Emmprin in epithelioid sarcoma: Expression in tumor cell membrane and stimulation of MMP‐2 production in tumor‐associated fibroblasts

Abstract

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.