Regulation of Epithelial Cancer by MMP-9/gelatinase B

描述：(申请人提供)人类癌症转基因小鼠模型 提供独特的机会来阐明重要的细胞和基因 癌症发展的途径，正常细胞通过这些途径逐渐 转化为异常的癌症。通过研究一种转基因小鼠模型 鳞状细胞癌的发展，我们已经确定了一个重要的旁分泌 上皮癌发生的修饰物，例如明胶酶B/基质 金属蛋白酶-9(MMP9)，以前认为它的作用是促进 基底膜降解。在肿瘤的发展过程中，基质金属蛋白酶-9调节 上皮细胞的增殖、分化和整体恶性程度 新出现的癌症，所有以前没有意识到的对此的监管能力 胞外蛋白酶。这些认识意味着基质金属蛋白酶-9发挥了更多的 在肿瘤进化的早期事件中发挥着深远的作用。这个项目的总体目标是 建议确定受基质金属蛋白酶-9调控的靶上皮细胞， 识别与MMP9相互作用的分子，介导增殖反应 并且，确定细胞内信号转导通路被激活为 基质金属蛋白酶-9诱导增殖的后果。我们将讨论这些特征 以及这些参数/机制在体内联合应用的功能意义 和体外实验方法。这项计划的具体目标是：目标1。 确定肿瘤上皮细胞增殖的调控机制 基质金属蛋白酶-9。我们将确定有反应的目标上皮细胞的身份 结合基质金属蛋白酶-9，并评估基质金属蛋白酶-9的候选蛋白底物 增殖反应。目的2.确定激活的机制(S) 负责基质金属蛋白酶-9诱导的增殖。利用体外细胞培养 体内观察到对基质金属蛋白酶-9有表型增殖反应的系统，我们 将决定关键蛋白质靶标和细胞内的识别 基质金属蛋白酶-9特异性激活的信号转导通路。目标3.确定 基质金属蛋白酶-9在肿瘤的启动、促进和恶变中的作用 多阶段上皮癌发生的步骤。它的功能重要性 基质金属蛋白酶-9在多阶段上皮癌发生中的离散步骤 使用经典的化学致癌的‘两阶段’模型来确定。 这些实验将揭示基质金属蛋白酶-9是否起到更重要的调节作用 在癌症的初始、发展或恶变阶段 发展。这项工作的直接后果是它的应用 使用基质金属蛋白酶抑制物(MMPI)作为抗癌药物。只有一个彻底的 了解基质金属蛋白酶-9的作用和作用将有效地指导药物的使用 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.