Tumor-derived HMGB1 induces CD62Ldim neutrophil polarization and promotes lung metastasis in triple-negative breast cancer
Tumor-derived HMGB1 induces CD62Ldim neutrophil polarization and promotes lung metastasis in triple-negative breast cancer
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肿瘤源性 HMGB1 诱导 CD62Ldim 中性粒细胞极化并促进三阴性乳腺癌肺转移。
DOI：
10.1038/s41389-020-00267-x
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发表时间：
2020-09-17
期刊：
影响因子：
6.2
通讯作者：
Huang, Jian
中科院分区：
文献类型：
--
作者：
Wang, Zhen;Yang, Chenghui;Huang, Jian
三阴性乳腺癌（TNBC）具有高度侵袭性，难以治疗，通常发生内脏转移，包括肺转移。我们观察到高迁移率组框1蛋白（HMGB1）在人类TNBC中高表达，并与肿瘤转移呈正相关。已知低氧肿瘤环境可调节HMGB1的分泌，但对肿瘤源性HMGB1调节间质成分并促进乳腺癌肺转移的潜在机制的理解仍不明确。本研究结果显示，小鼠TNBC模型外周血和肺组织中CD62L（dim）中性粒细胞数量显著增加，并受肿瘤源性HMGB1通过TLR2通路调控。CD62L（dim）中性粒细胞具有较强的产生中性粒细胞胞外陷阱（NETs）的能力。86例乳腺癌患者血清HMGB1水平与CD62L（dim）中性粒细胞呈正相关。我们证明了CD62L（dim）中性粒细胞加速肺转移，并且针对“HMGB1-CD62L（dim）中性粒细胞- nets”轴的干预可以抑制肺转移。我们的研究结果提示HMGB1和CD62L（dim）中性粒细胞的联合是乳腺癌肺转移的潜在标志物，是未来预防和治疗的新靶点。
Triple-negative breast cancer (TNBC) is highly aggressive, difficult to treat and commonly develops visceral metastasis, including lung metastasis. We observed that High mobility group box 1 protein (HMGB1) was highly expressed in human TNBC and positively correlated with cancer metastasis. The hypoxic tumor environment is known to regulate HMGB1 secretion, but an understanding of the underlying mechanism by which tumor-derived HMGB1 regulates interstitial components and promotes breast cancer lung metastasis has remained elusive. The results of the present study showed that the number of CD62L(dim)neutrophils, which have a strong ability to produce neutrophil extracellular traps (NETs), increased significantly in both peripheral blood and lung tissues in a mouse TNBC model and were regulated by tumor-derived HMGB1 through the TLR2 pathway. Furthermore, serum HMGB1 levels were positively correlated with CD62L(dim)neutrophils in 86 breast cancer patients. We demonstrated that CD62L(dim)neutrophils accelerated lung metastasis and that interventions targeting the "HMGB1-CD62L(dim)neutrophil-NETs" axis could inhibit lung metastasis. Our results suggest that the combination of HMGB1 and CD62L(dim)neutrophils is a potential marker for breast cancer lung metastasis and is novel target for future prevention and therapy.