Regulation of Ovarian Carcinoma Proteinases

描述（由申请人提供）：上皮性卵巢癌是妇科恶性肿瘤死亡的主要原因，因为75%患有这种疾病的女性死于转移引起的并发症;因此，旨在预防转移的策略将产生直接的临床影响。 转移主要局限于腹膜腔，表明调节腹膜内粘附、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-细胞接触的破坏和细胞外基质（ECM）约束的丧失，这是由于基质金属蛋白酶（MMP）的上调以及基质和机械转导的改变。 虽然正常卵巢上皮不表达MMP，但跨膜1型MMP（MT 1-MMP）在交界性和恶性肿瘤以及腹膜转移中显著升高。 整合素介导的卵巢癌细胞与间质胶原的相互作用，富含间皮细胞外基质，代表了卵巢癌转移性传播的一个重要的早期事件。 此外，我们发表的数据表明，参与胶原结合整合素增加MT 1-MMP的表达，并支持的结论，基质状态影响细胞表面和细胞周围基质降解的潜力。 这些数据共同支持了粘附和蛋白水解之间的功能联系调节卵巢癌侵袭和转移行为的假设。 目标1中提出的实验将集中在MT 1-MMP表面动力学，以阐明调节活性MT 1-MMP表面呈递的翻译后机制。 这将与目标2中的实验相结合，以评估基质相互作用和机械约束作为表观遗传因子的作用，表观遗传因子参与MT 1-MMP基因表达的转录调控、MT 1-MMP表面动力学的变化和侵袭性表型的获得。 整合素信号转导对连接性E-钙粘蛋白的丢失、？连环蛋白介导的转录和E-钙粘蛋白胞外域脱落将在目标3中评估。 总之，这些实验将提供新的信息机制，其中基质和机械线索在腹膜内微环境决定卵巢癌转移的潜力，通过蛋白酶调节途径。

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.