Effect of Matrix Metalloproteinase Inhibition on Pancreatic Cancer Invasion and Metastasis (original) (raw)

To investigate the effect of a matrix metalloproteinase (MMP) inhibitor, BB-94, on the viability, invasion, and metastases of pancreatic cancer. Summary Background Data Inhibitors of MMPs, enzymes that degrade extracellular matrix, have been tested as single chemotherapeutic agents for pancreatic cancer. Methods Capan1 and AsPC1 cell lines were studied. BB-94 cytotoxicity was evaluated by cell proliferation assays. Production of MMP2 and MMP9 in conditioned media was demonstrated by gelatin zymography. The in vitro effect of BB-94 on cell invasion was assayed using invasion chambers. Hepatic metastases from pancreatic cancer were induced by intrasplenic injections of Capan1 or AsPC1 cells in nude mice. The in vivo effect of BB-94 on liver metastases was evaluated by comparing animals receiving BB-94 treatment with controls receiving vehicle alone. Variables measured included death rate and tumor burden (liver-to-body weight ratio). Results BB-94 was not cytotoxic between 3 and 3,000 ng/mL. Zymography demonstrated production of MMP2 and MMP9 by both cell lines, with complete inhibition of these enzymes by BB-94 at 48 ng/mL. Invasion chamber assays showed that BB-94 (48-400 ng/mL) impeded cell invasion in vitro compared with untreated controls. In vivo, BB-94 prevented death or reduced the death rate from hepatic metastases in animals injected with Capan1 or AsPC1 cells. BB-94 treatment resulted in significant reductions in hepatic tumor burden compared with untreated controls. Conclusions Inhibition of MMP reduces both growth of pancreatic cancer metastases and the death rate. These actions do not reflect cytotoxicity but rather result from impaired cancer cell attachment, migration, and organ invasion. MMP inhibitors may provide an additive effect to cytotoxic agents in multidimensional treatment regimens for pancreatic cancer. The matrix metalloproteinases (MMPs) are a family of enzymes involved in degradation of extracellular matrix components such as collagen, gelatin, and fibronectin. 1 At least 17 of these enzymes are known, and secreted or membrane-bound types have been described. Secreted MMPs appear as proenzymes that require cleavage of a specific peptide for their activation. MMPs exist in equilibrium with physiologic tissue inhibitors of metalloproteinases (TIMPs), and their interaction is largely responsible for modification of the extracellular environment. 2 The proteolytic activity of MMPs is critically involved in embryonic development, normal tissue remodeling, growth, and wound healing. Disruption of the equilibrium between MMPs and TIMPs has been linked to pathologic conditions ranging from rheumatoid arthritis to cancer. 3,4 Cancer invasion and metastasis are two processes that MMPs, either from malignant cells or induced fibroblasts, are thought to mediate.