TIMP-1 Overexpression in Pancreatic Cancer Attenuates Tumor Growth, Decreases Implantation and Metastasis, and Inhibits Angiogenesis

Abstract

Background. Matrix metalloproteinases (MMPs) are involved in pancreatic cancer progression. This study was undertaken to determine the effects of overexpression of a natural tissue inhibitor of MMP (TIMP-1) on pancreatic cancer cell growth, metastasis, and angiogenesis.Methods. A poorly differentiated human pancreatic cancer cell line (PANC-1) underwent gene transfection to overexpress TIMP-1 (CD-1 cells). One million PANC-1 or CD-1 cells were injected into 40 nude mice subcutaneously (N = 20) or orthotopically (N = 20). Mice were sacrificed at 120 days. TIMP-1 overexpression by CD-1 cells was confirmed prior to injection and after necropsy. Immunohistochemical staining was undertaken after necropsy to evaluate tumors for TIMP-1, MMP-2, apoptosis (TUNEL), and angiogenesis (CD-31).Results. Tumors of CD-1 cells were less likely to implant (35% vs 70%, P = 0.05) and grew to smaller size (0.5 g ± 0.03 vs 1.5 g ± 0.20, P < 0.001) than tumors of PANC-1 cells. As well, subcutaneous CD-1 tumors appeared later than PANC-1 tumors (45 days ± 2.0 vs 27 days ± 2.2, P < 0.001). Orthotopic CD-1 tumors metastasized less often than PANC-1 tumors (20% vs 60%, P < 0.05). MMP-2 expression was similar in PANC-1 and CD-1 tumors, while CD-1 tumors showed increased TIMP-1 expression, increased apoptosis, and decreased angiogenesis relative to PANC-1 tumors.Conclusions. TIMP-1 overexpression reduces pancreatic cancer cell implantation, growth, metastasis, and angiogenesis, while increasing tumor apoptosis, all without altering MMP-2 production. This study demonstrates the potential role of TIMP-1 as a target in gene therapy for pancreatic cancer.