CXCR2 Mediates Distinct Neutrophil Behavior in Brain Metastatic Breast Tumor.
CXCR2 Mediates Distinct Neutrophil Behavior in Brain Metastatic Breast Tumor.
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DOI：
10.3390/cancers14030515
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发表时间：
2022-01-20
期刊：
影响因子：
5.2
通讯作者：
Chandrasekaran A
中科院分区：
文献类型：
--
作者：
Safarulla S;Madan A;Xing F;Chandrasekaran A
脑转移是乳腺癌常见的并发症之一。中性粒细胞形成循环白色血细胞的主要类型，并且在肿瘤发病机制中起重要作用。然而，中性粒细胞在乳腺癌脑转移演变中的作用尚未明确。使用简单的嗜中性粒细胞肿瘤细胞培养模型，我们研究了脑转移性乳腺癌细胞可能重新编程中性粒细胞作为肿瘤促进策略的可能生物分子机制，以及药物诱导的某些关键中性粒细胞功能的抑制如何有助于逆转这种行为。 脑转移是乳腺癌患者死亡的主要原因之一，但驱动这一过程的起源和机制仍然知之甚少。在这里，我们报告说，上调某些CXCR 2相关配体的脑转移性乳腺癌细胞（BrM）的变体动态激活相应的CXCR 2受体的中性粒细胞，从而导致某些关键功能的中性粒细胞对BrM的反应的调制。使用已建立的嗜中性粒细胞-肿瘤仿生共培养模型，我们表明CXCR 2的上调增加了肿瘤相关中性粒细胞（TAN）向BrM的募集，以使定位有利的神经细胞胞外陷阱（NET）形成。使用小分子拮抗剂AZD 5069抑制CXCR 2逆转了这种行为，限制了中性粒细胞对BrM的反应并延缓了相互的肿瘤发展。我们进一步证明，使用神经弹性蛋白酶抑制剂（NEI）消除NET形成显著降低了中性粒细胞向BrM的流入，但不降低其向其亲本肿瘤的流入，这表明脑转移瘤可以使用CXCR 2激活作为将肿瘤浸润性TAN编程为促NETotic状态的机制，从而呈现出独特的空间分布，其有助于转移性肿瘤细胞随后的迁移和侵袭。这一新的观点表明，CXCR 2是抑制脑转移中嗜酸性炎症的关键靶点。
Brain metastasis is one of the common complications associated with breast cancers. Neutrophils form the predominant type of circulating white blood cells and play an important role in tumor pathogenesis. However, the role of neutrophils in the evolution of brain metastasis of breast cancers has not been clearly understood. Using simple neutrophil-tumor cell-culture models, we studied the possible biomolecular mechanisms by which the brain-metastatic breast cancer cells could potentially re-program the neutrophils as a tumor-promoting strategy, and how drug-induced inhibition of certain key neutrophil functionalities could help reverse this behavior. Brain metastasis is one of the main causes of mortality among breast cancer patients, but the origins and the mechanisms that drive this process remain poorly understood. Here, we report that the upregulation of certain CXCR2-associated ligands in the brain metastatic variants of the breast cancer cells (BrM) dynamically activate the corresponding CXCR2 receptors on the neutrophils, thereby resulting in the modulation of certain key functional neutrophil responses towards the BrM. Using established neutrophil-tumor biomimetic co-culture models, we show that the upregulation of CXCR2 increases the recruitment of Tumor-Associated Neutrophils (TANs) towards the BrM, to enable location-favored formation of Neutrophil Extracellular Traps (NETs). Inhibition of CXCR2 using small molecule antagonist AZD5069 reversed this behavior, limiting the neutrophil responses to the BrM and retarding the reciprocal tumor development. We further demonstrate that abrogation of NETs formation using Neutrophil Elastase Inhibitor (NEI) significantly decreases the influx of neutrophils towards BrM but not to their parental tumor, suggesting that CXCR2 activation could be used by the brain metastatic tumors as a mechanism to program the tumor-infiltrating TANs into a pro-NETotic state, so as to assume a unique spatial distribution that assists in the subsequent migration and invasion of the metastatic tumor cells. This new perspective indicates that CXCR2 is a critical target for suppressing neutrophilic inflammation in brain metastasis.
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DOI：
10.1126/science.aao4227
发表时间：
2018-09-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Albrengues J;Shields MA;Ng D;Park CG;Ambrico A;Poindexter ME;Upadhyay P;Uyeminami DL;Pommier A;Küttner V;Bružas E;Maiorino L;Bautista C;Carmona EM;Gimotty PA;Fearon DT;Chang K;Lyons SK;Pinkerton KE;Trotman LC;Goldberg MS;Yeh JT;Egeblad M
通讯作者：
Egeblad M
影响因子：
5.2
作者：
Arpinati L;Kaisar-Iluz N;Shaul ME;Groth C;Umansky V;Fridlender ZG
通讯作者：
Fridlender ZG
影响因子：
64.5
作者：
Acharyya S;Oskarsson T;Vanharanta S;Malladi S;Kim J;Morris PG;Manova-Todorova K;Leversha M;Hogg N;Seshan VE;Norton L;Brogi E;Massagué J
通讯作者：
Massagué J
影响因子：
9
作者：
Azzouz D;Palaniyar N
通讯作者：
Palaniyar N
影响因子：
5.5
作者：
Christenson, Karin;Bjorkman, Lena;Bylund, Johan
通讯作者：
Bylund, Johan