EXPRESSION AND IN-SITU LOCALIZATION OF GENES-CODING FOR EXTRACELLULAR-MATRIX PROTEINS AND EXTRACELLULAR-MATRIX DEGRADING PROTEASES IN PANCREATIC-CANCER

Pancreatic cancer shows a strong desmoplastic reaction characterized b y a remarkable proliferation of interstitial connective tissue (collag ens type I and III, fibronectin). In this study we have analyzed the b alance of expression of mRNAs encoding extracellular matrix components (collagens I, III and IV, laminin, fibronectin), extracellular matrix -degrading metalloproteinases (MMP-1, -2, -3 and -9) and tissue inhibi tors of metalloproteinases (TIMP-1 and -2) in pancreatic cancer and co ntrol pancreatic tissue by Northern-blot analysis and mRNA in site hyb ridization. Transcripts for MMP-1 (interstitial collagenase) and MMP-3 (stromelysin-1) were not detectable in pancreatic cancer and control tissues. Steady-state levels of transcripts encoding extracellular mat rix proteins, MMP-2 (72-kDa collagenase IV), MMP-9 (92-kDa collagenase type IV), TIMP-1 and TIMP-2 were elevated in the majority of pancreat ic-cancer tissue samples as compared to control pancreatic tissue. A g ood correlation was seen between overexpression of these MMPs and TIMP s and the steady-state levels of transcripts coding for extracellular matrix proteins, the amount of collagen protein and the severity of th e desmoplastic reaction. In situ hybridization studies localized trans cripts coding for collagens type I and III to spindle-shaped stromal c ells, whereas transcripts for MMP-2, MMP-9, TIMP-1 and TIMP-2, were fo und in both stromal and tumor cells. However, MMP-2 transcripts appear ed to be more abundant in stromal cells, TIMP-1 and TIMP-2 transcripts were evenly distributed over tumor and stromal cells and relatively m ore MMP-9 transcripts were found in tumor cells. We conclude that, in human pancreatic cancer, MMP-2, MMP-9, TIMP-1 and TIMP-2 may be involv ed in processes leading to the strong desmoplastic reaction observed i n these tumors. Both stromal and tumor cells appear to be the source o f MMPs and TIMPs in human pancreatic cancer. (C) 1995 Wiley-Liss, Inc.