TIMP-1 antisense gene transfection attenuates the invasive potential of pancreatic cancer cells in vitro and inhibits tumor growth in vivo

Background: TIMP-1 overexpression decreases the invasive potential of pancreatic cancer cells. By tissue inhibitors of metalloproteinase (TIMP)-1 antisense gene transfection, we expected to produce aggressive pancreatic cancer cells with increased in vitro and in vivo invasive potential. Methods: PANC-1 cells were transfected with either TIMP-1 gene (CD-1), antisense TIMP-1 gene (AS-3), or empty vector (MB-3). The in vitro cell growth kinetics and invasive potential of each cell line were compared. Total and active matrix metalloproteinase (MMP)-2 levels were determined. Each cell line was then implanted in athymic mice and the resultant tumors were compared for size, weight, MMP activity, and TIMP-1 expression. Results: TIMP-1 modulation did not affect cell proliferation in vitro, but its underexpression and, to a lesser extent, overexpression resulted in attenuated tumor growth in vivo. AS-3 cells showed marked decreases in cell invasion and MMP-2 activity in vitro and in vivo. Conclusion: TIMP-1 manipulation, particularly underexpression, greatly reduces the invasive potential of pancreatic cancer by limiting MMP-2 activity without affecting in vitro cell growth. TIMP-I is a reasonable molecular target in pancreatic cancer therapy. (c) 2005 Excerpta Medica Inc. All rights reserved.