Macrophage and Cancer Cell Cross-talk via CCR2 and CX3CR1 Is a Fundamental Mechanism Driving Lung Cancer
Macrophage and Cancer Cell Cross-talk via CCR2 and CX3CR1 Is a Fundamental Mechanism Driving Lung Cancer
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DOI：
10.1164/rccm.201406-1137oc
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发表时间：
2015-02-15
影响因子：
24.7
通讯作者：
Savai, Rajkumar
中科院分区：
文献类型：
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作者：
Schmall, Anja;Al-tamari, Hamza M.;Savai, Rajkumar
基本原理：最近的研究表明，具有M2表型的肿瘤相关巨噬细胞（M Phi）可以影响癌症的进展和转移，但其调控途径仍不清楚。目的：本研究探讨了肿瘤相关M Phi在肺癌中的作用。M Phi与小鼠刘易斯肺癌（LLC 1）和10种不同的人肺癌细胞系的共培养（腺癌、鳞状细胞癌和大细胞癌）引起癌细胞和M Φ中CCR 2/CCL 2和CX 3CR 1/CX 3CL 1的上调。在M Phi-肿瘤细胞系统中，IL-10驱动CCR 2和CX 3CR 1上调，而CCL 1，粒细胞集落刺激因子，和MIP 1 α是上调CCL 2和CX 3CL 1所必需的。下游表型效应包括增强的LLC 1增殖和迁移以及M Phi M2极化。在体内，M（13）耗尽（氯屈膦酸盐、M Phi Fas-induced apoptosis小鼠）以及CCR 2和CX 3CR 1的基因消融都抑制了LLC 1肿瘤生长和转移，使肿瘤相关的M Phi向M1极化转变，抑制肿瘤血管生长，并提高生存率（转移模型）。此外，用CCR 2拮抗剂处理的小鼠模拟了CCR 2的基因消融，显示出减少的肿瘤生长和转移。在人类肺癌样本中，肿瘤M Phi浸润和CCR 2表达与肿瘤分期和metastasis.Conclusions相关：肿瘤相关M Phi在肺癌的生长和转移中发挥核心作用，M Phi和癌细胞之间的双向串扰通过CCR 2和CX 3CR 1信号传导作为一个中心的潜在机制。这些发现表明，阻断CCR 2和CX 3CR 1的治疗策略可能有助于阻止肺癌进展。
Rationale: Recent studies indicate that tumor-associated macrophages (M Phi) with an M2 phenotype can influence cancer progression and metastasis, but the regulatory pathways remain poorly characterized.Objectives: This study investigated the role of tumor-associated M Phi in lung cancer.Methods: Coculturing of M Phi with mouse Lewis lung carcinoma (LLC1) and 10 different human lung cancer cell lines (adenocarcinoma, squamous cell carcinoma, and large cell carcinoma) caused up-regulation of CCR2/CCL2 and CX3CR1/CX3CL1 in both the cancer cells and the M Phi.Measurements and Main Results: In the M Phi-tumor cell system, IL-10 drove CCR2 and CX3CR1 up-regulation, whereas CCL1, granulocyte colony-stimulating factor, and MIP1 alpha were required for the up-regulation of CCL2 and CX3CL1. Downstream phenotypic effects included enhanced LLC1 proliferation and migration and M Phi M2 polarization. In vivo, M(13 depletion (clodronate, M Phi Fas-induced apoptosis mice) and genetic ablation of CCR2 and CX3CR1 all inhibited LLC1 tumor growth and metastasis, shifted tumor-associated M Phi toward M1 polarization, suppressed tumor vessel growth, and enhanced survival (metastasis model). Furthermore, mice treated with CCR2 antagonist mimicked genetic ablation of CCR2, showing reduced tumor growth and metastasis. In human lung cancer samples, tumor M Phi infiltration and CCR2 expression correlated with tumor stage and metastasis.Conclusions: Tumor-associated M Phi play a central role in lung cancer growth and metastasis, with bidirectional cross-talk between M Phi and cancer cells via CCR2 and CX3CR1 signaling as a central underlying mechanism. These findings suggest that the therapeutic strategy of blocking CCR2 and CX3CR1 may prove beneficial for halting lung cancer progression.