Receptor Cross-Talk in Early Metastatic Dissemination

摘要 卵巢癌(OvCa)是最致命的妇科癌症，5年生存率低(27%)。幸存的 患有Ovca的女性30多年来没有明显的变化，大多数确诊的女性将死于疼痛 广泛播散性腹膜内(IP)转移引起的并发症。流行病学数据 表明年龄是OvCa发病率的重要独立危险因素；然而，在 这位年迈的寄主还没有经过实验检验。家长拨款中的实验解决了这一假设 宿主衰老会导致腹膜结构和功能的变化，从而影响肿瘤细胞的黏附和基质 锚定和最终转移的成功。AIM 1正在进行的研究检查年龄诱导的 腹膜间皮细胞(MC)及其对MC对转移种植敏感性的影响 重点研究亚MC胶原基质的老化，评价老化引起的基质交联性的变化 和生物物理特性，以及对转移锚定的影响；而Aim3将WNT5a作为一种 肿瘤的介体：老化的腹膜腔内的宿主串扰。在这项修订拨款中，我们建议增加一项 父母拨款的新目标是使用由NCI创新中心支持开发的新技术 分子分析技术(IMAT)计划。这项由张宏昌博士进行的研究开发了一种 用于从复杂生物体液中分离和裂解外切体和捕获的新型固态纳米孔技术 和外体microRNAs的定量。使用这项技术，修订应用程序的新目标4将 评估双向肿瘤的作用：通过外切体介导的miRNA传递在转移中的宿主沟通 在宿主老化的背景下的进展。成功完成拟议的实验将提供 对固态纳米孔技术进行严格的功能验证和基准测试 相关模型体系。同时，我们将加强家长赠款的影响，并提供 对介导肿瘤的分子和事件的前所未有的洞察：老年宿主中的宿主交流。

ABSTRACT 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 independent risk factor for OvCa incidence; however disease progression in the aged host has not been examined experimentally. Experiments in the parent grant address the hypothesis that host aging induces changes in peritoneal structure and function that influence tumor cell adhesion, matrix anchoring, and ultimate metastatic success. Ongoing studies in Aim 1 examine age-induced changes in peritoneal mesothelial cells (MCs) and the resulting impact on MC receptivity to metastatic implantation; Aim2 focuses on aging of the sub-MC collagen matrix, evaluation of aging-induced changes in matrix crosslinking and biophysical properties, and the influence on metastatic anchoring; and Aim3 investigates Wnt5a as a mediator of tumor:host cross-talk in the aging peritoneal cavity. In this ‘revision’ grant, we propose to add a new aim to the parent grant to employ novel technology developed through support from the NCI Innovative Molecular Analysis Technologies (IMAT) program. This research, conducted by Dr. H-C Chang, developed a novel solid-state nanopore technology for isolation and lysis of exosomes from complex biofluids and capture and quantitation of exosomal microRNAs. Using this technology, the new Aim 4 of the revision application will assess the role of bi-directional tumor:host communication via exosome-mediated miRNA delivery in metastatic progression in the context of host aging. Successful completion of the proposed experiments will provide rigorous functional validation and benchmarking of the solid-state nanopore technology in an interesting and relevant model system. Simultaneously we will enhance the impact of the parent grant and provide unprecedented insight into molecules and events that mediate tumor:host communication in the aged host.