STROMELYSIN-3 IS OVEREXPRESSED BY STROMAL ELEMENTS IN PRIMARY NON-SMALL-CELL LUNG CANCERS AND REGULATED BY RETINOIC ACID IN PULMONARY FIBROBLASTS

Stromelysin-3 (STR-3) is a recently characterized matrix metalloprotei nase (MMP) that was cloned on the basis of differential expression in benign and malignant breast tumors. This MMP has a unique processing m echanism and substrate specificity. Unlike previously characterized MM Ps that are secreted as inactive zymogens, STR-3 is processed within t he constitutive secretory pathway and secreted as an active enzyme. Al though STR-3 has a characteristic MMP structure, the enzyme does not h ydrolyze many of the extracellular matrix components that are substrat es for other MMPs. However, STR-3 cleaves certain serine protease inhi bitors (serpins), including the alpha 1 proteinase inhibitor (alpha 1 anti-trypsin). Because alpha 1 proteinase inhibitor deficiency has a k nown pathogenetic role in pulmonary disease, the role of STR-3 in non- small cell lung carcinomas (NSCLC) is of great interest. STR-3 transcr ipts and protein were significantly more abundant in primary NSCLC tha n in adjacent normal lung specimens in an extensive panel of stage I-I II squamous cell and adenocarcinomas. The major form of STR-3 detectab le in the primary NSCLC was the mature fully processed active enzyme. STR-3 transcripts and protein were primarily localized to NSCLC stroma l elements, prompting analysis of STR-3 induction in normal pulmonary fibroblasts. Although STR-3 could be induced in normal pulmonary fibro blasts with growth factors (basic fibroblast growth factor and platele t-derived growth factor) and/or 12-O-tetradecanoylphorbol-13-acetate, STR-3 induction was inhibited by all-trans retinoic acid, a commonly u sed chemopreventive agent for aerodigestive tract malignancies. Taken together, these data suggest that STR-3 may be a novel marker and pote ntial therapeutic target in NSCLC.