Background. An alteration in the expression of and response to transforming growth factor-beta 1 (TGF-β1) appears to be an important event during colorectal carcinogenesis. However, the precise role of TGF-β1 in colorectal carcinogenesis is not clear. We have previously described in detail the changes in cell proliferation and differentiation caused by chronic exposure to TGF-β1. In this study we sought to better characterize the changes in tumor cell-cell matrix interactions seen during TGF-β1-mediated intestinal transformation. Methods. Rat intestinal epithelial cells (RIE) and RIE cells transformed by chroinic exposure to TGF-β1 (RIE-Tr) were treated with TGF-β1 and production of components of the plasmin/plasminogen system measured by ELISA and Western blotting. TGF-β1 effects on invasion and adhesion were determined in vitro. The role of urokinase on TGF-β1-mediated invasion and adhesion were determined using immunoneutralization. The role of COX-2 was determined suing a specific COS-2 inhibitor. Results. TGF-β1 had no effect on RIE-1 adhesion to collagen types I and IV, fibronectin, and laminin, or invasion through collagen types I and IV. However, 5 ng/mL TGF-β1 significantly increased the invasiveness and decreased the adhesiveness of RIE-Tr. This effect of TGF-β1 on RIE-Tr was associated with a significant increase in plasmin activity secondary to increased expression of uPA. TGF-β1 had no effect on either uPA receptor or PAI-1 in this system. Antibodies to uPA completely blocked the TGF-β1-mediated invasiveness of the RIE-Tr cells and returned their adhesiveness to basement membrane proteins to baseline. Addition of the selective Cox-2 inhibitor SC-58125 resulted in a dose-dependent decrease in TGF-β1-mediated invasion and uPA expression. Conclusion. This study provides additional evidence for TGF-β1 as a tumor promoter during intestinal carcinogenesis and a possible new mechanism for Cox-2-related colon carcinogenesis.
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