Receptor Cross-Talk in Early Metastatic Dissemination

早期转移性播散中的受体串扰

基本信息

批准号：
10343706
负责人：
Mary Sharon Stack
金额：
$ 32.36万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10343706
关键词：
3-Dimensional Abdomen Address Adhesions Advanced Glycosylation End Products Age Aging Architecture Ascites Biochemistry Biological Models Biomechanics Cancer Etiology Cell Adhesion Cell Aging Cell Communication Cells Cessation of life Collagen Communication Data Diagnosis Disease Disease Progression Disseminated Malignant Neoplasm Event Funding Future Gene Expression Goals Greater sac of peritoneum Human In Vitro Incidence Intervention Intra-abdominal Knock-out Ligands Link Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mediating Mediator of activation protein Mesothelial Cell Mesothelium Metastatic to Modeling Molecular Mus Neoplasm Metastasis Organ Pain Pathway interactions Pattern Peritoneal Peritoneal Mesothelial Cell Prognosis Property Protein-Lysine 6-Oxidase ROR1 gene Receptor Activation Receptor Cross-Talk Receptor Protein-Tyrosine Kinases Regulation Research Risk Factors Role Secondary Lesion Structure Survival Rate Time Tissues Tumor Burden Woman age effect age related aged biophysical properties cancer cell cell age cohort crosslink epidemiologic data experimental study imaging modality implantation in vivo in vivo Model innovation insight intraperitoneal mimetics mortality neoplastic cell new therapeutic target receptor receptor for advanced glycation endproducts response success tumor tumor microenvironment

项目摘要

Ovarian cancer (OvCa) is the most fatal gynecologic cancer with a low (<27%) 5-year survival rate. Survival of women with OvCa has not changed appreciably in over 30 years and most women diagnosed will die of painful complications that arise as a result of widely disseminated intraperitoneal (IP) metastasis. Epidemiologic data indicate that age is a significant risk factor for OvCa incidence; however disease progression in the aged host has not been examined experimentally. In the previous funding period we developed a suite of new in vitro, ex vivo, and in vivo model systems and imaging modalities with which to examine the mechanistic link between host age and ovarian cancer metastatic success. Using these models, our preliminary data show age-related alterations in peritoneal mesothelial cells (MC) and sub-mesothelial collagen together with enhanced tumor burden in aged relative to young mice and suggest that Wnt5a can function as a mediator of tumor:host cross-talk in the peritoneal cavity. Experiments in the current project will address the hypothesis that host ageing induces changes in peritoneal structure and function that influence tumor cell adhesion, matrix anchoring, and subsequent metastatic success. To address this hypothesis, Aim 1 will examine age-induced changes in peritoneal MCs, the response of aged MCs to compression and strain, and the resulting impact on MC receptivity to metastatic implantation. Aim2 will focus on ageing of the sub-MC collagen matrix, evaluate age-induced matrix crosslinking and biophysical properties, and the ultimate effect on metastatic anchoring. Aim3 will investigate Wnt5a as a mediator of tumor:host cross-talk in the ageing peritoneal cavity. Successful completion of these aims will provide unparalleled insight into ageing and IP metastasis. As the high mortality of OvCa is directly attributable to IP metastasis, innovative approaches that integrate data from both tumor and host will identify critical determinants of metastatic success for future targeted intervention.

卵巢癌（OVCA）是最致命的妇科癌症，较低（<27％）的5年生存率。生存有OVCA的女性在30多年中没有明显改变，大多数被诊断的妇女将死于由于广泛传播的腹膜内（IP）转移而引起的痛苦并发症。流行病学数据表明，年龄是OVCA发病率的重要危险因素。但是疾病尚未对老年宿主的进展进行实验检查。在上一个资金期间我们开发了一套新的体外，离体和体内模型系统和成像方式的套件检查宿主年龄与卵巢癌转移性成功之间的机械联系。使用这些模型，我们的初步数据显示腹膜间皮细胞（MC）和亚皮物的年龄相关变化胶原蛋白以及相对于年轻小鼠的老年人的肿瘤负担增加，并建议Wnt5a可以充当肿瘤的介体：腹膜腔中的宿主串扰。当前项目中的实验将解决以下假设，即宿主衰老会诱导腹膜结构和功能的变化肿瘤细胞粘附，基质锚定和随后的转移性成功。为了解决这一假设，目标 1将检查年龄诱导的腹膜MC的变化，年龄MC对压缩和应变以及对MC接受转移性植入的影响。 AIM2将专注于衰老亚MC胶原蛋白基质，评估年龄诱导的基质交联和生物物理特性，以及对转移锚定的最终影响。 AIM3将调查Wnt5a作为肿瘤的调解人：宿主串扰衰老的腹膜腔。这些目标的成功完成将为衰老提供无与伦比的见解和IP转移。由于OVCA的高死亡率直接归因于IP转移，因此创新整合来自肿瘤和宿主数据的数据的方法将确定转移性的关键决定因素未来有针对性干预的成功。