Tissue transglutaminase is expressed as a host response to tumor invasion and inhibits tumor growth

A stable extracellular matrix (ECM) constitutes an important part of host response mechanism against tumor growth and invasion. Tissue transglutaminase (TG), a calcium-dependent enzyme, can cross-link all major ECM proteins to form a stable ECM, because these cross-links are resistant to proteolytic and mechanical damage. TG can also enhance stability and strength of the ECM by its ability to facilitate the activation of transforming growth factor-beta. We hypothesized that TG ECM-promoting abilities form an important part of the host response mechanism against tumor growth. Increased expression of TG was observed in the ECM of the host tumor interface of subcutaneously implanted rat mammary adenocarcinoma R3230 Ac. TG expression was also detected in the endothelial cells and macrophages. We also detected the cross-link product at the host tumor interface and within the tumor tissue, showing that TG was active. Western blots showed TG was degraded into three fragments of 55-, 50-, and 20-kDa forms. When recombinant wild-type TG was applied to R3230 Ac implanted in rat dorsal skin flap window chamber, it caused significant growth delay at day 7 compared with recombinant inactive TG controls. Collagen was detected in increased amounts in TG treated tumors, suggesting augmentation of production and stability of the ECM. We conclude that TG forms a distinct part of host response system against and acts to inhibit tumor growth.