Receptor Cross-Talk in Early Metastatic Dissemination

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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.