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ETS1 上调肿瘤来源的外泌体中的层粘连蛋白，重编程大网膜巨噬细胞，促进卵巢癌大网膜转移。

Laminins in tumor-derived exosomes upregulated by ETS1 reprogram omental macrophages to promote omental metastasis of ovarian cancer.

机构信息

Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.

General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.

出版信息

Cell Death Dis. 2022 Dec 7;13(12):1028. doi: 10.1038/s41419-022-05472-7.

DOI:10.1038/s41419-022-05472-7
PMID:36477408
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9729302/
Abstract

Tumor-derived exosomes participate in omental metastatic colonization of ovarian cancer by inducing an adaptive response in the tumor microenvironment. However, cell-cell communication via exosomes between primary tumor cells and the microenvironment of distant omentum and the mechanism of pre-metastatic niche formation are poorly understood. Here, we demonstrated that ETS1-overexpressing ovarian cancer cells secreted larger exosomes with higher laminin levels. In addition, ovarian cancer exosomes could be taken up by omental macrophages through integrin and laminin interaction. Compared with control exosomes, exosomes derived from ETS1-overexpressing ovarian cancer cells (LV-ETS1 Exos) stimulated the polarization of more macrophages toward the M2 phenotype (CD163 marker), as well as the production of more CXCL5 and CCL2 in macrophages, via integrin αvβ5/AKT/Sp1 signaling. In vivo experiments showed that LV-ETS1 Exos promoted omental metastasis of ovarian cancer by mediating the tumor-promoting effect of macrophages, which could be neutralized by integrin ανβ5 inhibitor cilengitide. These results indicated that ETS1 could drive ovarian cancer cells to release exosomes with higher laminin levels, thereby accelerating the exosome-mediated pro-metastatic effects of omental macrophages via the integrin αvβ5/AKT/Sp1 signaling pathway, and the integrin ανβ5 inhibitor cilengitide could inhibit omental metastasis of ovarian cancer driven by tumor-derived exosomes.

摘要

肿瘤来源的外泌体通过诱导肿瘤微环境中的适应性反应参与卵巢癌的大网膜转移定植。然而，原发肿瘤细胞与远处大网膜微环境之间通过外泌体的细胞间通讯以及前转移龛形成的机制尚不清楚。在这里，我们证明了 ETS1 过表达的卵巢癌细胞分泌的外泌体具有更高的层粘连蛋白水平。此外，卵巢癌细胞外泌体可以通过整合素和层粘连蛋白相互作用被大网膜巨噬细胞摄取。与对照外泌体相比，源自 ETS1 过表达卵巢癌细胞的外泌体（LV-ETS1 Exos）通过整合素 αvβ5/AKT/Sp1 信号通路刺激更多的巨噬细胞向 M2 表型（CD163 标志物）极化，并增加巨噬细胞中 CXCL5 和 CCL2 的产生。体内实验表明，LV-ETS1 Exos 通过介导巨噬细胞的促肿瘤作用促进卵巢癌大网膜转移，而整合素ανβ5 抑制剂 cilengitide 可以中和这种作用。这些结果表明，ETS1 可以促使卵巢癌细胞释放具有更高层粘连蛋白水平的外泌体，从而通过整合素 αvβ5/AKT/Sp1 信号通路加速外泌体介导的大网膜巨噬细胞的促转移效应，而整合素 ανβ5 抑制剂 cilengitide 可以抑制肿瘤衍生外泌体驱动的卵巢癌大网膜转移。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c7e/9729302/5bd6702b51f0/41419_2022_5472_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c7e/9729302/94ca7602f6b4/41419_2022_5472_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c7e/9729302/0f6b218e602d/41419_2022_5472_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c7e/9729302/0e244eb1143f/41419_2022_5472_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c7e/9729302/d85b801d740a/41419_2022_5472_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c7e/9729302/5bd6702b51f0/41419_2022_5472_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c7e/9729302/94ca7602f6b4/41419_2022_5472_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c7e/9729302/74f113f7c1ad/41419_2022_5472_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c7e/9729302/03243fc67cfc/41419_2022_5472_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c7e/9729302/32c72a90b6ba/41419_2022_5472_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c7e/9729302/0f6b218e602d/41419_2022_5472_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c7e/9729302/0e244eb1143f/41419_2022_5472_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c7e/9729302/d85b801d740a/41419_2022_5472_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c7e/9729302/5bd6702b51f0/41419_2022_5472_Fig8_HTML.jpg

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