Senescent cancer-associated fibroblasts secrete active MMP-2 that promotes keratinocyte dis-cohesion and invasion.
Senescent cancer-associated fibroblasts secrete active MMP-2 that promotes keratinocyte dis-cohesion and invasion.
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DOI：
10.1038/bjc.2014.438
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发表时间：
2014-09-09
影响因子：
8.8
通讯作者：
Prime, S. S.
中科院分区：
文献类型：
--
作者：
Hassona, Y.;Cirillo, N.;Heesom, K.;Parkinson, E. K.;Prime, S. S.
关键词：
以往的研究表明，衰老的癌症相关的成纤维细胞（CAFs）从遗传不稳定的口腔鳞状细胞癌（GU-OSCC），不像非衰老的CAFs从遗传稳定的癌（GS-OSCC），促进角质形成细胞在体外的侵袭，在旁分泌的方式。发生这种情况的机制尚不清楚。以前的工作，以确定衰老相关的分泌表型（SASP）使用抗体阵列，技术是有限的，合适的抗体的可用性。为了以公正的方式扩展这项工作，我们使用2D凝胶电泳和质谱进行蛋白质鉴定。采用明胶酶谱法和蛋白质印迹法对基质金属蛋白酶（MMPs）进行研究。中和抗体用于阻断角质形成细胞粘附和侵袭功能测定中的关键分子。在GS-OSCC和GU-OSCC的CAF之间差异表达的多种蛋白质中，MMP-2是GU-OSCC来源的衰老CAF-CM的主要成分。明胶酶谱法证实了活性MMP-2的存在。衰老CAF-CM来源的MMP-2以TGF-β依赖的方式诱导角质形成细胞解聚和上皮侵入胶原凝胶。GU-OSCC的衰老CAF通过产生活性MMP-2、破坏上皮粘附和诱导角质形成细胞侵袭而促进更具侵袭性的口腔癌表型。
Previous studies have demonstrated that senescent cancer-associated fibroblasts (CAFs) derived from genetically unstable oral squamous cell carcinomas (GU-OSCC), unlike non-senescent CAFs from genetically stable carcinomas (GS-OSCC), promoted keratinocyte invasion in vitro in a paracrine manner. The mechanism by which this occurs is unclear. Previous work to characterise the senescent-associated secretory phenotype (SASP) has used antibody arrays, technology that is limited by the availability of suitable antibodies. To extend this work in an unbiased manner, we used 2D gel electrophoresis and mass spectroscopy for protein identification. Matrix metalloproteinases (MMPs) were investigated by gelatin zymography and western blotting. Neutralising antibodies were used to block key molecules in the functional assays of keratinocyte adhesion and invasion. Among a variety of proteins that were differentially expressed between CAFs from GU-OSCC and GS-OSCC, MMP-2 was a major constituent of senescent CAF-CM derived from GU-OSCC. The presence of active MMP-2 was confirmed by gelatine zymography. MMP-2 derived from senescent CAF-CM induced keratinocyte dis-cohesion and epithelial invasion into collagen gels in a TGF-β-dependent manner. Senescent CAFs from GU-OSCC promote a more aggressive oral cancer phenotype by production of active MMP-2, disruption of epithelial adhesion and induction of keratinocyte invasion.
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影响因子：
3.7
作者：
Fullar, Alexandra;Kovalszky, Ilona;Bitsche, Mario;Romani, Angela;Schartinger, Volker Hans;Sprinzl, Georg Mathias;Riechelmann, Herbert;Dudas, Jozsef
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作者：
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通讯作者：
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影响因子：
3.6
作者：
Cirillo, Nicola;Campisi, Giuseppina;Lanza, Alessandro
通讯作者：
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