J Exp Clin Cancer Res|同济医院王剑明团队提出了一条介导胆管癌进展和化疗耐药性的反馈调节通路

2022年8月3日 0条评论 487次阅读 0人点赞

最新细胞功能及机制文献分享

胆管癌（CCA）是恶性程度最高、致死率最高的癌症之一，总生存期有限，并因其进展快速、早期转移和治疗产生耐药性而臭名昭著。即使采用积极的手术治疗，CCA患者的5年生存率仍不能令人满意。最近的数据表明，巨噬细胞可与癌细胞相互作用，促进肿瘤进展和化疗耐药，但在CCA中的相互作用尚不清楚。

2022年1月15日，华中科技大学同济医学院附属同济医院胆胰外科/肿瘤研究中心王剑明团队在Journal of Experimental and Clinical Cancer Research上发表了题为“Macrophages-aPKC_ι-CCL5 Feedback Loop Modulates the Progression and Chemoresistance in Cholangiocarcinoma”的研究论文。在本研究中，团队证明了巨噬细胞-aPKC_ι-CCL5反馈回路在CCA中的作用，并提出了一种新的治疗策略，即脂质体联合aPKC_ι-siRNA和GEM治疗CCA。

临床上，采用吉西他滨（Gemcitabine，GEM）化疗是CCA的一线治疗策略，但它并不能显著提高CCA患者的总体生存率。众所周知，肿瘤微环境（TME）在促进癌症进展、侵袭、转移和化疗耐药中发挥重要作用，TME中的巨噬细胞，即肿瘤相关巨噬细胞（TAM），由于病原体或细胞因子的刺激而表现出不同的表型和功能特征。在大多情况下，TAM通常表现出M2表型，并可增强肿瘤恶性程度，且癌细胞可主动调节巨噬细胞的募集和激活，从而促进肿瘤生长和转移。CCA的特点就是高度促纤维增生和血管不足的微环境。已经有研究证明，上皮-间质转化（EMT）是一种分化的上皮细胞丧失极性并获得间充质表型的过程，主要与化疗耐药、癌症干细胞和免疫微环境相关。

团队前期研究证明aPKC_ι可能在癌细胞和TME之间起关键作用。在本篇文章中，团队首次报道了巨噬细胞与癌细胞之间的正反馈回路，其可促进CCA进展和化学耐药性。研究结果表明，M2巨噬细胞分泌的TGFβ1通过CCA中的aPKC_ι-NF-κB信号通路诱导癌细胞EMT和化学抗性。相应地，在aPKC_ι诱导EMT的CCA细胞上清液中，CCL5水平显著增加，从而调节巨噬细胞的募集和活化。

化疗药物联合siRNA治疗已被认为是一种提高抗肿瘤效率的选择，鉴于aPKC_ι的关键作用，团队制备了阳离子脂质体来共同递送GEM和aPKC_ι-siRNA，以提高CCA的化疗反应和治疗效果。结果证实，其可显著抑制巨噬细胞浸润和CCA进展。至此，团队研究为CCA患者提供了一种新的aPKC_ι-siRNA和GEM联合治疗策略。

《J Exp Clin Cancer Res|同济医院王剑明团队提出了一条介导胆管癌进展和化疗耐药性的反馈调节通路》

图本文图形摘要示意图。GEM-aPKC_ι-siRNA结构与抗肿瘤机制（上图），巨噬细胞-aPKC_ι-CCL5反馈回路参与调节CCA进展和改善化疗反应示意图（下图）。

期刊及DOI号

J Exp Clin Cancer Res. 2022 Jan 15.

doi: 10.1186/s13046-021-02235-8.

题目

Macrophages-aPKC_ι-CCL5 Feedback Loop Modulates the Progression and Chemoresistance in Cholangiocarcinoma

摘要

背景：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.

方法：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 aPKC_ι 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 lipo-some-mediated co-delivery of gemcitabine and aPKC_ι-siRNA and detect the antitumor effects in CCA.

结果：M2 macrophage showed tumor-promoting properties in CCA. High levels of aPKC_ι expression and M2 mac-rophage infiltration were associated with metastasis and poor prognosis in CCA patients. Moreover, CCA patients with low M2 macrophages infiltration or low aPKC_ι expression benefited from postoperative gemcitabine-based chemo-therapy. Further studies showed that M2 macrophages-derived TGFβ1 induced epithelial-mesenchymal transition (EMT) and gemcitabine resistance in CCA cells through aPKC_ι-mediated NF-κB signaling pathway. Reciprocally, CCL5 was secreted more by CCA cells undergoing aPKC_ι-induced EMT and consequently modulated macrophage recruit-ment and polarization. Furthermore, the cationic liposome-mediated co-delivery of GEM and aPKC_ι-siRNA signifi-cantly inhibited macrophages infiltration and CCA progression.

结论：our study demonstrates the role of Macrophages-aPKC_ι-CCL5 Feedback Loop in CCA, and proposes a novel therapeutic strategy of aPKC_ι-siRNA and GEM co-delivered by liposomes for CCA.

关键词：Cholangiocarcinoma, Positive Feedback Loop, Macrophages, aPKC_ι, Chemoresistance