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Enhanced Peritoneal Ovarian Tumor Dissemination by Tissue Transglutaminase

Departments of ¹ Medicine, ² Pathology and Laboratory Medicine, ³ Obstetrics and Gynecology, ⁴ Surgery, and ⁵ Biochemistry and Molecular Biology; ⁶ Indiana University Cancer Center; and ⁷ Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana and ⁸ Department of Surgery, University of California at San Francisco, San Francisco, California

Requests for reprints: Daniela Matei, Division of Hematology-Oncology, Indiana University School of Medicine, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202. Phone: 317-278-8844; Fax: 317-278-0074; E-mail: dmatei{at}iupui.edu.

Tissue transglutaminase (TG2) is involved in Ca²⁺-dependent aggregation and polymerization of proteins. We previously reported that TG2 mRNA is up-regulated in epithelial ovarian cancer (EOC) cells compared with normal ovarian epithelium. Here, we show overexpression of the TG2 protein in ovarian cancer cells and tumors and its secretion in ascites fluid and define its role in EOC. By stable knockdown and overexpression, we show that TG2 enhances EOC cell adhesion to fibronectin and directional cell migration. This phenotype is preserved in vivo, where the pattern of tumor dissemination in the peritoneal space is dependent on TG2 expression levels. TG2 knockdown diminishes dissemination of tumors on the peritoneal surface and mesentery in an i.p. ovarian xenograft model. This phenotype is associated with deficient ß₁ integrin-fibronectin interaction, leading to weaker anchorage of cancer cells to the peritoneal matrix. Highly expressed in ovarian tumors, TG2 facilitates i.p. tumor dissemination by enhancing cell adhesion to the extracellular matrix and modulating ß₁ integrin subunit expression. [Cancer Res 2007;67(15):7194–202]

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