Emmprin in epithelioid sarcoma: Expression in tumor cell membrane and stimulation of MMP-2 production in tumor-associated fibroblasts
Emmprin in epithelioid sarcoma: Expression in tumor cell membrane and stimulation of MMP-2 production in tumor-associated fibroblasts
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DOI：
10.1002/ijc.22412
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发表时间：
2007-02-15
影响因子：
6.4
通讯作者：
Iwasaki, Hiroshi
中科院分区：
文献类型：
--
作者：
Koga, Kaori;Nabeshima, Kazuki;Iwasaki, Hiroshi
细胞外基质金属蛋白酶诱导因子是一种跨膜糖蛋白，可刺激肿瘤周围成纤维细胞产生基质金属蛋白酶。细胞外基质金属蛋白酶原及其诱导的基质金属蛋白酶在人类恶性上皮肿瘤的侵袭、转移和肿瘤进展中起着至关重要的作用。然而，只有少数报告指出了它在软组织肉瘤中的作用。本研究旨在探讨上皮样肉瘤（epithelioid sarcoma，ES）中细胞外基质金属蛋白酶诱导因子（emmprin）的表达及其作用。2 ES细胞系的免疫印迹研究表明，他们表达emmprin，这些ES细胞与真皮成纤维细胞的共培养导致成纤维细胞中明胶酶A（MMP-2）的上调，如酶谱，免疫印迹和酶免疫分析所示。这种刺激被抑制的活性阻断肽对emmprin和antiemmprin抗体。此外，在体内，5例ES患者的免疫组化分析表明，ES细胞中弥漫性emmprin表达，ES细胞和肿瘤周围成纤维细胞中MMP-2表达。组织病理学发现，不与表达emmprin的ES细胞直接接触的瘤周成纤维细胞表现出MMP-2的上调，这促使我们寻找可溶形式的emmprin。在条件培养基中检测到从ES细胞释放的可溶性全长emmprin，并显示其刺激成纤维细胞产生MMP-2。总之，emmprin在ES中以膜和可溶形式表达，并通过与成纤维细胞的相互作用刺激MMP-2的产生，这可能在ES细胞间质侵袭和血管受累中发挥作用。(c)2006年威利-利斯。Inc.
Emmprin is a transmembrane glycoprotein on tumor cells that stimulates peritumoral fibroblasts to produce matrix metalloproteinases (MMPs). Emmprin and the induced MMPs play a crucial role in tumor progression, invasion and metastasis of human carcinomas (epithelial malignancies). However, only a few reports have addressed its role in soft tissue sarcomas. This study investigated the expression and role of emmprin in epithelioid sarcoma (ES). Immunoblot studies of 2 ES cell lines showed that they express emmprin, and co-culture of these ES cells with dermal fibroblasts resulted in upregulation of gelatinase A (MMP-2) in fibroblasts, as shown by zymography, immunoblotting and enzyme immunoassay. This stimulation was inhibited by an activity-blocking peptide against emmprin and by antiemmprin antibody. In addition, in vivo, immunohistochemical analysis of 5 ES patient cases demonstrated diffuse emmprin expression in ES cells and MMP-2 expression in both ES cells and peritumoral fibroblasts. The histopathological findings that peritumoral fibroblasts that were not in direct contact with emmprin-expressing ES cells exhibit upregulated MMP-2 prompted us to look for a soluble form of emmprin. Soluble full-length emmprin released from ES cells was detected in conditioned medium and shown to stimulate MMP-2 production by fibroblasts. In conclusion, emmprin is expressed in ES in both membrane and soluble forms and stimulates MMP-2 production via interactions with fibroblasts, which could play a role in ES cell stromal invasion and vascular involvement. (c) 2006 Wiley-Liss. Inc.