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%患有这种疾病的妇女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。转移瘤主要局限于腹腔，表明调节腹腔内粘连、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。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，转移表型的获得涉及细胞间接触的破坏和细胞外基质（ECM）约束的丧失。虽然正常卵巢上皮不表达MMPs，但跨膜膜型1-MMP （MT1-MMP）在交界性肿瘤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是卵巢癌转移性传播的重要早期事件。间质胶原富含间质上皮细胞外基质。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，这些数据支持黏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。Aim 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Aim 2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。整合素信号传导对连接e -钙粘蛋白缺失的贡献，激活？-catenin介导的转录和E-cadherin外畴脱落将在Aim 3中进行评估。总之，这些实验将提供关于基质和机械线索在腹腔内微环境中通过蛋白酶调节途径决定卵巢癌转移潜力的机制的新信息。

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.