Emmprin in epithelioid sarcoma: expression in tumor cell membrane and stimulation of MMP-2 production in tumor-associated fibroblasts.
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.
Koga
Kaori
K
Department of Pathology, Fukuoka University School of medicine, Fukuoka, Japan.
Nabeshima
Kazuki
K
Aoki
Mikiko
M
Kawakami
Takehito
T
Hamasaki
Makoto
M
Toole
Bryan P
BP
Nakayama
Juichiro
J
Iwasaki
Hiroshi
H
D000328:Adult; D000368:Aged; D051926:Basigin / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism* / Q000473:pathology; D018920:Coculture Techniques; D015622:Epithelioid Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D012509:Sarcoma / Q000378:metabolism* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
D051926:Basigin; D020778:Matrix Metalloproteinase 2