Robert Beauchamp
Principal Investigator
Last active: 10/31/2018

Intestinal transformation results in transforming growth factor-beta-dependent alteration in tumor cell-cell matrix interactions.

Berger DH, O'Mahony CA, Sheng H, Shao J, Albo D, DuBois RN, Beauchamp RD
Surgery. 2003 133 (5): 568-79

PMID: 12773985 · DOI:10.1067/msy.2003.125

BACKGROUND - An alteration in the expression of and response to transforming growth factor-beta 1 (TGF-beta 1) appears to be an important event during colorectal carcinogenesis. However, the precise role of TGF-beta 1 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-beta 1. In this study we sought to better characterize the changes in tumor cell-cell matrix interactions seen during TGF-beta 1-mediated intestinal transformation.

METHODS - Rat intestinal epithelial cells (RIE) and RIE cells transformed by chronic exposure to TGF-beta 1 (RIE-Tr) were treated with TGF-beta 1 and production of components of the plasmin/plasminogen system measured by ELISA and Western blotting. TGF-beta 1 effects on invasion and adhesion were determined in vitro. The role of urokinase on TGF-beta 1-mediated invasion and adhesion were determined using immunoneutralization. The role of COX-2 was determined using a specific COS-2 inhibitor.

RESULTS - TGF-beta 1 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-beta 1 significantly increased the invasiveness and decreased the adhesiveness of RIE-Tr. This effect of TGF-beta 1 on RIE-Tr was associated with a significant increase in plasmin activity secondary to increased expression of uPA. TGF-beta 1 had no effect on either uPA receptor or PAI-1 in this system. Antibodies to uPA completely blocked the TGF-beta 1-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-beta 1-mediated invasion and uPA expression.

CONCLUSION - This study provides additional evidence for TGF-beta 1 as a tumor promoter during intestinal carcinogenesis and a possible new mechanism for Cox-2-related colon carcinogenesis.

MeSH Terms (21)

Animals Cell Adhesion Cell Line Cell Line, Transformed Cells, Cultured Cell Transformation, Neoplastic Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Cyclooxygenase Inhibitors Dose-Response Relationship, Drug Extracellular Matrix Fibrinolysin Intestinal Mucosa Isoenzymes Neoplasm Invasiveness Prostaglandin-Endoperoxide Synthases Pyrazoles Rats Transforming Growth Factor beta Transforming Growth Factor beta1 Urokinase-Type Plasminogen Activator

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