The capture of extracellular vesicles endogenously released by xenotransplanted tumours induces an inflammatory reaction in the premetastatic niche.
The capture of extracellular vesicles endogenously released by xenotransplanted tumours induces an inflammatory reaction in the premetastatic niche.
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因异种移植肿瘤内源释放的细胞外囊泡的捕获会引起前转移壁裂的炎症反应。
DOI：
10.1002/jev2.12326
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发表时间：
2023-05
影响因子：
16
通讯作者：
中科院分区：
文献类型：
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肿瘤微环境（TME）中的细胞捕获肿瘤来源的细胞外囊泡（TEVs）有助于转移，尤其有助于转移前微环境（PMN）的形成。然而，由于在体内模拟小细胞外囊泡释放存在挑战，针对内源性释放的TEVs所形成PMN的动力学尚未得到研究。在此，我们研究了原位植入释放绿色荧光蛋白标记的细胞外囊泡（GFTEVs）的转移性人黑色素瘤（MEL）和神经母细胞瘤（NB）细胞的小鼠体内TEVs的内源性释放，以及宿主细胞对其的捕获情况，以证明TEVs对转移的积极作用。体外实验中，小鼠巨噬细胞捕获人GFTEVs后导致绿色荧光蛋白囊泡和人外泌体miR - 1246的转移。原位植入MEL或NB细胞的小鼠在植入后5到28天之间血液中出现TEVs。此外，对驻留细胞捕获TEVs相对于产生TEVs的肿瘤细胞在转移器官中的到达和增殖的动力学分析表明，肺和肝细胞对TEVs的捕获先于转移性肿瘤细胞的归巢，这与TEVs在PMN形成中的关键作用一致。重要的是，在未来转移部位对TEVs的捕获与miR - 1246向肺巨噬细胞、肝巨噬细胞和星状细胞的转移有关。这首次证明内源性释放的TEVs的捕获具有器官趋向性，表现为仅在转移器官中存在捕获TEVs的细胞，而在非转移器官中不存在。PMN中对TEVs的捕获诱导了炎症基因表达的动态变化，随着微环境向转移状态发展，这种变化演变为促肿瘤发生反应。因此，我们的工作描述了一种在体内追踪TEVs的新方法，为其在转移进展的最早阶段的作用提供了更多见解。
The capture of tumour‐derived extracellular vesicles (TEVs) by cells in the tumour microenvironment (TME) contributes to metastasis and notably to the formation of the pre‐metastatic niche (PMN). However, due to the challenges associated with modelling release of small EVs in vivo, the kinetics of PMN formation in response to endogenously released TEVs have not been examined. Here, we have studied the endogenous release of TEVs in mice orthotopically implanted with metastatic human melanoma (MEL) and neuroblastoma (NB) cells releasing GFP‐tagged EVs (GFTEVs) and their capture by host cells to demonstrate the active contribution of TEVs to metastasis. Human GFTEVs captured by mouse macrophages in vitro resulted in transfer of GFP vesicles and the human exosomal miR‐1246. Mice orthotopically implanted with MEL or NB cells showed the presence of TEVs in the blood between 5 and 28 days after implantation. Moreover, kinetic analysis of TEV capture by resident cells relative to the arrival and outgrowth of TEV‐producing tumour cells in metastatic organs demonstrated that the capture of TEVs by lung and liver cells precedes the homing of metastatic tumour cells, consistent with the critical roles of TEVs in PMN formation. Importantly, TEV capture at future sites of metastasis was associated with the transfer of miR‐1246 to lung macrophages, liver macrophages, and stellate cells. This is the first demonstration that the capture of endogenously released TEVs is organotropic as demonstrated by the presence of TEV‐capturing cells only in metastatic organs and their absence in non‐metastatic organs. The capture of TEVs in the PMN induced dynamic changes in inflammatory gene expression which evolved to a pro‐tumorigenic reaction as the niche progressed to the metastatic state. Thus, our work describes a novel approach to TEV tracking in vivo that provides additional insights into their role in the earliest stages of metastatic progression.
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影响因子：
3.7
作者：
Jablonski KA;Amici SA;Webb LM;Ruiz-Rosado Jde D;Popovich PG;Partida-Sanchez S;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
影响因子：
16
作者：
Henrich SE;McMahon KM;Plebanek MP;Calvert AE;Feliciano TJ;Parrish S;Tavora F;Mega A;De Souza A;Carneiro BA;Thaxton CS
通讯作者：
Thaxton CS
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D
影响因子：
4.4
作者：
Iinuma, Hisae;Okinaga, Kota;Kaneko, Michio
通讯作者：
Kaneko, Michio
影响因子：
7.5
作者：
Choi H;Lee DS
通讯作者：
Lee DS