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%）。生存 患有OvCa的妇女在30多年来没有明显变化，大多数诊断出的妇女将死于疼痛。 广泛播散的腹膜内（IP）转移导致的并发症。流行病学数据 表明年龄是OvCa发病率重要独立危险因素;然而， 老化的主机尚未经过实验检验。父母补助金的实验解决了这个假设 宿主衰老诱导腹膜结构和功能的变化，影响肿瘤细胞粘附、基质 锚定和最终的转移成功。目标1中正在进行的研究检查了年龄引起的 腹膜间皮细胞（MC）及其对转移性植入MC接受性的影响; Aim 2 重点关注亚MC胶原基质的老化，评价老化诱导的基质交联变化 和生物物理特性，以及对转移锚定的影响; Aim 3研究了Wnt 5a作为一种 肿瘤介质：老化腹膜腔中的宿主串扰。在这项“修订”拨款中，我们建议增加一项 新的目标，家长赠款采用新的技术开发的支持下，从国家癌症研究所创新 分子分析技术（IMAT）计划。这项研究由H-C Chang博士进行，开发了一种 用于从复杂生物流体中分离和裂解外来体并捕获外来体的新型固态纳米孔技术 和外泌体microRNA的定量。利用这项技术，修订版应用程序的新目标4将 评估双向肿瘤的作用：通过外泌体介导的miRNA递送在转移性肿瘤中的宿主通讯 在宿主老化的背景下进展。成功完成拟议的实验将提供 严格的功能验证和基准测试的固态纳米孔技术在一个有趣的， 相关模型系统。同时，我们将加强家长补助金的影响， 对介导肿瘤的分子和事件的前所未有的洞察：老年宿主中的宿主通讯。

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.