title: Differential regulation of matrix metalloproteinases in human cancer cells by exogenous factors.
abstract: Matrix degradation by cancer cells is an important attribute of malignant behaviour. We have postulated that during invasion and metastasis, matrix metalloproteinase (MMP) production by cancer cells is modulated by microenvironmental factors. To determine this, we screened human cancer cell lines of diverse histogenesis for their secreted MMP profile following exposure to a diversity of soluble and insoluble agents. Enzymatic changes were observed in the presence of phorbol ester (TPA) and hydrogen peroxide (H2O2). More specifically, we observed: (a) increased secretion and/or activation of gelatinases A (MMP-2) and B (MMP-9) after exposure of 8 cell lines to 10(-6) M TPA; (b) increased activation of interstitial collagenase (MMP-1) caseinolysis after stimulation of 3 cancer cell lines with 10(-7) M TPA; and (c) increased activation of MMP-2 after exposure of 2 cell lines to 0.5 mM H3O2. In functional assays, exposure of lung Calu-6 carcinoma cells to 0.5 mM H2O2 and PC-3 cells to TPA, increased their ability to degrade radiolabelled endothelial cell-derived and osteoblast-like-derived basement membranes, respectively. RNA hybridization studies confirmed and further documented these observations. We conclude that modulation of MMP activity in human cancer cells is a common phenomenon regardless of lineage. Modulatory mechanisms such as increased de novo pro-enzyme synthesis and/or release, and enhanced proenzyme activation may be involved. Furthermore, our results provide evidence that extracellular matrix degradation by human cancer cells during invasion and metastasis may be stimulated by soluble matrix-derived factors in a cell type-specific fashion.
authors.affiliation: MCMASTER UNIV,DEPT PATHOL,HAMILTON,ON L8V 5C2,CANADA. MCMASTER UNIV,ONCOL RES GRP,HAMILTON,ON L8V 5C2,CANADA. UNIV SAO PAULO,DEPT PATHOL,BR-14049 RIBEIRAO PRET,BRAZIL. UNIV WESTERN ONTARIO,LONDON REG CANC CTR,LONDON,ON,CANADA. UNIV MANITOBA,DEPT PATHOL,WINNIPEG,MB R3T 2N2,CANADA.
authors.forename: O
authors.initials: O
authors.lastname: Sanchezsweatman
authors.forename: F
authors.initials: F
authors.lastname: Soares
authors.forename: M
authors.initials: M
authors.lastname: Whaley
authors.forename: R
authors.initials: R
authors.lastname: Khokha
authors.forename: F
authors.initials: F
authors.lastname: Orr
authors.forename: G
authors.initials: G
authors.lastname: Singh