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Activation of EDTA-Resistant Gelatinases in Malignant Human Tumors

Departments of ¹ Medicine and ² Obstetrics, Gynecology, and Reproductive Medicine, Stony Brook University, Stony Brook, New York; ³ Department of Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan; ⁴ Department of Pathology, The National Hospital-The Norwegian Radium Hospital, University of Oslo, Oslo, Norway; ⁵ Department of Gynecology and Obstetrics, Zhengzhou University, Henan, China; ⁶ Department of Applied Medical Science, University of Southern Maine, Portland, Maine; ⁷ Department of Pathology, Faculty of Medicine, Yamanashi Medical University, Shimokato Tamaho Nakakoma, Yamanashi, Japan; ⁸ Department of Pathology, School of Medicine, Nihon University, Itabashi, Tokyo, Japan; and ⁹ Dipartimento di Biologia Cellulare e dello Sviluppo, Università di Palermo, Palermo, Italy

Requests for reprints: Wen-Tien Chen, Department of Medicine, Stony Brook University, HSC T-15, Room 053, Stony Brook, NY 11794-8151. Phone: 631-444-6948; Fax: 631-444-7530; E-mail: wenchen{at}notes.cc.sunysb.edu.

Among the many proteases associated with human cancer, seprase or fibroblast activation protein , a type II transmembrane glycoprotein, has two types of EDTA-resistant protease activities: dipeptidyl peptidase and a 170-kDa gelatinase activity. To test if activation of gelatinases associated with seprase could be involved in malignant tumors, we used a mammalian expression system to generate a soluble recombinant seprase (r-seprase). In the presence of putative EDTA-sensitive activators, r-seprase was converted into 70- to 50-kDa shortened forms of seprase (s-seprase), which exhibited a 7-fold increase in gelatinase activity, whereas levels of dipeptidyl peptidase activity remained unchanged. In malignant human tumors, seprase is expressed predominantly in tumor cells as shown by in situ hybridization and immunohistochemistry. Proteins purified from experimental xenografts and malignant tumors using antibody- or lectin-affinity columns in the presence of 5 mmol/L EDTA were assayed for seprase activation in vivo. Seprase expression and activation occur most prevalently in ovarian carcinoma but were also detected in four other malignant tumor types, including adenocarcinoma of the colon and stomach, invasive ductal carcinoma of the breast, and malignant melanoma. Together, these data show that, in malignant tumors, seprase is proteolytically activated to confer its substrate specificity in collagen proteolysis and tumor invasion. (Cancer Res 2006; 66(20): 9977-85)