METALLOPROTEINASE INHIBITORS IN TUMOR PROGRESSION

肿瘤进展中的金属蛋白酶抑制剂

• 批准号: 7197977
• 负责人: Yves A DeClerck
• 金额: $ 25.4万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7197977
• 关键词: Adenocarcinoma; Affect; Apoptosis; Binding; Biological Availability; Breast Cancer Model; Cell Proliferation; Cells; Chemoprevention; Cleaved cell; Clinical Trials; Collagen; Data; Dependence; Deposition; Development; Diagnostic Neoplasm Staging; E-Cadherin; Endopeptidases; Epithelial; Epithelial Cells; Event; Extracellular Matrix; Extracellular Matrix Degradation; Fibrillar Collagen; Funding; Gelatinase B; Grant; Growth Factor; Human; Image; Imaging Techniques; Immigration; Inhibition of Matrix Metalloproteinases Pathway; Intraductal Hyperplasia; Investigation; Laboratories; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Mesenchymal; Metalloproteases; Modeling; Mus; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Patients; Peptide Hydrolases; Peptides; Play; Protein Overexpression; Role; Signal Pathway; Signal Transduction; Staging; Stromelysin 1; Testing; Therapeutic; Tissue Inhibitor of Metalloproteinases; Tissues; Transgenes; Transgenic Organisms; Tumor Cell Invasion; angiogenesis; base; carcinogenesis; cytokine; design; human tissue; in vivo; inhibitor/antagonist; malignant breast neoplasm; migration; neoplastic; preclinical study; prevent; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): For the last 20 years matrix metalloproteinases (MMPs) have been identified as important contributors to tumor progression on the basis of their abundant presence in neoplastic tissues, their ability to degrade all components of the extracellular matrix (ECM), and preclinical studies demonstrating the potent anti-tumor activity of MMP inhibitors (MPIs). In our laboratory and over the last 15 years of funding from this grant we have moved from an initial focus on MMP inhibition as a mechanism to prevent tumor invasion and metastasis to a focus on earlier stages of tumorigenesis. Our recent data in the MMTV-Wnt-1 de novo mouse mammary tumor model suggest that MMPs play a critical role in epithelial-mesenchymal transformation (EMT) and in tumor growth and angiogenesis. We hypothesize that there is a specific temporal expression of MMPs during Wnt-1 induced mammary tumorigenesis, with an initial dependence on neoplastic-derived MMP-3 for EMT and later dependence on MMP-9 for angiogenesis and tumor growth and that by targeting these two proteases, MPIs can inhibit tumorigenesis. This hypothesis is based on the observation that upon transformation with Wnt-1 mammary epithelial cells overexpress MMP-3, whereas Wnt-1 induced mammary tumors express MMP-9. In support of the hypothesis, we also observed that overexpression of a human tissue inhibitor of metalloproteinase-2 (TIMP- 2) transgene in the mammary gland of MMTV-Wnt-1 mice prevents or significantly delays the formation of tumors and results in slower growing tumors that are rich in collagen and contain less vessels. We propose 3 specific aims. The first aim will examine the function of MMP-3 in Wnt-1 mediated EMT, exploring whether MMP-3 is a downstream event in the Wnt-1 signaling pathway that is necessary or sufficient for transformation and determining the role of MMP-3 and the ECM in migration and invasion of Wnt-1 transformed mammary epithelial cells. The second aim will focus on examining the mechanisms of tumor inhibition by TIMP-2 and MPIs in MMTV-Wnt-1 mice, with particular emphasis on identifying the role of MMP- 3, MMP-9 and fibrillar collagen in tumor growth and angiogenesis, and on documenting proteolytic activity by imaging techniques. The third aim will determine whether MMPs are involved in tumor development in other de novo mammary tumor models that more closely mimic human breast cancer and in testing the role of MPIs in these models as chemoprevention. These studies will bring our understanding of MMP and MMP inhibition in cancer to a next level, and will generate information that could be critical in the design of better therapeutic or chemoprevention trials with MPIs.

描述（由申请人提供）：在过去的20年中，基质金属蛋白酶（MMP）已被确定为肿瘤进展的重要促进因素，基于它们在肿瘤组织中的大量存在，它们降低了细胞外基质（ECM）的所有成分的能力，并且表明了有力的抗毒剂抗肌肉的活性（MMP）。在我们的实验室和过去15年的资金中，我们从最初的焦点抑制了MMP抑制作用，作为防止肿瘤侵袭和转移的一种机制，转而着重于肿瘤发生的早期阶段。我们最近在MMTV-WNT-1 DE NOKEM乳腺肿瘤模型中的数据表明，MMP在上皮间质转化（EMT）以及肿瘤生长和血管生成中起关键作用。我们假设在WNT-1诱导的乳腺肿瘤发生过程中，MMP的特定时间表表达，并且对EMT的肿瘤衍生的MMP-3的初始依赖性依赖于EMT，然后对MMP-9的血管生成和肿瘤生长依赖于MMP-9，并且通过靶向这两种蛋白酶，MPIS可以抑制thmoriginease。该假设是基于这样的观察结果：在Wnt-1乳腺上皮细胞转化后，MMP-3过表达MMP-3，而Wnt-1诱导的乳腺肿瘤表示MMP-9。为了支持该假设，我们还观察到，在MMTV-WNT-1小鼠的乳腺中，人体组织抑制剂的过表达是金属蛋白酶-2（TIMP-2）转基因的过表达，可防止或显着延迟肿瘤的形成，并在较慢的胶原蛋白和容器中富含较慢的肿瘤形成，并导致较慢的生长肿瘤。我们提出了3个具体目标。第一个目标将检查MMP-3在Wnt-1介导的EMT中的功能，探索MMP-3是否是Wnt-1信号传导途径中的下游事件，对于转化和确定MMP-3和ECM在WNT-1迁移和入侵Wnt-1转化的乳腺上皮细胞中所必需或足够的作用。第二个目的将着重于检查MMTV-WNT-1小鼠中TIMP-2和MPI抑制肿瘤的机制，尤其强调确定MMP-3，MMP-9和Fibrillar胶原蛋白在肿瘤生长和血管生成中的作用，以及通过成像技术记录蛋白质溶解活性。第三个目标将确定MMP是否参与了其他从头乳腺肿瘤模型中的肿瘤发展，这些模型更紧密地模仿了人类乳腺癌，并在这些模型中测试MPI作为化学预防的作用。这些研究将使我们对癌症中MMP和MMP抑制作用的理解达到一个新水平，并将产生可能对使用MPI进行更好治疗或化学预防试验至关重要的信息。