Receptor Cross-Talk in Early Metastatic Dissemination

早期转移性播散中的受体串扰

• 批准号: 7634470
• 负责人: Mary Sharon Stack
• 金额: $ 24.35万
• 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 2011-04-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7634470
• 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; Dissociation; Down-Regulation; E-Cadherin; 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; 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（由申请人提供）：弥散的腹腔内转移是上皮卵巢癌女性死亡的主要原因，表明对转移过程的干预可能会显着改善卵巢癌患者的长期生存。 转移表型的获取涉及一系列复杂的相互关联的细胞事件，导致恶性细胞与原发性肿瘤的解离（脱落）。 此过程中的关键事件是通过调节细胞间连接组件的调制来破坏细胞细胞接触。 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的理解将转化为新颖的诊断和治疗策略。 原发性良好的卵巢癌的一个独特特征是细胞 - 细胞粘附分子E-钙粘着蛋白的表达增加，随后丧失 E-钙粘蛋白的表达和/或功能在转移过程中。 我们目前的发现表明，表皮生长因子受体（EGFR）的配体，突变或反式激活调节连接溶解和随后的细胞传播所需的关键细胞事件。 提出的实验将检验以下假设：微环境因子通过激活的EGFR和钙粘着蛋白之间的串扰来影响转移性传播，从而调节电子 - 钙粘蛋白的表达和功能，从而导致从原发性肿瘤中脱离转移细胞。 为了解决这一假设，AIM 1将通过检查EGFR激活对E-钙粘蛋白表达，功能和运输的调节的影响，评估电子钙粘着蛋白连接蛋白结合完整性的微环境调节剂。 电子 - 钙粘蛋白功能下调对获得间充质标记和蛋白酶表达的采集的影响也将得到评估。 AIM 2将表征E-钙粘着蛋白外节域（SE-钙粘蛋白）蛋白水解释放的动力学，并评估使用器官型传播模型对SE-钙粘着蛋白对细胞细胞粘附和细胞分散体的影响。 AIM 3中提出的翻译研究将评估卵巢肿瘤微阵列中EGFR激活，蛋白酶表达，钙粘蛋白的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剂。 提出的整合分析将填补知识的巨大空白，并提供有关早期和晚期肿瘤和转移的E-和N-钙粘蛋白状态的新数据，（（b）卵巢肿瘤从良好分化肿瘤到较差的卵巢肿瘤进展中的EGFR激活和EMT，以及（c）（c）（c）在可溶性微环境调节器中的存在，用于维持tumor互动的可溶性微环境调节器的位置。 相关性：拟议的研究利用一种新型的综合方法来解决增强卵巢癌转移的分子机制。 靶向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。