Retinoic Acid in Pulmonary Fibroblasts Primary Non-Small Cell Lung Cancers and Regulated by Stromelysin-3 Is Overexpressed by Stromal Elements in

Stromelysin-3 (STR-3) is a recently characterized matrix metalloproteinase i MMI'i that was cloned on the basis of differential expression in benign and malignant breast tumors. This M Ml' has a unique processing mechanism and substrate specificity. Unlike previously characterized MMi's that are secreted as inactive zymogens, STR-3 is processed within the constitutive secretory pathway and secreted as an active enzyme. Although STR-3 has a characteristic MM I' structure, the enzyme does not hydrolyze many of the extracellular matrix components that are sub strates for other MMI's. However, STR-3 cleaves certain serine protease inhibitors (serpins), including the al proteinase inhibitor (al anti-trypsin). Because al proteinase inhibitor deficiency has a known pathogenetic role in pulmonary disease, the role of STR-3 in non-small cell lung carcinomas (NSCLC) is of great interest. STR-3 transcripts and protein were significantly more abundant in primary NSCLC than in adjacent normal lung specimens in an extensive panel of stage I 111squamous cell and adenocarcinomas. The major form of STR-3 detectable in the pri mary NSCLC was the mature fully processed active enzyme. STR-3 transcripts and protein were primarily localized to NSCLC stromal ele ments, prompting analysis of STR-3 induction in normal pulmonary fibroblasts. Although STR-3 could be induced in normal pulmonary fibroblasts with growth factors (basic fibroblast growth factor and plateletderived growth factor) and/or ^-O-tetradecanoylphorbol-O-acetate, STR-3 induction was inhibited by all-trans retinole acid, a commonly used chemopreventive agent for aerodigestive tract malignancies. Taken to gether, these data suggest that STR-3 may be a novel marker and potential therapeutic target in NSCLC.