Receptor Cross-Talk in Early Metastatic Dissemination

描述（申请人提供）：弥散性腹内转移是上皮性卵巢癌女性死亡的主要原因，表明干预转移过程可显著提高卵巢癌患者的长期生存率。转移表型的获得涉及一系列复杂的相互关联的细胞事件，导致恶性细胞从原发肿瘤中分离（脱落）。这一过程中的一个关键事件是通过调节细胞间连接成分破坏细胞-细胞接触。该项目的总体目标是确定导致恶性细胞传播的事件之间的相互关系，因为对这些过程的更详细了解将转化为新的诊断和治疗策略。原发性高分化卵巢癌的一个独特特征是细胞-细胞粘附分子e -钙粘蛋白的表达增加，随后丧失

DESCRIPTION (provided by applicant): Disseminated intra-abdominal metastasis is the leading cause of death for women with epithelial ovarian carcinoma, indicating that intervention with the metastatic process may significantly improve long-term survival of ovarian cancer patients. Acquisition of the metastatic phenotype involves a complex series of interrelated cellular events leading to dissociation (shedding) of malignant cells from the primary tumor. A key event in this process is disruption of cell-cell contacts via modulation of intercellular junctional components. The overall goal of this project is to define the interrelationships between events that contribute to dissemination of malignant cells, as a more detailed understanding of these processes will translate into novel diagnostic and therapeutic strategies. A unique feature of primary well-differentiated ovarian cancers is an increase in expression of the cell-cell adhesion molecule E-cadherin, with subsequent loss of E-cadherin expression and/or function during progression to metastasis. Our current findings indicate that ligand-, mutational-, or trans-activation of the epidermal growth factor receptor (EGFR) modulates key cellular events required for junction dissolution and subsequent cellular dissemination. Proposed experiments will test the hypothesis that microenvironmental factors influence metastatic dissemination by initiating cross-talk between activated EGFR and cadherins, thereby modulating E-cadherin expression and function, resulting in shedding of metastatic cells from the primary tumor. To address this hypothesis, Aim 1 will evaluate microenvironmental regulators of E-cadherin junctional integrity by examining the effect of EGFR activation on modulation of E-cadherin expression, function and trafficking. The impact of E-cadherin functional downregulation on acquisition of mesenchymal markers and proteinase expression will also be evaluated. Aim 2 will characterize the kinetics of proteolytic release of the E-cadherin ectodomain (sE-cadherin) and evaluate the effects of sE-cadherin on cell-cell adhesion and cellular dispersion using organotypic dissemination models. Translational studies proposed in Aim 3 will evaluate the relationship between EGFR activation, proteinase expression, cadherin status and ectodomain shedding in ovarian tumor microarrays and investigate microenvironmental regulators in ascites. The proposed integrative analysis will fill significant gaps in knowledge and provide novel data regarding (a) E- and N-cadherin status of early and late stage tumors and metastases, (b) EGFR activation and EMT in ovarian tumor progression from well- to poorly- differentiated tumors, and (c) the presence of soluble microenvironmental regulators positioned for sustained interaction with tumor tissues. Relevance: The proposed studies utilize a novel integrative approach to address molecular mechanisms that potentiate ovarian cancer metastasis. A major clinical need remains for ovarian cancer-specific therapies that target metastatic disease.