Abstract
Stromelysin‐3 (STR‐3) is a matrix metalloproteinase with a unique pattern of expression and substrate specificity. During embryogenesis and remodeling of normal adult tissues, STR‐3 is produced by stromal cells in direct contact with epithelial cells undergoing regional apoptosis and selective cell survival. STR‐3 is also overexpressed by interdigitating stromal cells in primary epithelial malignancies. Although STR‐3 does not degrade classic extracellular matrix components, the enzyme promotes the establishment of local tumors in nude mice by as yet undefined mechanisms. STR‐3 is induced when malignant epithelial cells come into contact with surrounding stromal elements; the active stromal cell‐derived 45 kDa enzyme is subsequently processed to a 35 kDa protein without enzymatic activity. We have generated MCF‐7 transfectants expressing wild type or catalytically inactive 45 kDa STR‐3 (STR‐3~wt~ and STR‐3~cat‐~) or secreted 35 kDa STR‐3 (35 kDa STR‐3~sec~) and evaluated their implantation and survival in nude mice. Tumors developed significantly more rapidly in animals receiving STR‐3~wt~, rather than vector‐only, STR‐3~cat‐~ or 35 kDa STR‐3~sec~ transfectants. Most importantly, STR‐3~wt~ tumors had a significantly lower percentage of apoptotic cells than tumors derived from vector‐only, STR‐3~cat‐~ or 35 kDa STR‐3~sec~ transfectants. Taken together, these studies suggest that the active STR‐3 enzyme may increase tumor take by suppressing tumor cell apoptosis and that 45 kDa to 35 kDa STR‐3 processing limits STR‐3 activity at the tumor/stromal interface. Because STR‐3 is secreted as an active enzyme rather than a proform, subsequent 45 kDa to 35 kDa STR‐3 processing may represent a novel mechanism for regulating enzymatic activity. J. Cell. Biochem. 82: 549–555, 2001. © 2001 Wiley‐Liss, Inc.