Safavi-Sohi Reihaneh, Johnson Jeff, Liu Yueying, Yang Jing, Hilliard Tyvette S, Wang Zhikun, Barile Christopher, Mijares Josh, Wang Ceming, Chang Hsueh-Chia, Whelan Rebecca J, Stack M Sharon
Department of Chemistry and Biochemistry, Seton Hall University, South Orange Village, NJ, USA.
Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
Cell Commun Signal. 2025 Jul 1;23(1):308. doi: 10.1186/s12964-025-02273-1.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
背景：上皮性卵巢癌（OvCa）仍是妇科癌症中导致死亡的主要原因。向腹膜转移，其特征为肿瘤细胞黏附并侵袭腹腔间皮衬里，是OvCa转移进展中的一个关键早期事件。诊断的中位年龄为63岁，高龄、OvCa发病率和疾病分期之间存在很强的相关性。此外，老年腹腔是转移性播散的有利微环境。 方法：为了研究影响转移进展中宿主-肿瘤通讯的年龄相关因素，本研究从健康、未接触肿瘤的年轻（3 - 6个月）和老年（20 - 22个月）小鼠的腹腔灌洗中分离出小细胞外囊泡（sEVs）。使用液相色谱-串联质谱法（LC-MS/MS）分析sEVs以鉴定sEV蛋白成分，并与小鼠和人OvCa细胞孵育以评估对促转移行为的影响。 结果：相对于用年轻宿主来源的sEVs处理的OvCa细胞，在三维体外中膜模拟培养试验中，用健康老年宿主来源的sEVs处理人或小鼠OvCa细胞可显著增强其对腹膜间皮细胞的黏附，在短期体内黏附试验中可增强其对完整大网膜的黏附。老年宿主来源的sEVs也增强了OvCa细胞对胶原凝胶的侵袭。对sEV蛋白成分的蛋白质组学分析确定了从老年与年轻宿主获得的sEVs中差异表达的蛋白质，这些蛋白质可能在黏附调节中起重要作用。使用功能阻断抗体或小分子抑制剂进行的中膜模拟黏附试验证实了这一点，支持了几种蛋白质在促进老年宿主腹膜内播散中的潜在作用。 结论：结果表明，来自老年腹膜微环境的sEVs可显著促进疾病进展，突出了sEV介导的宿主-肿瘤通讯作为干预老年宿主OvCa进展或复发的潜在治疗靶点。
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