Regulation of Ovarian Carcinoma Proteinases

上皮性卵巢癌是妇科恶性肿瘤的主要死亡原因，75%的女性 这种疾病容易出现转移引起的并发症；因此，旨在预防 转移会立即产生临床影响。转移瘤主要局限于腹膜。 空洞，表明调节腹膜内黏附、运动和运动的微环境因素 侵袭性在卵巢病理生物学中起主导作用。获得转移性表型包括 细胞-细胞接触中断和细胞外基质(ECM)约束丧失，原因是上调 基质金属蛋白酶(MMPs)与基质和机械转导的变化。虽然正常 卵巢上皮细胞不表达MMPs，跨膜型1-MMPs(MT1-MMPs)是 在交界性肿瘤、恶性肿瘤和腹膜转移瘤中显著升高。整合素介导的 卵巢癌细胞与富含间皮下ECM的间质胶原的相互作用代表着一种 卵巢癌转移扩散所特有的重要早期事件。此外，我们公布的数据 证明胶原结合整合素的参与增加了MT1-MMP的表达，并支持 结论基质状态影响细胞表面和细胞周围基质的降解能力。同舟共济 这些数据支持一种假设，即黏附和蛋白分解之间的功能联系调节卵巢 癌症侵袭和转移行为。目标1中提出的实验将集中在MT1-MMP面上 动力学，以阐明翻译后机制，调节活性的MT1-基质金属蛋白酶的表面呈现。 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作用的作用 作为参与MT1-MMPs基因转录调控的表观遗传因子， MT1-基质金属蛋白酶表面动力学的变化和侵袭性表型的获得。的贡献 整合素信号转导连接E-钙粘附素丢失、激活p-连环素介导的转录和E-钙粘附素 钙粘蛋白胞外结构域脱落将在目标3中进行评估。这些实验将共同提供新的 关于腹膜微环境中基质和机械线索的机制的信息 通过蛋白水解酶调节途径决定卵巢癌的转移潜能。

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 p-catenin-mediated transcription and E- cadherin ectodomain shedding will be assesesed 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.