Regulation of Ovarian Carcinoma Proteinases

描述(申请人提供)：卵巢上皮癌是妇科恶性肿瘤死亡的主要原因，因为75%的患有这种疾病的妇女死于转移引起的并发症；因此，旨在防止转移的策略将立即产生临床效果。转移瘤主要局限于腹膜腔内，表明调节腹膜内黏附、运动和侵袭的微环境因素在卵巢病理生物学中起主导作用。转移表型的获得涉及细胞-细胞接触的中断和细胞外基质(ECM)限制的丧失，这是由于基质金属蛋白酶(MMPs)的上调以及基质和机械转导的改变。正常卵巢上皮细胞不表达MMPs，而交界性肿瘤、恶性肿瘤和腹膜转移瘤中的跨膜型1-MMPs(MT1-MMPs)显著升高。整合素介导人卵巢癌细胞与间皮下ECM丰富的间质胶原的相互作用，是卵巢癌转移扩散的一个重要的早期事件。此外，我们发表的数据表明，胶原结合整合素的参与增加了MT1-MMP的表达，并支持了基质状态影响细胞表面和细胞周围基质降解潜力的结论。总之，这些数据支持一种假设，即黏附和蛋白降解之间的功能联系调节卵巢癌的侵袭和转移行为。目标1中提出的实验将侧重于MT1-MMP表面动力学，以阐明调节活性MT1-MMP表面呈现的翻译后机制。这将与目标2中的实验相结合，以评估作为表观遗传因素的基质相互作用和机械约束的作用，这些因素参与MT1-MMP基因表达的转录调控、MT1-MMP表面动力学的变化和侵袭性表型的获得。整合素信号在连接性E-钙粘素丢失、β-连环素介导的转录激活和E-钙粘蛋白胞外结构域脱落中的作用将在目标3中进行评估。这些实验将提供新的信息，说明腹膜微环境中的基质和机械信号通过蛋白酶调节途径决定卵巢癌转移潜能的机制。

DESCRIPTION (provided by applicant): Epithelial ovarian carcinoma is the leading cause of death from gynecologic malignancy, as 75% of women with this disease succumb to complications resulting from metastasis; thus, strategies aimed at prevention of metastasis would generate immediate clinical impact. Metastases are largely confined to the peritoneal cavity, indicating that microenvironmental factors that modulate intraperitoneal adhesion, motility and invasion play a predominant role in ovarian pathobiology. Acquisition of the metastatic phenotype involves disruption of cell-cell contacts and loss of extracellular matrix (ECM) constraints due to upregulation of matrix metalloproteinases (MMPs) and alterations in matrix- and mechano-transduction. While normal ovarian epithelium does not express MMPs, the transmembrane membrane type 1-MMP (MT1-MMP) is significantly elevated in borderline and malignant tumors and in peritoneal metastases. Integrin-mediated interaction of ovarian cancer cells with interstitial collagens, rich in the submesothelial ECM, represents an important early event unique to ovarian cancer metastatic dissemination. Further, our published data demonstrate that engagement of collagen binding integrins increases MT1-MMP expression and support the conclusion that matrix status influences cell surface and peri-cellular matrix degrading potential. Together these data support the hypothesis that a functional link between adhesion and proteolysis regulates ovarian cancer invasive and metastatic behavior. Experiments proposed in Aim 1 will focus on MT1-MMP surface dynamics to elucidate post-translational mechanisms that regulate surface presentation of active MT1-MMP. This will be integrated with experiments in Aim 2 to evaluate the role of matrix interactions and mechanical constraints as epigenetic factors that participate in transcriptional regulation of MT1-MMP gene expression, changes in MT1-MMP surface dynamics and acquisition of the invasive phenotype. The contribution of integrin signaling to loss of junctional E-cadherin, activation of ?-catenin-mediated transcription and E-cadherin ectodomain shedding will be assessed in Aim 3. Together these experiments will provide novel information on mechanisms by which matrix and mechanical cues in the intraperitoneal microenvironment dictate ovarian cancer metastatic potential through proteinase regulation pathways.