Exosomal ANXA2 facilitates ovarian cancer peritoneal metastasis by activating peritoneal mesothelial cells through binding with TLR2.

IF 8.2 2区生物学 Q1 CELL BIOLOGY Cell Communication and Signaling Pub Date : 2024-12-21 DOI:10.1186/s12964-024-01987-y

Jingni Zhang, Hongmei Liu, Qiulei Wu, Tong Liu, Xiaoli Liu, Jing Cai, Xiaoqing Yi, Zehua Wang, Lingling Gao

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Abstract

Background: Peritoneal dissemination of ovarian cancer (OvCa) can be largely attributed to the formation of a metastatic microenvironment driven by tumoral exosomes. Here, we aimed to elucidate the mechanisms through which exosomal annexin A2 (ANXA2) derived from OvCa cells induces an HPMC phenotypic shift in favour of peritoneal metastasis.

Methods: Immunohistochemistry and orthotopic and intraperitoneal OvCa xenograft mouse models were used to clarify the relationship between tumour ANXA2 expression and peritoneal metastasis. Exosomes were isolated from OvCa cell lines via ultracentrifugation. Functional experiments on cell proliferation and motility, and western blot were performed to investigate the activation of HPMCs and its impact on tumour cell in vitro. High-throughput transcriptional sequencing and rescue experiments in which ANXA2 inhibitor (LCKLSL) or the toll-like receptor 2 (TLR2) inhibitor (C29) was used to co-culture the HPMCs with exosome were employed to identify the crucial functional molecules through which exosomal ANXA2 activates HPMCs. The impact of exosomal ANXA2-activated HPMCs on tumour progression was assessed via functional experiments.

Results: Primary OvCa samples with high ANXA2 expression exhibited a stronger tendency to metastasize to the abdominal cavity. Tumoral ANXA2 promoted OvCa peritoneal metastasis through the secretion of exosomes carrying ANXA2. ANXA2-loaded exosomes activated HPMCs through exosomal ANXA2 binding to TLR2, shifting the phenotype of HPMCs towards mesenchymal cells, increasing their migration and invasion capacities, and elevating the expression of lipocalin 2 (LCN2). High LCN2 expression in HPMCs promoted OvCa cell adhesion, proliferation, motility, and lipid metabolism reprogramming.

Conclusion: Exosomal ANXA2 secreted by tumour cells activates HPMCs and induces the expression of LCN2, which in turn promotes the peritoneal metastasis of OvCa.

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外泌体ANXA2通过与TLR2结合激活腹膜间皮细胞，促进卵巢癌腹膜转移。

背景：卵巢癌的腹膜传播（OvCa）在很大程度上归因于肿瘤外泌体驱动的转移性微环境的形成。在这里，我们的目的是阐明来自OvCa细胞的外泌体膜联蛋白A2 （ANXA2）诱导HPMC表型转移以促进腹膜转移的机制。方法：采用免疫组化和原位、腹腔OvCa异种移植小鼠模型，明确肿瘤ANXA2表达与腹膜转移的关系。通过超离心从OvCa细胞系中分离出外泌体。通过细胞增殖和运动的功能实验，以及western blot研究hpmc的体外活化及其对肿瘤细胞的影响。采用高通量转录测序和挽救实验，利用ANXA2抑制剂（LCKLSL）或toll样受体2 （TLR2）抑制剂（C29）与外泌体共培养hpmc，鉴定外泌体ANXA2激活hpmc的关键功能分子。通过功能实验评估外泌体anxa2激活的hpmc对肿瘤进展的影响。结果：高ANXA2表达的原发OvCa具有更强的腹腔转移倾向。肿瘤中的ANXA2通过携带ANXA2的外泌体分泌促进OvCa腹膜转移。负载ANXA2的外泌体通过外泌体ANXA2与TLR2结合激活hpmc，将hpmc的表型向间充质细胞转移，增加其迁移和侵袭能力，并提高脂钙蛋白2 （LCN2）的表达。在hpmc中，LCN2的高表达促进了OvCa细胞的粘附、增殖、运动和脂质代谢重编程。结论：肿瘤细胞分泌外泌体ANXA2激活hpmc，诱导LCN2的表达，进而促进OvCa的腹膜转移。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

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.