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Stromelysin‐3 suppresses tumor cell apoptosis in a murine model *
Author(s) -
Wu Erxi,
Mari Bernard P.,
Wang Fengfei,
Anderson Ian C.,
Sunday Mary E.,
Shipp Margaret A.
Publication year - 2001
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.1181
Subject(s) - stromal cell , apoptosis , extracellular matrix , biology , cell culture , microbiology and biotechnology , matrix metalloproteinase , cell , programmed cell death , cancer research , biochemistry , genetics
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.