Receptor Cross-Talk in Early Metastatic Dissemination

卵巢癌(OvCa)是最致命的妇科癌症，5年生存率低(27%)。生死存亡 患Ovca的妇女的比例在30多年里没有明显变化，大多数确诊的妇女将死于 广泛播散性腹膜内(IP)转移引起的疼痛并发症。 流行病学数据表明，年龄是OvCa发病率的重要危险因素；然而，疾病 在老年宿主中的进展还没有得到实验研究。在上一个资助期，我们 开发了一套新的体外、体外和体内模型系统和成像方式，用于 研究宿主年龄和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)和腹膜下间皮细胞的年龄相关性改变 胶原蛋白与相对于年轻小鼠的肿瘤负担增加，并提示Wnt5a可以 作为肿瘤的中介物：在腹膜腔内引起串扰。当前项目中的实验将 解决宿主老化引起腹膜结构和功能改变的假设，这会影响 肿瘤细胞黏附、基质锚定和随后的转移成功。为了解决这一假设，Aim 1将研究年龄引起的腹膜微血管的变化，老年微血管对压迫和 菌株，以及由此对MC对转移性植入的接受性的影响。AIM2将重点关注老年人的老龄化 SubMC胶原基质，评估AGE诱导的基质交联性和生物物理性质，以及 对转移锚定的最终影响。AIM3将研究Wnt5a作为肿瘤的介质：主持人在 老化的腹膜腔。成功完成这些目标将提供对老龄化的无与伦比的洞察力 和IP转移。由于OvCa的高死亡率直接归因于IP转移，创新 整合肿瘤和宿主数据的方法将确定转移的关键决定因素 为未来的定向干预取得成功。

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.