Peritoneal cavity-derived small extracellular vesicles from aged tumor-naïve hosts promote ovarian cancer adhesion and invasion
Epithelial ovarian cancer (OvCa) remains a leading cause of mortality among gynecological cancers. Metastasis to the peritoneum, characterized by tumor cell adhesion to and invasion of the mesothelial lining of the abdominal cavity, represents a critical early event in OvCa metastatic progression. The median age of diagnosis is 63 and there exists a strong correlation between advanced age, OvCa incidence and disease stage. Moreover, the aged peritoneal cavity represents a permissive niche for metastatic dissemination. To investigate age-related factors that influence host-tumor communication in metastatic progression, the current study isolated small extracellular vesicles (sEVs) from the peritoneal lavage of healthy tumor-naïve young (3-6 month) and aged (20-22 month) mice. sEVs were analyzed using LC-MS/MS to identify sEV protein cargoes and incubated with murine and human OvCa cells to evaluate effect on pro-metastatic behaviors. Treatment of human or murine OvCa cells with sEVs from healthy aged hosts significantly enhanced adhesion to peritoneal mesothelial cells in a three-dimensional in vitro meso-mimetic culture assay and to the intact omentum in a short-term in vivo adhesion assay relative to OvCa cells treated with sEVs from young hosts. OvCa cell invasion of collagen gels was also enhanced by aged host-derived sEVs. Proteomic analysis of sEV protein cargos identified differentially expressed proteins in sEVs obtained from aged vs. young hosts that may play a significant role in regulation of adhesion. This was confirmed using meso-mimetic adhesion assays with function blocking antibodies or small molecule inhibitors, supporting a potential role for several proteins in promoting intra-peritoneal dissemination in the aged host. Results suggest that sEVs derived from the aged peritoneal microenvironment can contribute significantly to disease progression, highlighting sEV-mediated host: tumor communication as a potential therapeutic target for intervention in OvCa progression or recurrence in the aged host.
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Telemedicine, Caregivers, and Rural Population HealthHigh-Throughput Electrokinetic Fractionation and Analysis of Extracellular RNA Nano-CarriersThe Impact of Maternal Obesity on the Reprogramming of the Metastatic MicroenvironmentNational Institutes of Health,United States Grant RO1CA109545National Institutes of Health,United States Grant KO1CA218305Aging and the Ovarian Tumor MicroenvironmentTelemedicine, Caregivers, and Rural Population HealthReceptor Cross-Talk in Early Metastatic DisseminationTargeted proteomics of MUC16 to enable early detection of ovarian cancer recurrenceHigh-Throughput Electrokinetic Fractionation and Analysis of Extracellular RNA Nano-CarriersNIH HHS Grant UO1CA236979A Novel Janus Bead Blood Assay for Point-of-Care Assessment of HCV Viral Load and Associated Liver DamageTargeted proteomics of MUC16 to enable early detection of ovarian cancer recurrenceNational Institutes of Health Grant UO1CA236979