Adenoviral delivery of TIMP1 or TIMP2 can modify the invasive behavior of pancreatic cancer and can have a significant antitumor effect in vivo

Abstract

Pancreatic carcinomas overexpress several matrix metalloproteinases (MMPs), in particular MMP2 and MMP9. These enzymes are involved in the degradation of the extracellular matrix to aid tumor cell invasion. The aim of this study was to investigate the effect of TIMP gene therapy on human pancreatic cancer. Human TIMP1 or TIMP2 has been introduced in pancreatic tumor cells under the control of a constitutive promoter using adenoviral vectors, and the effect on tumor invasion observed. It has been demonstrated in vitro that the TIMP-expressing pancreatic tumor cells were significantly less invasive than those cells transfected with a control vector. In vivo, adenoviral delivery of TIMP1 or TIMP2 to nude mice harboring intraperitoneal human pancreatic cancers resulted in prolonged survival compared with control mice if the gene therapy was given early (P<.009 and P<.0293, respectively). The in vivo experiments demonstrated evidence of gene transfer by adenoviral vectors to tumor cells and murine mesenteric cells. There was no evidence of transgene expression in distant organs. These experiments have proved the hypothesis that TIMP overexpression in pancreatic cancer cells can modify the invasive phenotype. Also, TIMP gene transfer to human tumor cells is possible both in vitro and in vivo.