Tumor-associated macrophages promote neuroblastoma via STAT3 phosphorylation and up-regulation of c-MYC.
Tumor-associated macrophages promote neuroblastoma via STAT3 phosphorylation and up-regulation of c-MYC.
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DOI：
10.18632/oncotarget.21066
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发表时间：
2017-10-31
期刊：
影响因子：
--
通讯作者：
Asgharzadeh S
中科院分区：
文献类型：
--
作者：
Hadjidaniel MD;Muthugounder S;Hung LT;Sheard MA;Shirinbak S;Chan RY;Nakata R;Borriello L;Malvar J;Kennedy RJ;Iwakura H;Akamizu T;Sposto R;Shimada H;DeClerck YA;Asgharzadeh S
肿瘤相关巨噬细胞（TAM）与缺乏MYCN扩增的神经母细胞瘤的存活率低密切相关。为了研究TAM在神经母细胞瘤中的作用，我们使用了一种新的缺乏MYCN扩增的自发性神经母细胞瘤小鼠模型，并观察了TAM的募集和极化，这反过来又增强了神经母细胞瘤的增殖和生长。在鼠和人神经母细胞瘤细胞中，我们发现TAM增加了神经母细胞瘤细胞中的STAT 3激活，并在转录上上调了MYC癌基因。对人神经母细胞瘤肿瘤标本的分析显示，MYC上调与TAM浸润标志物相关。在IL 6 ko神经母细胞瘤模型中，IL-6蛋白的缺乏对肿瘤发展没有影响，并且既不能阻止STAT 3活化也不能阻止MYC上调。相比之下，使用AZD 1480或临床上可接受的抑制剂ruxolitinib抑制JAK-STAT激活可显著降低NOD scid gamma小鼠皮下植入的TAM介导的神经母细胞瘤生长。我们的研究结果指出了一种独特的机制，其中TAM通过上调来自同一基因家族的不同癌基因的转录表达来促进缺乏恶性肿瘤常见癌基因扩增的肿瘤细胞，并强调了IL-6非依赖性激活STAT 3在该机制中的作用。在大约一半的高危肿瘤中观察到MYCN的扩增或MYC蛋白的组成性上调;我们的研究结果表明TAM在缺乏独立癌基因激活的神经母细胞瘤中作为MYC表达诱导剂的新作用。
Tumor-associated macrophages (TAMs) are strongly associated with poor survival in neuroblastomas that lack MYCN amplification. To study TAM action in neuroblastomas, we used a novel murine model of spontaneous neuroblastoma lacking MYCN amplification, and observed recruitment and polarization of TAMs, which in turn enhanced neuroblastoma proliferation and growth. In both murine and human neuroblastoma cells, we found that TAMs increased STAT3 activation in neuroblastoma cells and transcriptionally up-regulated the MYC oncogene. Analysis of human neuroblastoma tumor specimens revealed that MYC up-regulation correlates with markers of TAM infiltration. In an IL6ko neuroblastoma model, the absence of IL-6 protein had no effect on tumor development and prevented neither STAT3 activation nor MYC up-regulation. In contrast, inhibition of JAK-STAT activation using AZD1480 or the clinically admissible inhibitor ruxolitinib significantly reduced TAM-mediated growth of neuroblastomas implanted subcutaneously in NOD scid gamma mice. Our results point to a unique mechanism in which TAMs promote tumor cells that lack amplification of an oncogene common to the malignancy by up-regulating transcriptional expression of a distinct oncogene from the same gene family, and underscore the role of IL-6-independent activation of STAT3 in this mechanism. Amplification of MYCN or constitutive up-regulation of MYC protein is observed in approximately half of high-risk tumors; our findings indicate a novel role of TAMs as inducers of MYC expression in neuroblastomas lacking independent oncogene activation.
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影响因子：
4.8
作者：
Chang, Qing;Bournazou, Eirini;Bromberg, Jacqueline
通讯作者：
Bromberg, Jacqueline
影响因子：
10.3
作者：
Asgharzadeh, Shahab;Pique-Regi, Roger;Seeger, Robert C.
通讯作者：
Seeger, Robert C.
DOI：
10.1158/1078-0432.ccr-14-1144
发表时间：
2015-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Margol AS;Robison NJ;Gnanachandran J;Hung LT;Kennedy RJ;Vali M;Dhall G;Finlay JL;Erdreich-Epstein A;Krieger MD;Drissi R;Fouladi M;Gilles FH;Judkins AR;Sposto R;Asgharzadeh S
通讯作者：
Asgharzadeh S
影响因子：
11.2
作者：
Ara T;Song L;Shimada H;Keshelava N;Russell HV;Metelitsa LS;Groshen SG;Seeger RC;DeClerck YA
通讯作者：
DeClerck YA
影响因子：
32.4
作者：
Noy, Roy;Pollard, Jeffrey W.
通讯作者：
Pollard, Jeffrey W.