BIOLOGY OF STR-3 AND ITS ROLE IN LUNG CANCER

描述（申请人的描述）：肺癌是目前主要的 男性和女性癌症相关死亡的原因主要是因为患者 存在转移性或微转移性疾病， 有效治疗。 因此，新的识别方法 以及局部侵袭性和微转移性疾病的治疗。 降解结构支持网络的基质金属蛋白酶（MMP） 促进肿瘤细胞新生血管的形成和肿瘤细胞的沉积 是新治疗方法的有吸引力的靶点。 基质分解素-3 （STR-3）是最近表征的MMP，其是基于 在良性和恶性肿瘤中的差异表达。 尽管STR-3 一种特征性的MMP结构，该酶具有独特的底物 特异性，水解某些丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂） 包括α 1抗胰蛋白酶（α 1蛋白酶抑制剂，α 1-PI）。 由于α 1抗胰蛋白酶（α 1-PI）缺乏症具有已知的致病性， α-1-PI可直接抑制肿瘤细胞 STR-3在非小细胞肺癌中的作用 （NSCLC）是非常重要的。 调查人员发现，STR-3 转录本在原发性NSCLC中显著更丰富，从93 58例NSCLC的配对肿瘤和相邻正常肺标本的百分比 患者 由于STR-3免疫染色主要定位于肿瘤， 基质元素，他们的特点是其调节肺 成纤维细胞 STR-3可在正常胎儿和成人肺组织中诱导表达， 成纤维细胞与生长因子（bFGF和PDGF）和/或TPA，和STR-3 诱导被抑制维甲酸，一种常用的化学预防剂 用于呼吸消化道恶性肿瘤的药剂。 总的来说，数据 提示STR-3可能是一种新标记物和潜在的治疗靶点 对于NSCLC。 进一步明确STR-3在NSCLC中的作用，并确定 无论这种酶是否是一个合适的治疗靶点，研究人员 将表征STR-3和相关新底物在 原发性NSCLC。 研究人员将开发测定STR-3的方法 血清和痰液中的蛋白质并表征STR-3酶活性。 此外，他们还将确定STR-3的阳性和阴性调节因子， 包括血管生成剂和抗血管生成剂的表达， 化学预防类维生素A 最后，它们将在体内和体外发育 模型来表征这种独特的MMP在侵袭、转移 和血管生成。

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.