Small cell lung cancer: Recruitment of macrophages by circulating tumor cells
Small cell lung cancer: Recruitment of macrophages by circulating tumor cells
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DOI：
10.1080/2162402x.2015.1093277
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Hochmair, Maximilan J.
中科院分区：
文献类型：
--
作者：
Hamilton, Gerhard;Rath, Barbara;Hochmair, Maximilan J.
肿瘤相关巨噬细胞（Tumor-associated macrophages，TAMs）在肿瘤进展、抗肿瘤免疫抑制和肿瘤播散中起重要作用。血液单核细胞浸润肿瘤区域，并通过局部微环境条件引发以促进肿瘤生长和侵袭。虽然许多相互作用的细胞因子和因子是已知的肿瘤-巨噬细胞的相互作用，循环肿瘤细胞（CTC）的推定的贡献是未知的。这些特化细胞的特征在于增加的移动性、降解细胞外基质（ECM）和进入血流并产生继发性病变的能力，继发性病变是大多数肿瘤患者死亡的主要原因。首次从晚期小细胞肺癌（SCLC）患者的血液样本中建立了两个永久性CTC细胞系，即BHGc 7和10，使我们能够研究CTC与免疫细胞的相互作用。将外周血单核细胞（PBMNCs）与CTC共培养或加入CTC条件培养基（CTC-CM）体外培养可导致单核-巨噬细胞分化，并出现表达TAM标志物的CD 14（+）、CD 163（弱）和CD 68（+）巨噬细胞。此外，我们筛选了CTC引发的巨噬细胞的上清液中存在的约100种细胞因子，并将其表达与局部转移性SCLC 26 A细胞系诱导的表达进行比较。SCLC 26 A-CM招募的巨噬细胞显示骨桥蛋白（OPN）、单核细胞趋化蛋白-1（MCP-1）、IL-8、几丁质酶3样1（CHI 3L 1）、血小板因子（Pf 4）、IL-1 ra和基质金属蛋白酶-9（MMP-9）以及其他次要细胞因子/趋化因子的表达。相反，BHGc 7-CM诱导补体因子D（CFD）/adipsin和维生素D-BP（VDBP）的显著过表达，以及OPN、脂质运载蛋白-2（LCN 2）、CHI 3L 1、uPAR、MIP-1和GDF-15/MIC-1的分泌增加。BHGc 10独立于复发的SCLC，显示出几乎相同的模式，增加了ENA-78/CXCL 5的表达。非肿瘤HEK 293细胞系的CM显示没有诱导巨噬细胞，而PBMNCs与重组CHI 3 L1一起孵育则得到阳性结果。因此，SCLC中CTC的特异性贡献影响CFD/adipsin（可能参与免疫/恶病质）、VDBP（产生组特异性组分蛋白衍生的巨噬细胞活化因子（GcMAF））、GDF-15/MIC-1（增强肿瘤细胞的恶性表型）和ENA-78/CXCL 5（吸引血管生成中性粒细胞）。总之，CTC能够特异性地操纵TAM以增加侵袭性、血管生成、免疫抑制和可能的脂质代谢。
Tumor-associated macrophages (TAMs) play an important role in tumor progression, suppression of antitumor immunity and dissemination. Blood monocytes infiltrate the tumor region and are primed by local microenvironmental conditions to promote tumor growth and invasion. Although many of the interacting cytokines and factors are known for the tumor-macrophage interactions, the putative contribution of circulating tumor cells (CTCs) is not known so far. These specialized cells are characterized by increased mobility, ability to degrade the extracellular matrix (ECM) and to enter the blood stream and generate secondary lesions which is a leading cause of death for the majority of tumor patients. The first establishment of two permanent CTC lines, namely BHGc7 and 10, from blood samples of advanced stage small cell lung cancer (SCLC) patients allowed us to investigate the CTC-immune cell interaction. Cocultures of peripheral blood mononuclear cells (PBMNCs) with CTCs or addition of CTC-conditioned medium (CTC-CM) in vitro resulted in monocyte-macrophage differentiation and appearance of CD14(+), CD163(weak) and CD68(+) macrophages expressing markers of TAMs. Furthermore, we screened the supernatants of CTC-primed macrophages for presence of approximately 100 cytokines and compared the expression with those induced by the local metastatic SCLC26A cell line. Macrophages recruited by SCLC26A-CM showed expression of osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), IL-8, chitinase3-like 1 (CHI3L1), platelet factor (Pf4), IL-1ra and matrix metalloproteinase-9 (MMP-9) among other minor cytokines/chemokines. In contrast, BHGc7-CM induced marked overexpression of complement factor D (CFD)/adipsin and vitamin D-BP (VDBP), as well as increased secretion of OPN, lipocalin-2 (LCN2), CHI3L1, uPAR, MIP-1 and GDF-15/MIC-1. BHGc10, derived independently from relapsed SCLC, revealed an almost identical pattern with added expression of ENA-78/CXCL5. CMs of the non-tumor HEK293 cell line revealed no induction of macrophages, whereas incubation of PBMNCs with recombinant CHI3L1 gave positive results. Thus, the specific contributions of CTCs in SCLC affect CFD/adipsin, possibly involved in immunity/cachexia, VDBP which gives rise to group-specific component protein-derived macrophage-activating factor (GcMAF), GDF-15/MIC-1 which enhances the malignant phenotype of tumor cells and ENA-78/CXCL5 which attracts angiogenic neutrophils. In conclusion, CTCs are competent to specifically manipulate TAMs to increase invasiveness, angiogenesis, immunosuppression and possibly lipid catabolism.