The cell-cell interaction between tumor-associated macrophages and small cell lung cancer cells is involved in tumor progression via STAT3 activation
The cell-cell interaction between tumor-associated macrophages and small cell lung cancer cells is involved in tumor progression via STAT3 activation
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DOI：
10.1016/j.lungcan.2017.01.003
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发表时间：
2017-04-01
期刊：
影响因子：
5.3
通讯作者：
Komohara, Yoshihiro
中科院分区：
文献类型：
--
作者：
Iriki, Toyohisa;Ohnishi, Koji;Komohara, Yoshihiro
目的：小细胞肺癌（small cell lung cancer，SCLC）是一种侵袭性强、预后差的恶性肿瘤.众所周知，各种基质细胞，包括巨噬细胞，在几种类型的恶性肿瘤的肿瘤进展中发挥作用;然而，肿瘤相关巨噬细胞（TAM）在SCLC中的意义尚未完全阐明。信号转导子和转录激活子3（STAT 3）是众所周知的与肿瘤进展相关的分子。在本研究中，我们研究了TAM和SCLC细胞的关系，以检验TAM通过STAT 3激活诱导SCLC肿瘤进展的假设。材料和方法：我们使用手术切除的肿瘤标本进行免疫组织化学分析，并使用人SCLC细胞系和人单核细胞衍生的巨噬细胞进行体外共培养实验。我们首先通过免疫染色证明，肿瘤细胞中的STAT 3活化主要在基质中TAM附近存在的肿瘤巢的外周区域中观察到。SCLC细胞和巨噬细胞的间接共培养诱导两种细胞类型中的STAT 3活化，并且巨噬细胞衍生的培养上清液（CS）显著活化SCLC细胞中的STAT 3。巨噬细胞来源的CS通过STAT 3激活诱导肿瘤细胞增殖和侵袭。此外，巨噬细胞来源的CS也增加了化疗抗性和球体形成。巨噬细胞来源的白细胞介素-6和CC趋化因子配体4（CCL 4/MIP-1（3））被认为与SCLC细胞中STAT 3的激活有关。结论：TAM可能通过激活STAT 3参与SCLC的发生发展，TAM来源的IL-6可能是与STAT 3激活有关的分子之一。因此，TAM和SCLC细胞之间的细胞-细胞相互作用可能是治疗的靶点。(C)2017 Elsevier B. V.版权所有。
Objectives: Small cell lung cancer (SCLC) is an aggressive tumor with a poor prognosis. It is well known that various stromal cells, including macrophages, play a role in tumor progression in several types of malignant tumors; however, the significance of tumor-associated macrophages (TAMs) in SCLC has not been fully elucidated. Signal transducer and activator of transcription 3 (STAT3) is a molecule well-known to be related to tumor progression. In the present study, we investigated the relationship of TAMs and SCLC cells to test the hypothesis that TAMs induce tumor progression in SCLC via STAT3 activation.Materials and methods: We performed immunohistochemical analysis using surgically resected tumor specimens and in vitro co-culture experiments using human SCLC cell lines and human monocyte-derived macrophages.Results: We first demonstrated via immunostaining that STAT3 activation in tumor cells was predominantly observed in the peripheral areas of tumor nests existing near TAMs in stroma. The indirect co-culture of SCLC cells and macrophages induced STAT3 activation in both cell types, and macrophage derived culture supernatant (CS) significantly activated STAT3 in SCLC cells. Macrophage-derived CS induced tumor cell proliferation and invasion via STAT3 activation. In addition, chemo-resistance and sphere formation were also increased by macrophage-derived CS. Macrophage-derived interleukin-6 and CC chemokine ligand 4 (CCL4/MIP-1(3) were suggested to be associated with STAT3 activation in SCLC cells. CS-induced STAT3 activation in SCLC cells was suppressed by anti-IL-6 receptor antibody, but not by anti-CCL4/MIP-1S antibody.Conclusion: These results suggest that TAMs are likely involved in SCLC progression via STAT3 activation and TAM-derived IL-6 is indicated to be one of molecules related to STAT3 activation in SCLC cells. Thus, the cell-cell interaction between TAMs and SCLC cells might be a target for therapy. (C) 2017 Elsevier B.V. All rights reserved.