Receptor Cross-Talk in Early Metastatic Dissemination

早期转移性播散中的受体串扰

• 批准号: 7254916
• 负责人: Mary Sharon Stack
• 金额: $ 25.64万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254916
• 关键词: Address; Adhesives; Ascites; Cadherins; Cancer Patient; Cause of Death; Cell Adhesion Molecules; Cell-Cell Adhesion; Cells; Clinical; Complex; Data; Diagnostic Neoplasm Staging; Disease; Disruption; Dissociation; Down-Regulation; E-Cadherin; Endopeptidases; Environment; Epidermal Growth Factor Receptor; Epithelial; Event; Generations; Goals; Greater sac of peritoneum; Intervention; Intra-abdominal; Kinetics; Knowledge; Ligands; Loss of E-cadherin Expression; Malignant neoplasm of ovary; Mediating; Mesenchymal; Modeling; Molecular; N-Cadherin; Neoplasm Metastasis; Ovarian Carcinoma; Peptide Hydrolases; Phenotype; Positioning Attribute; Primary Neoplasm; Process; Receptor Activation; Receptor Cross-Talk; Role; Series; Testing; Therapeutic; Translating; Tumor Tissue; Tumor stage; Woman; cancer cell; improved; lysophosphatidic acid; metastatic process; novel; novel diagnostics; ovarian neoplasm; proteinase In; research study; trafficking; translational study; tumor; tumor progression

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.

描述（申请人提供）：腹腔内播散性转移是上皮性卵巢癌女性死亡的主要原因，表明对转移过程的干预可以显着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解离（脱落）。 该过程中的一个关键事件是通过调节细胞间连接成分来破坏细胞与细胞的接触。 该项目的总体目标是定义有助于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间粘附分子 E-钙粘蛋白的表达增加，随后丧失 E-钙粘蛋白在进展至转移过程中的表达和/或功能。 我们目前的研究结果表明，表皮生长因子受体（EGFR）的配体激活、突变激活或反式激活可调节连接溶解和随后的细胞传播所需的关键细胞事件。 拟议的实验将验证以下假设：微环境因素通过启动激活的 EGFR 和钙粘蛋白之间的串扰来影响转移扩散，从而调节 E-钙粘蛋白的表达和功能，导致原发肿瘤转移细胞脱落。 为了解决这一假设，目标 1 将通过检查 EGFR 激活对 E-钙粘蛋白表达、功能和运输调节的影响来评估 E-钙粘蛋白连接完整性的微环境调节剂。 还将评估 E-钙粘蛋白功能下调对间充质标记物和蛋白酶表达的影响。 目标 2 将表征 E-钙粘蛋白胞外域 (sE-cadherin) 的蛋白水解释放动力学，并使用器官传播模型评估 sE-钙粘蛋白对细胞间粘附和细胞分散的影响。 目标 3 中提出的转化研究将评估卵巢肿瘤微阵列中 EGFR 激活、蛋白酶表达、钙粘蛋白状态和胞外域脱落之间的关系，并研究腹水中的微环境调节因子。 所提出的综合分析将填补知识上的重大空白，并提供有关以下方面的新数据：(a) 早期和晚期肿瘤和转移灶的 E-和 N-钙粘蛋白状态，(b) 卵巢肿瘤从良好到不良进展中的 EGFR 激活和 EMT -分化的肿瘤，以及(c)可溶性微环境调节剂的存在，用于与肿瘤组织持续相互作用。 相关性：拟议的研究利用一种新颖的综合方法来解决增强卵巢癌转移的分子机制。 对于针对转移性疾病的卵巢癌特异性疗法仍然存在主要的临床需求。