Regulation of Epithelial Cancer by MMP-9/gelatinase B

描述：（由申请人提供）人类癌症的转基因小鼠模型 提供了独特的机会来阐明重要的细胞和遗传 癌症发展的途径，通过这些途径，正常细胞逐渐 转化为异常的癌症通过研究转基因小鼠模型， 鳞状细胞癌的发展，我们已经确定了一个重要的旁分泌 上皮癌发生的修饰剂，例如，明胶酶B/基质 金属蛋白酶-9（MMP9），其作用以前被认为是促进 基底膜降解在肿瘤发展过程中，MMP-9调节 上皮细胞增殖、分化和总体恶性程度 所有以前未被重视的调节能力， 胞外蛋白酶这些认识意味着MMP-9发挥了更多的作用， 在肿瘤演变的早期事件中发挥着重要作用。这个项目的总体目标是 建议是识别受MMP-9调节的靶上皮细胞， 鉴定与介导增殖反应的MMP 9相互作用的分子 并确定细胞内信号转导途径激活作为一个 MMP-9诱导的增殖的结果。我们将讨论 这些参数/机制的功能意义，通过结合体内 和体外方法。该项目的具体目标是：目标1。到 确定调节肿瘤上皮细胞增殖的机制， MMP-9。我们将确定目标上皮细胞的身份， 并评估MMP-9介导的候选蛋白底物， 增殖反应。目标二。确定激活机制 负责MMP-9诱导的增殖。用体外细胞培养 在体内观察到的对MMP-9的表型复制增殖反应的系统，我们 将确定关键蛋白质靶点的识别和细胞内 MMP-9特异性激活的信号转导通路。目标3：确定 MMP-9在肿瘤发生、发展及恶变中的作用 多阶段上皮癌变的步骤。的功能重要性 MMP-9在多阶段上皮癌发生的不连续步骤中的表达将是 使用化学致癌作用的经典"两阶段"模型确定。 这些实验将揭示MMP-9是否发挥更重要的调节作用 在癌症的起始、促进或恶性转化阶段 发展这项工作的直接后果是它的应用 涉及MMP抑制剂（MMPI）作为抗癌剂的用途。只有彻底的 了解MMP-9的作用和影响将有效地指导使用 MMPIs在癌症治疗中的应用

DESCRIPTION: (provided by applicant) Transgenic mouse models of human cancers present unique opportunities to elucidate important cellular and genetic pathways of cancer development, through which normal cells progressively are converted into aberrant cancers. By studying a transgenic mouse model of squamous cell carcinoma development, we have identified an important paracrine modifier of epithelial carcinogenesis, e.g., gelatinase B/matrix metalloproteinase-9 (MMP9), whose role previously was believed to facilitate basement membrane degradation. During neoplastic development, MMP-9 regulates epithelial cell proliferation, differentiation, and overall malignancy of emergent cancers, all previously unappreciated regulatory capabilities for this extracellular proteinase. These realizations imply that MMP-9 exerts a more profound role during early events in tumor evolution. The overall goal of this proposal is to identify the target epithelial cells regulated by MMP-9, identify molecules that interact with MMP9 mediating proliferative responses and, identify intracellular signal transduction pathways activated as a consequence of MMP-9-induced proliferation. We will address the characteristics and functional significance of these parameters/mechanisms by combined in vivo and in vitro approaches. The specific aims of this project are: Aim 1. To determine mechanisms regulating neoplastic epithelkil cell proliferation by MMP-9. We will determine the identity of the target epithelial cells responsive to MMP-9 and assess candidate protein substrates of MMP-9 mediating proliferative responses. Aim 2. To determine the mechanism(s) of activation responsible for MMP-9 -induced proliferation. Using in vitro cell culture systems that phenocopy proliferative responses to MMP-9 observed in vivo, we will determine the identify of critical protein targets and intracellular signal transduction pathways specifically activated by MMP-9. Aim 3. Determine the impact of MMP-9 on the initiation, promotion, and malignant conversion steps of multistage epithelial carcinogenesis. The functional importance of MMP-9 at discrete steps of multi-stage epithelial carcinogenesis will be ascertained using the classical 'two-stage' model of chemical carcinogenesis. These experiments will reveal if MMP-9 plays a more significant modifier role at the initiation, promotion, or malignant conversion stages of cancer development. The immediate ramifications of this work are in its applications to use of MMP-Inhibitors (MMPIs) as anticancer agents. Only a thorough understanding of the actions and effects of MMP-9 will effectively guide use of MMPIs in the treatment of cancer.