Macrophages-aPKC(ɩ)-CCL5 Feedback Loop Modulates the Progression and Chemoresistance in Cholangiocarcinoma.
Macrophages-aPKC(ɩ)-CCL5 Feedback Loop Modulates the Progression and Chemoresistance in Cholangiocarcinoma.
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巨噬细胞-aPKCβ-CCL5 反馈环路调节胆管癌的进展和化疗耐药
DOI：
10.1186/s13046-021-02235-8
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发表时间：
2022-01-15
期刊：
影响因子：
--
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Yang T;Deng Z;Xu L;Li X;Yang T;Qian Y;Lu Y;Tian L;Yao W;Wang J
近年来的研究表明，巨噬细胞与癌细胞之间可能存在相互作用，从而促进肿瘤的进展和化疗耐药，但在胆管癌中的相互作用尚不清楚。使用10 x Genomics单细胞测序技术来鉴定巨噬细胞在CCA中的作用。然后，我们测量了巨噬细胞标志物和aPKC β在70例人CCA组织中的表达和预后作用。此外，我们构建了从外周血单核细胞（PBMC）产生的单核细胞衍生的巨噬细胞（MDM），并将其极化为M1/M2巨噬细胞。建立人CCA细胞系（TFK-1、EGI-1）与分化的PBMCs-巨噬细胞共培养实验，并进行体内外功能研究，以探讨癌细胞与M2巨噬细胞之间的相互作用。在此基础上，我们建立了阳离子脂质体介导的吉西他滨和aPKC β-siRNA共转染系统，并检测了其对CCA的抗肿瘤作用。M2巨噬细胞在CCA中表现出促瘤特性。aPKC β 1高表达和M2巨噬细胞浸润与CCA患者的转移和不良预后相关。此外，具有低M2巨噬细胞浸润或低aPKC β表达的CCA患者受益于术后基于吉西他滨的化疗。进一步研究表明，M2巨噬细胞源性TGFβ1通过aPKC β 1介导的NF-κB信号通路诱导CCA细胞发生上皮-间质转化（EMT）和吉西他滨耐药。相反，经历aPKC β诱导的EMT的CCA细胞分泌更多的CCL 5，从而调节巨噬细胞募集和极化。此外，阳离子脂质体介导的GEM和aPKC β-siRNA的共递送显著抑制巨噬细胞浸润和CCA进展。我们的研究证实了巨噬细胞-aPKC β-CCL 5反馈环在CCA中的作用，并提出了一种新的治疗CCA的新策略，即脂质体共递送aPKC β-siRNA和GEM。在线版本包含补充材料，可通过10.1186/s13046-021-02235-8获得。
Recent data indicated that macrophages may mutually interact with cancer cells to promote tumor progression and chemoresistance, but the interaction in cholangiocarcinoma (CCA) is obscure. 10x Genomics single-cell sequencing technology was used to identified the role of macrophages in CCA. Then, we measured the expression and prognostic role of macrophage markers and aPKCɩ in 70 human CCA tissues. Moreover, we constructed monocyte-derived macrophages (MDMs) generated from peripheral blood monocytes (PBMCs) and polarized them into M1/M2 macrophages. A co-culture assay of the human CCA cell lines (TFK-1, EGI-1) and differentiated PBMCs-macrophages was established, and functional studies in vitro and in vivo was performed to explore the interaction between cancer cells and M2 macrophages. Furthermore, we established the cationic liposome-mediated co-delivery of gemcitabine and aPKCɩ-siRNA and detect the antitumor effects in CCA. M2 macrophage showed tumor-promoting properties in CCA. High levels of aPKCɩ expression and M2 macrophage infiltration were associated with metastasis and poor prognosis in CCA patients. Moreover, CCA patients with low M2 macrophages infiltration or low aPKCɩ expression benefited from postoperative gemcitabine-based chemotherapy. Further studies showed that M2 macrophages-derived TGFβ1 induced epithelial-mesenchymal transition (EMT) and gemcitabine resistance in CCA cells through aPKCɩ-mediated NF-κB signaling pathway. Reciprocally, CCL5 was secreted more by CCA cells undergoing aPKCɩ-induced EMT and consequently modulated macrophage recruitment and polarization. Furthermore, the cationic liposome-mediated co-delivery of GEM and aPKCɩ-siRNA significantly inhibited macrophages infiltration and CCA progression. our study demonstrates the role of Macrophages-aPKCɩ-CCL5 Feedback Loop in CCA, and proposes a novel therapeutic strategy of aPKCɩ-siRNA and GEM co-delivered by liposomes for CCA. The online version contains supplementary material available at 10.1186/s13046-021-02235-8.
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影响因子：
11.2
作者：
Frankenberger C;Rabe D;Bainer R;Sankarasharma D;Chada K;Krausz T;Gilad Y;Becker L;Rosner MR
通讯作者：
Rosner MR
肝外胆管癌患者的肿瘤炎性和免疫细胞。
影响因子：
8.8
作者：
Kitano Y;Okabe H;Yamashita YI;Nakagawa S;Saito Y;Umezaki N;Tsukamoto M;Yamao T;Yamamura K;Arima K;Kaida T;Miyata T;Mima K;Imai K;Hashimoto D;Komohara Y;Chikamoto A;Ishiko T;Baba H
通讯作者：
Baba H
影响因子：
50.3
作者：
Kumar V;Donthireddy L;Marvel D;Condamine T;Wang F;Lavilla-Alonso S;Hashimoto A;Vonteddu P;Behera R;Goins MA;Mulligan C;Nam B;Hockstein N;Denstman F;Shakamuri S;Speicher DW;Weeraratna AT;Chao T;Vonderheide RH;Languino LR;Ordentlich P;Liu Q;Xu X;Lo A;Puré E;Zhang C;Loboda A;Sepulveda MA;Snyder LA;Gabrilovich DI
通讯作者：
Gabrilovich DI
影响因子：
64.5
作者：
Acharyya S;Oskarsson T;Vanharanta S;Malladi S;Kim J;Morris PG;Manova-Todorova K;Leversha M;Hogg N;Seshan VE;Norton L;Brogi E;Massagué J
通讯作者：
Massagué J
影响因子：
4.8
作者：
Lamark, T;Perander, M;Johansen, T
通讯作者：
Johansen, T