Prostate cancer addiction to oxidative stress defines sensitivity to anti-tumor neutrophils.
Prostate cancer addiction to oxidative stress defines sensitivity to anti-tumor neutrophils.
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DOI：
10.1007/s10585-022-10170-x
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发表时间：
2022-08
影响因子：
4
通讯作者：
Cook, Leah M.
中科院分区：
文献类型：
--
作者：
Costanzo-Garvey, Diane L.;Case, Adam J.;Watson, Gabrielle F.;Alsamraae, Massar;Chatterjee, Arpita;Oberley-Deegan, Rebecca E.;Dutta, Samikshan;Abdalla, Maher Y.;Kielian, Tammy;Lindsey, Merry L.;Cook, Leah M.
骨转移性前列腺癌（BM-PCa）仍然是最难治疗的癌症之一，由于癌症和基质细胞的复杂相互作用。我们以前表明，骨髓嗜中性粒细胞引起的抗肿瘤免疫反应对BM-PCa。此外，我们证明了BM-PCa诱导中性粒细胞氧化爆发，其先前已被鉴定为促进其他癌症的原发性肿瘤生长，并且本研究的目标是确定中性粒细胞氧化爆发在BM-PCa中的重要性。为了做到这一点，我们首先检查了消耗活性氧（ROS）的影响，通过系统删除吞噬细胞中ROS的主要来源，NADPH氧化酶（Nox）2，我们发现它抑制前列腺肿瘤在骨中的生长。此外，使用药理学ROS抑制剂和Nox 2-null中性粒细胞，我们发现ROS耗竭特异性抑制雄激素不敏感的前列腺癌细胞的生长。在使用批量RNA测序分析进行更仔细的检查后，我们确定转移性前列腺癌诱导中性粒细胞转录组学变化，其激活与氧化应激反应相关的途径。串联地，前列腺癌细胞通过细胞外（即，调节中性粒细胞）和谷胱甘肽合成（最有效的细胞抗氧化剂）的细胞内改变。这些发现表明，BM-PCa在氧化应激条件下茁壮成长，因此可以利用ROS和谷胱甘肽编程的调节来靶向BM-PCa进展。在线版本包含补充材料，可通过10.1007/s10585-022-10170-x获得。
Bone metastatic prostate cancer (BM-PCa) remains one of the most difficult cancers to treat due to the complex interactions of cancer and stromal cells. We previously showed that bone marrow neutrophils elicit an anti-tumor immune response against BM-PCa. Further, we demonstrated that BM-PCa induces neutrophil oxidative burst, which has previously been identified to promote primary tumor growth of other cancers, and a goal of this study was to define the importance of neutrophil oxidative burst in BM-PCa. To do this, we first examined the impact of depletion of reactive oxygen species (ROS), via systemic deletion of the main source of ROS in phagocytes, NADPH oxidase (Nox)2, which we found to suppress prostate tumor growth in bone. Further, using pharmacologic ROS inhibitors and Nox2-null neutrophils, we found that ROS depletion specifically suppresses growth of androgen-insensitive prostate cancer cells. Upon closer examination using bulk RNA sequencing analysis, we identified that metastatic prostate cancer induces neutrophil transcriptomic changes that activates pathways associated with response to oxidative stress. In tandem, prostate cancer cells resist neutrophil anti-tumor response via extracellular (i.e., regulation of neutrophils) and intracellular alterations of glutathione synthesis, the most potent cellular antioxidant. These findings demonstrate that BM-PCa thrive under oxidative stress conditions and such that regulation of ROS and glutathione programming could be leveraged for targeting of BM-PCa progression. The online version contains supplementary material available at 10.1007/s10585-022-10170-x.
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