BIOLOGY OF STR-3 AND ITS ROLE IN LUNG CANCER

描述(申请人描述)：肺癌是目前最主要的癌症 男性和女性癌症相关死亡的原因主要是因为患者 有转移性或微转移性疾病，不能 有效治疗。出于这个原因，新的身份识别方法 以及局部侵袭性和微转移疾病的治疗是必要的。 降解结构支撑网的基质金属蛋白酶(MMP) 促进肿瘤细胞沉积的新生血管形成 是新的治疗方法的有吸引力的靶点。基质分解素-3 (STR-3)是最近鉴定的一种基质金属蛋白酶，它是在以下基础上克隆的 在良、恶性肿瘤中的差异表达。尽管STR-3已经 作为一种特有的基质金属蛋白酶结构，该酶具有独特的底物 专一性，能降解某些丝氨酸蛋白酶抑制剂(丝氨酸酶) 包括α1抗胰蛋白酶(α1蛋白水解酶抑制剂，α1-PI)。 因为α1抗胰蛋白酶(α1-PI)缺乏症有一个已知的病因 在肺部疾病中的作用和α-1-PI可能直接抑制肿瘤细胞 STR-3在非小细胞肺癌生长侵袭中的作用 (NSCLC)引起了极大的兴趣。调查人员发现，STR-3 在93例原发非小细胞肺癌中，转录本明显更丰富 58例非小细胞肺癌配对肿瘤及邻近正常肺标本的百分比 病人。因为STR-3免疫染色主要局限于肿瘤 基质元素，它们表征了其在肺组织中的调节 成纤维细胞。STR-3可在正常胎儿和成人肺中诱导 含生长因子(碱性成纤维细胞生长因子和PDGF)和/或TPA和STR-3的成纤维细胞 诱导被维甲酸抑制，维甲酸是一种常用的化学预防药物 治疗呼吸道恶性肿瘤的药物。总而言之，这些数据 提示STR-3可能是一种新的标志物和潜在的治疗靶点 用于非小细胞肺癌。进一步定义STR-3在非小细胞肺癌中的作用并确定 这种酶是否是合适的治疗靶点，研究人员 将表征STR-3和相关新底物在 原发非小细胞肺癌。研究人员将开发出定量检测STR-3的方法 检测血清和痰中蛋白质含量，并对STR-3酶活性进行鉴定。 此外，他们还将确定STR-3的积极和消极调节因素 表达包括血管生成和抗血管生成因子和 化学预防类维甲酸。最后，它们将在体内和体外发育。 表征这种独特的基质金属蛋白酶在侵袭、转移中作用的模型 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.