Department of Gastric Cancer, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
Int J Cancer. 2019 Sep 15;145(6):1648-1659. doi: 10.1002/ijc.32196. Epub 2019 Feb 20.
The lymphatic network remodeling may guide tumor metastasis in a sentinel lymph node (SLN). Although tumor-derived exosomes have been demonstrated to modify the microenvironment in adjacent organs and initiate a premetastatic niche, their influence on the lymphatic network in SLNs has not been explained. Here, we show that CT26 cell exosomes (Exo) promote the proliferation of lymphatic endothelial cells and the formation of lymphatic network in SLN, facilitating the SLN metastasis of colorectal cancer (CRC). Uptake of Exo by macrophages promoted VEGFC secretion both in vivo and in vitro. Exo increased the frequency of F4/80 macrophages in the SLN. Macrophage ablation by clodrosome prevented the exosomal effect on lymphatic network remodeling and SLN metastasis. Exosomal IRF-2 was highly expressed in serum exosomes isolated from CRC patients with LN metastasis relative to patients without LN metastasis and healthy controls. Mechanistically, exosomal IRF-2 induced the release of VEGFC by macrophages. An IRF-2 knockdown attenuated the lymphatic network remodeling in the SLN and suppressed the SLN metastasis. Our data suggest that exosomal IRF-2 remodels the lymphatic network in an SLN and may predict the development of CRC LN metastases.
淋巴管网重塑可能会指导前哨淋巴结 (SLN) 中的肿瘤转移。尽管已经证明肿瘤衍生的外泌体可以改变相邻器官的微环境并启动预先转移的生态位，但它们对 SLN 中淋巴管网的影响尚未得到解释。在这里，我们表明 CT26 细胞外泌体 (Exo) 促进了 SLN 中淋巴管内皮细胞的增殖和淋巴管网的形成，促进了结直肠癌 (CRC) 的 SLN 转移。外泌体被巨噬细胞摄取后，无论是在体内还是体外，都促进了 VEGFC 的分泌。外泌体增加了 SLN 中 F4/80 巨噬细胞的频率。用氯膦酸盐对巨噬细胞进行消融，可防止外泌体对淋巴管网重塑和 SLN 转移的影响。与无淋巴结转移和健康对照组的患者相比，来自有淋巴结转移的 CRC 患者血清外泌体中高度表达外泌体 IRF-2。在机制上，外泌体 IRF-2 诱导巨噬细胞释放 VEGFC。IRF-2 敲低减弱了 SLN 中的淋巴管网重塑，并抑制了 SLN 转移。我们的数据表明，外泌体 IRF-2 重塑了 SLN 中的淋巴管网，并且可能预测 CRC 淋巴结转移的发展。
