Receptor Cross-Talk in Early Metastatic Dissemination

早期转移性播散中的受体串扰

• 批准号: 10090457
• 负责人: Mary Sharon Stack
• 金额: $ 33.02万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090457
• 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

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，5 年生存率较低 (<27%)。生存 30 多年来，患有 OvCa 的女性比例没有明显变化，大多数被诊断出的女性将死于 由于广泛播散的腹膜内（IP）转移而引起的痛苦并发症。 流行病学数据表明，年龄是 OvCa 发病的重要危险因素；然而疾病 尚未通过实验检查老年宿主的进展情况。在上一个资助期间，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 检查宿主年龄与卵巢癌转移成功之间的机制联系。使用这些模型， 我们的初步数据显示腹膜间皮细胞（MC）和间皮下细胞发生与年龄相关的变化 与年轻小鼠相比，老年小鼠中的胶原蛋白加上肿瘤负荷增加，表明 Wnt5a 可以 作为肿瘤的介质：腹膜腔内的宿主串扰。当前项目中的实验将 提出了这样的假设：宿主衰老会引起腹膜结构和功能的变化，从而影响 肿瘤细胞粘附、基质锚定以及随后的转移成功。为了解决这个假设，目标 1 将检查年龄引起的腹膜 MC 的变化、老年 MC 对压迫的反应和 应变，以及由此产生的对 MC 对转移植入的接受性的影响。 Aim2 将重点关注老龄化问题 sub-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 将研究 Wnt5a 作为肿瘤：宿主串扰的介质 老化的腹膜腔。成功完成这些目标将为衰老提供无与伦比的洞察力 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的数据的方法将确定转移的关键决定因素 未来有针对性的干预的成功。