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.

肿瘤来源的外泌体通过在肿瘤微环境中诱导适应性反应参与卵巢癌的网膜转移定植。然而，人们对原发性肿瘤细胞与远处网膜微环境之间通过外泌体进行的细胞间通讯以及转移前生态位形成的机制知之甚少。在这里，我们证明了 ETS1 过表达的卵巢癌细胞分泌具有更高层粘连蛋白水平的更大的外泌体。此外，卵巢癌外泌体可通过整合素和层粘连蛋白相互作用被网膜巨噬细胞摄取。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) 刺激了更多巨噬细胞向 M2 表型（CD163 标记）的极化，以及在巨噬细胞中产生更多的 CXCL5 和 CCL2，通过整合素 αvβ5/AKT/Sp1 信号。体内实验表明，LV-ETS1 Exos 通过介导巨噬细胞的促瘤作用促进卵巢癌的网膜转移，而巨噬细胞的促瘤作用可被整合素 ανβ5 抑制剂西仑吉肽中和。这些结果表明，ETS1可以驱动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网膜巨噬细胞的促转移作用，并且整合素ανβ5抑制剂西仑吉肽可以抑制肿瘤来源的外泌体驱动卵巢癌的网膜转移。其可被整合素ανβ5抑制剂西仑吉肽中和。这些结果表明，ETS1可以驱动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网膜巨噬细胞的促转移作用，并且整合素ανβ5抑制剂西仑吉肽可以抑制肿瘤来源的外泌体驱动卵巢癌的网膜转移。其可被整合素ανβ5抑制剂西仑吉肽中和。这些结果表明，ETS1可以驱动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网膜巨噬细胞的促转移作用，并且整合素ανβ5抑制剂西仑吉肽可以抑制肿瘤来源的外泌体驱动卵巢癌的网膜转移。