BIOLOGY OF STR-3 AND ITS ROLE IN LUNG CANCER

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DESCRIPTION (Applicant's Description): Lung cancer is currently the leading cause of cancer-related death in men and women largely because patients present with metastatic or micrometastatic disease that cannot be effectively treated. For this reason, new approaches to the identification and treatment of locally invasive and micrometastatic disease are needed. Matrix metalloproteinases (MMP) that degrade the structural support network for tumor cells and promote the neovascularization of tumor cell deposits are attractive targets for novel therapeutic approaches. Stromelysin-3 (STR-3) is a recently characterized MMP that was cloned on the basis of differential expression in benign and malignant tumors. Although STR-3 has a characteristic MMP structure, the enzyme has a unique substrate specificity, hydrolyzing certain serine protease inhibitors (serpins) including alpha1 anti-trypsin (alpha1 proteinase inhibitor, alpha1-PI). Because alpha1 antitrypsin (alpha1-PI) deficiency has a known pathogenetic role in pulmonary disease and alpha-1-PI may directly suppress tumor cell growth and invasion, the role of STR-3 in non small cell lung carcinomas (NSCLC) is of great interest. The investigators found that STR-3 transcripts were significantly more abundant in primary NSCLCs from 93 percent of paired tumor and adjacent normal lung specimens from 58 NSCLC patients. Because STR-3 immunostaining was primarily localized to tumor stromal elements, they characterized its regulation in pulmonary fibroblasts. STR-3 could be induced in normal fetal and adult pulmonary fibroblasts with growth factors (bFGF and PDGF) and/or TPA, and STR-3 induction was inhibited by retinoic acid, a commonly used chemopreventive agent for aerodigestive tract malignancies. Taken together, the data suggest that STR-3 may be a novel marker and potential therapeutic target for NSCLC. To further define the role for STR-3 in NSCLC and to determine whether the enzyme is an appropriate therapeutic target, the investigators will characterize expression of STR-3 and relevant novel substrates in primary NSCLC. The investigators will develop assays to quantitate STR-3 protein in serum and sputum and to characterize STR-3 enzymatic activity. Additionally, they will identify positive and negative regulators of STR-3 expression including angiogenic and anti-angiogenic agents and chemopreventive retinoids. Finally, they will develop in vivo and in vitro models to characterize the role of this unique MMP in invasion, metastasis and angiogenesis.