老年tumor-naïve宿主腹膜腔来源的细胞外小泡促进卵巢癌的粘附和侵袭。

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Reihaneh Safavi-Sohi, Jeff Johnson, Yueying Liu, Jing Yang, Tyvette S Hilliard, Zhikun Wang, Christopher Barile, Josh Mijares, Ceming Wang, Hsueh-Chia Chang, Rebecca J Whelan, M Sharon Stack
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引用次数: 0

摘要

背景:上皮性卵巢癌(OvCa)仍然是妇科癌症死亡的主要原因。转移到腹膜,以肿瘤细胞粘附和侵袭腹腔间皮内膜为特征,是OvCa转移进展的关键早期事件。中位诊断年龄为63岁,高龄、OvCa发病率与疾病分期有较强相关性。此外,老化的腹膜腔为转移性传播提供了一个允许的生态位。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tumor-naïve幼年(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(sev)。采用LC-MS/MS对sEV进行分析,鉴定sEV蛋白载体,并与小鼠和人OvCa细胞孵育,以评估其对促转移行为的影响。结果:与用年轻宿主的sev处理的OvCa细胞相比,用健康老年宿主的sev处理的人或小鼠OvCa细胞在三维体外模拟中显著增强了对腹膜间皮细胞的粘附,在短期体内粘附实验中显著增强了对完整网膜的粘附。衰老宿主源性sev也增强了OvCa细胞对胶原凝胶的侵袭。sEV蛋白货物的蛋白质组学分析发现,从老年和年轻宿主获得的sEV中差异表达的蛋白可能在粘附调节中发挥重要作用。使用功能阻断抗体或小分子抑制剂进行的中模拟粘附试验证实了这一点,支持几种蛋白质在促进老年宿主腹膜内传播中的潜在作用。结论:研究结果表明,来自老年腹膜微环境的sev可显著促进疾病进展,强调sev介导的宿主-肿瘤通讯是干预老年宿主OvCa进展或复发的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Peritoneal cavity-derived small extracellular vesicles from aged tumor-naïve hosts promote ovarian cancer adhesion and invasion.

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.

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来源期刊
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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