The HMGB1/RAGE axis induces bone pain associated with colonization of 4T1 mouse breast cancer in bone.
The HMGB1/RAGE axis induces bone pain associated with colonization of 4T1 mouse breast cancer in bone.
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HMGB1/RAGE轴诱导与4T1小鼠乳腺癌在骨中的定殖相关的骨痛。
DOI：
10.1016/j.jbo.2020.100330
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发表时间：
2021-03
影响因子：
3.4
通讯作者：
Yoneda T
中科院分区：
文献类型：
--
作者：
Okui T;Hiasa M;Ryumon S;Ono K;Kunisada Y;Ibaragi S;Sasaki A;Roodman GD;White FA;Yoneda T
4 T1小鼠乳腺癌经皮下注射诱发骨痛。4 T1乳腺癌分泌促进感觉神经元轴突发生的高迁移率族蛋白1（HMGB 1）。HMGB 1抗体和晚期糖基化终产物受体拮抗剂可减轻骨痛。骨痛是乳腺癌（BC）骨转移的常见并发症，是发病率和死亡率增加的主要原因。虽然BC相关骨痛（BCABP）的机制仍然知之甚少，BC产品在BCABP的病理生理学参与已被提出。侵袭性癌症分泌与特定DAMP受体结合并调节癌症微环境的损伤相关分子模式（DAMP）。一种原型DAMP，高迁移率族蛋白1（HMGB 1），作为晚期糖基化终产物（AGEs）和Toll样受体（TLR）受体的配体，在BC患者中表达增加，预后不良。在这里，我们表明，4 T1小鼠BC细胞殖民骨上调表达的分子疼痛标志物，磷酸化ERK 1/2（pERK）和pCREB，在背根神经节（DRG）支配骨和诱导BCABP后爪机械超敏反应进行评估。重要的是，通过shRNA沉默4 T1 BC细胞中的HMGB 1减少了pERK和pCREB以及BCABP，同时降低了骨中的HMGB 1水平。此外，施用HMGB 1中和抗体或HMGB 1拮抗剂FPS-ZM 1改善了pERK、pCREB和BCABP，而TLR 4拮抗剂TAK 242没有显示出效果。与这些体内结果一致，F11感觉神经元样细胞与4 T1 BC细胞在微流体培养平台中的共培养增加了F11细胞的神经突生长，这被HMGB 1抗体阻断。我们的研究结果表明，BC细胞分泌的HMGB 1通过与感觉神经元的轴突结合来诱导BCABP，并表明HMGB 1/轴突可能是BCABP潜在的新的治疗靶点。
The 4T1 mouse breast cancer injected in tibiae induced bone pain. The 4T1 breast cancer secreted high mobility group box 1 (HMGB1) that promotes axogenesis of sensory neurons. Bone pain was reduced by HMGB1 antibody and an antagonist for the receptor for advanced glycation end products. Bone pain is a common complication of breast cancer (BC) bone metastasis and is a major cause of increased morbidity and mortality. Although the mechanism of BC-associated bone pain (BCABP) remains poorly understood, involvement of BC products in the pathophysiology of BCABP has been proposed. Aggressive cancers secrete damage-associated molecular patterns (DAMPs) that bind to specific DAMP receptors and modulate cancer microenvironment. A prototypic DAMP, high mobility group box 1 (HMGB1), which acts as a ligand for the receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs), is increased in its expression in BC patients with poor outcomes. Here we show that 4T1 mouse BC cells colonizing bone up-regulate the expression of molecular pain markers, phosphorylated ERK1/2 (pERK) and pCREB, in the dorsal root ganglia (DRGs) innervating bone and induced BCABP as evaluated by hind-paw mechanical hypersensitivity. Importantly, silencing HMGB1 in 4T1 BC cells by shRNA reduced pERK and pCREB and BCABP with decreased HMGB1 levels in bone. Further, administration of a neutralizing antibody to HMGB1 or an antagonist for RAGE, FPS-ZM1, ameliorated pERK, pCREB and BCABP, while a TLR4 antagonist, TAK242, showed no effects. Consistent with these in vivo results, co-cultures of F11 sensory neuron-like cells with 4T1 BC cells in microfluidic culture platforms increased neurite outgrowth of F11 cells, which was blocked by HMGB1 antibody. Our results show that HMGB1 secreted by BC cells induces BCABP via binding to RAGE of sensory neurons and suggest that the HMGB1/RAGE axis may be a potential novel therapeutic target for BCABP.
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影响因子：
8.8
作者：
Das N;Dewan V;Grace PM;Gunn RJ;Tamura R;Tzarum N;Watkins LR;Wilson IA;Yin H
通讯作者：
Yin H
影响因子：
5.6
作者：
Hasegawa K;Okui T;Shimo T;Ibaragi S;Kawai H;Ryumon S;Kishimoto K;Okusha Y;Monsur Hassan NM;Sasaki A
通讯作者：
Sasaki A
影响因子：
11.2
作者：
Hiasa M;Okui T;Allette YM;Ripsch MS;Sun-Wada GH;Wakabayashi H;Roodman GD;White FA;Yoneda T
通讯作者：
Yoneda T
DOI：
10.1158/1078-0432.ccr-13-0495
发表时间：
2013-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kang R;Zhang Q;Zeh HJ 3rd;Lotze MT;Tang D
通讯作者：
Tang D
HMGB 1信号通路激活雪旺细胞的炎症反应
影响因子：
6.1
作者：
Man LL;Liu F;Wang YJ;Song HH;Xu HB;Zhu ZW;Zhang Q;Wang YJ
通讯作者：
Wang YJ