Interaction between tumor cell TNFR2 and monocyte membrane-bound TNF-α triggers tumorigenic inflammation in neuroblastoma.
Interaction between tumor cell TNFR2 and monocyte membrane-bound TNF-α triggers tumorigenic inflammation in neuroblastoma.
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DOI：
10.1136/jitc-2022-005478
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发表时间：
2023-03
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
--
作者：
神经母细胞瘤（NB）是一种常见的儿童癌症，其患儿的肿瘤进展和治疗抵抗通常与产生炎性细胞因子的单核细胞和巨噬细胞浸润有关。然而，肿瘤支持性炎症启动和传播的机制仍然未知。在这里，我们描述了一种新的促肿瘤发生的电路之间的NB细胞和单核细胞，是触发和持续的肿瘤坏死因子α（TNF-α）。我们使用TNF-α和TNFRSF 1A mRNA（TNFR 1）/TNFRSF 1B mRNA（TNFR 2）的NB敲除（科斯）和TNF-α蛋白酶抑制剂（TAPI，一种调节TNF-α亚型表达的药物）来评估单核细胞相关促肿瘤性炎症中每种成分的作用。此外，我们采用NB-单核细胞共培养物，并用临床级依那西普（一种Fc-TNFR 2融合蛋白）处理，以中和膜结合（m）和可溶性（s）TNF-α亚型的信号传导。此外，我们用依那西普处理携带皮下NB/人单核细胞异种移植物的NOD/SCID/IL 2 R γ（null）小鼠，并评估对肿瘤生长和血管生成的影响。基因集富集分析（GSEA）用于确定TNF-α信号传导是否与NB患者的临床结局相关。我们发现NB TNFR 2和单核细胞膜结合肿瘤坏死因子α的表达是单核细胞活化和白细胞介素（IL）-6产生所需的，而NB TNFR 1和单核细胞可溶性TNF-α是NB核因子kappa B亚基1（NF-κB）活化所需的。B）。用临床级依那西普处理NB-单核细胞共培养物完全消除了IL-6、粒细胞集落刺激因子（G-CSF）、IL-1α和IL-1β的释放，并消除了体外单核细胞诱导的NB细胞增殖增强。此外，依那西普治疗抑制肿瘤生长，消融肿瘤血管生成，并抑制皮下NB/人单核细胞异种移植小鼠的致癌信号。最后，GSEA显示复发的NB患者中TNF-α信号显著富集。我们已经描述了NB中肿瘤促进炎症的新机制，该机制与患者结局密切相关，并且可以通过治疗靶向。
Tumor progression and resistance to therapy in children with neuroblastoma (NB), a common childhood cancer, are often associated with infiltration of monocytes and macrophages that produce inflammatory cytokines. However, the mechanism by which tumor-supportive inflammation is initiated and propagated remains unknown. Here, we describe a novel protumorigenic circuit between NB cells and monocytes that is triggered and sustained by tumor necrosis factor alpha (TNF-α). We used NB knockouts (KOs) of TNF-α and TNFRSF1A mRNA (TNFR1)/TNFRSF1B mRNA (TNFR2) and TNF-α protease inbitor (TAPI), a drug that modulates TNF-α isoform expression, to assess the role of each component in monocyte-associated protumorigenic inflammation. Additionally, we employed NB-monocyte cocultures and treated these with clinical-grade etanercept, an Fc-TNFR2 fusion protein, to neutralize signaling by both membrane-bound (m) and soluble (s)TNF-α isoforms. Further, we treated NOD/SCID/IL2Rγ(null) mice carrying subcutaneous NB/human monocyte xenografts with etanercept and evaluated the impact on tumor growth and angiogenesis. Gene set enrichment analysis (GSEA) was used to determine whether TNF-α signaling correlates with clinical outcomes in patients with NB. We found that NB expression of TNFR2 and monocyte membrane-bound tumor necrosis factor alpha is required for monocyte activation and interleukin (IL)-6 production, while NB TNFR1 and monocyte soluble TNF-α are required for NB nuclear factor kappa B subunit 1 (NF-κB) activation. Treatment of NB-monocyte cocultures with clinical-grade etanercept completely abrogated release of IL-6, granulocyte colony-stimulating factor (G-CSF), IL-1α, and IL-1β and eliminated monocyte-induced enhancement of NB cell proliferation in vitro. Furthermore, etanercept treatment inhibited tumor growth, ablated tumor angiogenesis, and suppressed oncogenic signaling in mice with subcutaneous NB/human monocyte xenografts. Finally, GSEA revealed significant enrichment for TNF-α signaling in patients with NB that relapsed. We have described a novel mechanism of tumor-promoting inflammation in NB that is strongly associated with patient outcome and could be targeted with therapy.
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影响因子：
8.8
作者：
Gundry MC;Brunetti L;Lin A;Mayle AE;Kitano A;Wagner D;Hsu JI;Hoegenauer KA;Rooney CM;Goodell MA;Nakada D
通讯作者：
Nakada D
DOI：
10.1038/nrclinonc.2016.217
发表时间：
2017-07
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Mantovani A;Marchesi F;Malesci A;Laghi L;Allavena P
通讯作者：
Allavena P
影响因子：
5.4
作者：
Huang M;Weiss WA
通讯作者：
Weiss WA
影响因子：
10.3
作者：
Asgharzadeh, Shahab;Pique-Regi, Roger;Seeger, Robert C.
通讯作者：
Seeger, Robert C.
CRISPR-CAS9介导的基因失活的高度活性SGRNA的合理设计。
影响因子：
46.9
作者：
Doench, John G.;Hartenian, Ella;Graham, Daniel B.;Tothova, Zuzana;Hegde, Mudra;Smith, Ian;Sullender, Meagan;Ebert, Benjamin L.;Xavier, Ramnik J.;Root, David E.
通讯作者：
Root, David E.