MMP-2 and TIMP-1 Are Derived from, Not in Response to, Pancreatic Cancer

Abstract

Introduction. Genetic therapy aimed at disturbing the balance between matrix metalloproteinases (MMP) and their natural tissue inhibitors (TIMP) in treatment of pancreatic cancer requires an understanding of whether MMP and TIMP are tumor- or host-derived. This study was undertaken to determine whether production of MMP-2 and TIMP-1 is by, or in response to, pancreatic cancer.Methods. PANC-1 (poorly differentiated human pancreatic cancer) or CD-1 (PANC cells transfected to overproduce TIMP-1) cells were implanted into the pancreata of 20 nude mice. After sacrifice, tumors and peritumoral stroma underwent immunohistochemical staining for human and murine MMP-2 and TIMP-1. Normal murine pancreas served as control. All stains were reviewed in a “blinded” manner by a pathologist and graded relative to normal control pancreata.Results. Control pancreata displayed faint murine MMP-2 and TIMP-1 staining and no human MMP-2 or TIMP-1. MMP-2 was most prominent in peritumoral stroma, while TIMP-1 was most prominent in tumors. CD-1 tumors contained very high levels of TIMP-1 compared to PANC-1 tumors and control pancreata. Tumoral and peritumoral MMP-2 were overwhelmingly human. As well, tumoral TIMP-1 was predominantly human.Conclusions. In a murine model for human pancreatic cancer, nearly all TIMP-1 and MMP-2 expression is tumor-derived (i.e., human). Pharmacologic and gene therapy aimed at disturbing the MMP/TIMP balance in pancreatic cancer should be targeted toward tumor-specific mechanisms and warrants continued investigation.