Receptor Cross-Talk in Early Metastatic Dissemination

早期转移性播散中的受体串扰

• 批准号: 8680171
• 负责人: Mary Sharon Stack
• 金额: $ 28.91万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680171
• 关键词: 3-Dimensional; Accounting; Address; Adhesions; Affect; Ascites; Biochemical; Biological Assay; Biomechanics; Biophysics; Cadherins; Cancer Etiology; Cause of Death; Cell Line; Cells; Cessation of life; Collagen; Complement; Data; Development; Disease; E-Cadherin; EGF gene; Environment; Epithelial; Epithelial ovarian cancer; Epithelium; Event; Funding; Gel; Goals; Greater sac of peritoneum; Gynecologic; Human; Hybrid Cells; Hybrids; In Vitro; Intervention; Life; Liquid substance; Lysophospholipids; Malignant Neoplasms; Measures; Mechanics; Mesenchymal; Mesothelium; Metalloproteases; Metastatic Lesion; Metastatic to; Modeling; Molecular; Mus; N-Cadherin; Neoplasm Metastasis; Newly Diagnosed; Ovarian; Ovarian Carcinoma; Patients; Peritoneal; Peritoneal Fluid; Population; Prevalence; Primary Neoplasm; Prognostic Factor; Proliferating; Property; Proteins; Receptor Cross-Talk; Regulation; Role; Secondary Lesion; Shapes; Signal Transduction; Stretching; Surface; Suspension substance; Suspensions; Therapeutic; Woman; base; design; implantation; improved; in vitro Assay; in vivo; intraperitoneal; lysophosphatidic acid; metastatic process; mimetics; model development; ovarian neoplasm; pressure; research study; shear stress; success; tumor

DESCRIPTION (provided by applicant): Receptor Cross-Talk in Metastatic Dissemination Epithelial ovarian carcinoma (EOC) will affect 1 out of every 69 women born in the US today. Currently, 80% of women newly diagnosed with EOC already have metastatic disease, indicating that intervention in the metastatic process will improve long-term survival of women with EOC. Metastasis occurs through a unique mechanism involving shedding of non-adherent cells as multi-cellular aggregates (MCAs) into the peritoneal cavity followed by intra-peritoneal (IP) implantation, and is often associated with peritoneal ascites. The factors that regulate the terminal transition from free-floating MCA to life-threatening peritoneally anchored metastatic lesion are currently unknown. Studies in the previous funding period highlighted the role of the soluble microenvironmental regulators EGF and lysophosphatidic acid (LPA) in regulation of epithelial (E)-cadherin (Ecad) expression and function. These mechanistic studies generated exciting new data on metalloproteinase-catalyzed Ecad ectodomain shedding, the role of the soluble Ecad ectodomain in human EOC ascites, and on changes in ?-catenin dynamics resulting from altered junctional integrity. Further, we performed a detailed IHC analysis of Ecad expression in primary human EOC, developed a panel of assays with which to evaluate MCA dynamics and metastatic success, and identified a set of gene products regulated by altering the mechanical environment of the cell. These results form the basis of the current hypothesis that cadherin switching and IP mechanobiology actively contribute to metastatic success. Studies in Aim 1 will focus on cadherin switching and MCA dynamics using a panel of cadherin-modified cell lines and a suite of in vitro assays designed to mechanistically evaluate the effect of cadherin composition on key cellular events in EOC metastasis. Experiments in Aim 2 will evaluate the effect of altered peritoneal mechanobiology on the suite of measures of MCA metastatic success and will determine whether IP mechanical forces affect mesothelial receptivity to metastatic implantation. Aim 3 will combine analysis of human tumors and murine IP metastasis models for a direct examination of altered cadherin profiles, IP mechanobiology, and metastatic dissemination in vivo. The long-term goal of these studies is to cultivate a molecular level understanding of EOC metastasis, necessary for the development of EOC-specific therapies that effectively target metastatic disease.

描述（由申请人提供）：转移性传播上皮卵巢癌（EOC）中的受体串扰将影响今天在美国出生的每69名妇女中的1个。目前，有80％的新诊断为EOC的妇女已经患有转移性疾病，表明在转移过程中进行干预将改善EOC女性的长期生存。转移是通过一种独特的机制发生的，涉及将非粘附细胞作为多细胞聚集体（MCA）脱落到腹膜腔内，然后是腹膜内（IP）植入，并且通常与腹膜腹水有关。目前尚不清楚调节从自由浮动MCA到威胁生命的腹膜转移性病变的终末过渡的因素。在上一个资金期间的研究强调了可溶性微环境调节剂EGF和溶血磷脂酸（LPA）在上皮（E） - 钙粘蛋白（ECAD）表达和功能中的调节中的作用。这些机械研究产生了有关金属蛋白酶催化的ECAD外生域脱落的令人兴奋的新数据，可溶性ECAD胞外域在人EOC腹水中的作用，以及因连接式完整性改变而导致的 - 钙蛋白动力学的变化。此外，我们对原代人EOC中的ECAD表达进行了详细的IHC分析，开发了一个测定面板，以评估MCA动力学和转移性成功，并通过改变细胞的机械环境来确定一组基因产物。这些结果构成了当前假设的基础，即钙粘蛋白转换和IP机械生物学积极地有助于转移性成功。 AIM 1中的研究将使用一组钙粘蛋白改性的细胞系和一套体外测定套件，专注于钙粘蛋白的开关和MCA动力学，旨在机械学评估钙粘蛋白组成对EOC转移中关键细胞事件的影响。 AIM 2中的实验将评估腹膜机械生物学改变对MCA转移成功量度的套件的影响，并将确定IP机械力是否影响间皮接受转移性植入。 AIM 3将结合对人类肿瘤和鼠IP转移模型的分析，以直接检查体内钙粘蛋白轮廓，IP机械生物学和转移性传播。这些研究的长期目标是培养对EOC转移的分子水平理解，这是开发有效靶向转移性疾病的EOC特异性疗法所必需的。