瘤特异性表达，推测受纤连蛋白ITGA 5 B6途径调节。在共培养的SCC-25和PDL成纤维细胞中，ITGA 5是可诱导的，但ITGB 6表达是肿瘤（SCC-25）特异性的。基于先前的报道[41]，MMP-9可能在与CD-44的相互作用中被激活，并且根据我们的明胶酶测定结果，它保持与肿瘤细胞结合（A）。该研究的结果表明，MMP-2以其前（非活性）形式由肿瘤细胞周围的CAF分泌，并且在较低程度上也由肿瘤细胞本身分泌。MMP-2的活化需要位于SCC-25癌细胞上的MT 1-MMP [31]或整合素，其中预期αv整合素（ITGA 5）参与（A）。MMPs-1、3和TIMPs-1、3在PDL成纤维细胞中产生，其表达可能受炎性细胞因子（包括SCC-25细胞产生的IL-1-β）的调节。TIMP-1和TIMP-3的表达是MMPs-1和MMPs-3的20-70倍。地塞米松（DEX）降低MMP-1; 2、TIMP-1和TIMP-3的基因表达（B）。
Co-culture of periodontal ligament (PDL) fibroblasts and SCC-25 oral squamous carcinoma cells (OSCC), results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs). Paracrin circuits between CAFs and OSCC cells were hypothesized to regulate the gene expression of matrix remodeling enzymes in their co-culture, which was performed for 7 days, followed by analysis of the mRNA/protein expression and activity of metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and other relevant genes. Interleukin1-β, transforming growth factor-β1, fibronectin and αvβ6 integrin have shown to be involved in the regulation of the MMP and TIMP gene expression in co-culture of CAFs and tumor cells. In addition, these cells also cooperated in activation of MMP pro-enzymes. It is particularly interesting that the fibroblast-produced inactive MMP-2 has been activated by the tumor-cell-produced membrane-type 1 matrix metalloproteinase (MT1-MMP). The crosstalk between cancer- and the surrounding fibroblast stromal-cells is essential for the fine tuning of cancer cells invasivity. Summary of the suggested mechanism for the regulation of MMPs and TIMPs in the paracrine interplay between SCC-25 cells and fibroblasts. MMP-9 showed a tumor specific expression, regulated presumably by the fibronectin ITGA5B6 pathway. The ITGA5 was inducible in both SCC-25 and PDL fibroblasts in co-culture, but ITGB6 expression was tumor (SCC-25) specific. Based on a previous report [41], MMP-9 might be activated in the interaction with CD-44, and according to our gelatinase assay results, it remains bound with the tumor cells (A). The results of this study suggest that MMP-2 is secreted in its pro- (inactive-) form by CAFs surrounding the tumor cells, and at a lower extent also by the tumor cells themselves. Activation of MMP-2 either requires MT1-MMP localized on the SCC-25 cancer cells [31], or integrins, where the involvement of αv integrins (ITGA5) is expected (A). MMPs-1, 3 and TIMPs-1, 3 are produced in the PDL fibroblasts, and their expression might be regulated by inflammatory cytokines, including IL1-β produced by SCC-25 cells. The expression of TIMP-1 and TIMP-3 is 20–70-times higher than that of MMPs-1 and 3. The gene expression of MMP-1; 2, TIMP-1 and TIMP-3 was reduced by dexamethasone (DEX) (B).
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影响因子：
9.7
作者：
Higashikawa, Koichiro;Yoneda, Shingo;Kamata, Nobuyuki
通讯作者：
Kamata, Nobuyuki
影响因子：
2.7
作者：
Miyazawa, K;Mori, A;Okudaira, H
通讯作者：
Okudaira, H
影响因子：
3.7
作者：
Dudás J;Fullár A;Bitsche M;Schartinger V;Kovalszky I;Sprinzl GM;Riechelmann H
通讯作者：
Riechelmann H
DOI：
10.1038/labinvest.2010.172
发表时间：
2011-03
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
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影响因子：
4.1
作者：
Dudás, J;Ramadori, G;Kovalszky, I
通讯作者：
Kovalszky, I