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%）。生存 OvCa妇女的死亡率在30多年来没有明显变化，大多数诊断出OvCa的妇女将死于 广泛播散的腹膜内（IP）转移导致的疼痛并发症。 流行病学数据表明，年龄是OvCa发病率的重要危险因素;然而， 在老年宿主中的进展尚未通过实验检验。在上一个融资周期，我们 开发了一套新的体外、离体和体内模型系统和成像模式， 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）和间皮下细胞（sub-mesothelium） 与年轻小鼠相比，老年小鼠中的胶原蛋白以及增强的肿瘤负荷，并表明Wnt 5a可以 作为肿瘤的介质：腹膜腔中的宿主串扰。本项目的实验将 解决宿主衰老诱导腹膜结构和功能变化的假设， 肿瘤细胞粘附、基质锚定和随后的转移成功。为了解决这个问题，Aim 1将检查年龄引起的腹膜MC的变化，老年MC对压缩的反应， 菌株，以及由此产生的对MC对转移性植入的感受性的影响。第二个目标将侧重于 亚MC胶原基质，评估年龄诱导的基质交联和生物物理性质， 对转移锚定的最终影响。Aim 3将研究Wnt 5a作为肿瘤：宿主串扰的介质， 老化的腹膜腔成功地完成这些目标将提供无与伦比的洞察老龄化 和IP转移。由于OvCa的高死亡率直接归因于IP转移，因此创新性地将OvCa的高死亡率归因于IP转移。 整合来自肿瘤和宿主的数据的方法将确定转移性肿瘤的关键决定因素。 未来有针对性的干预措施。

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.