Department of Medicine, Division of Endocrinology and Metabolism, University of Rochester Medical Center, Rochester, New York.
Department of Medicine, Division of Allergy/Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York.
Mol Cancer Res. 2017 Sep;15(9):1138-1152. doi: 10.1158/1541-7786.MCR-17-0003. Epub 2017 May 16.
Tissue infiltration and elevated peripheral circulation of granulocytic myeloid-derived cells is associated with poor outcomes in prostate cancer and other malignancies. Although myeloid-derived cells have the ability to suppress T-cell function, little is known about the direct impact of these innate cells on prostate tumor growth. Here, it is reported that granulocytic myeloid-derived suppressor cells (MDSC) are the predominant tumor-infiltrating cells in prostate cancer xenografts established in athymic nude mice. MDSCs significantly increased in number in the peripheral circulation as a function of xenograft growth and were successfully depleted by Gr-1 antibody treatment. Importantly, MDSC depletion significantly decreased xenograft growth. We hypothesized that granulocytic MDSCs might exert their protumorigenic actions in part through neutrophil elastase (), a serine protease released upon granulocyte activation. Indeed, it was determined that NE is expressed by infiltrating immune cells and is enzymatically active in prostate cancer xenografts and in prostate tumors of prostate-specific -null mice. Importantly, treatment with sivelestat, a small-molecule inhibitor specific for NE, significantly decreased xenograft growth, recapitulating the phenotype of Gr-1 MDSC depletion. Mechanistically, NE activated MAPK signaling and induced MAPK-dependent transcription of the proliferative gene in prostate cancer cells. Functionally, NE stimulated proliferation, migration, and invasion of prostate cancer cells IHC on human prostate cancer clinical biopsies revealed coexpression of NE and infiltrating CD33 MDSCs. This report suggests that MDSCs and NE are physiologically important mediators of prostate cancer progression and may serve as potential biomarkers and therapeutic targets. .
组织浸润和粒细胞髓系来源细胞的外周循环升高与前列腺癌和其他恶性肿瘤的不良预后相关。尽管髓系来源细胞具有抑制 T 细胞功能的能力，但人们对这些先天细胞对前列腺肿瘤生长的直接影响知之甚少。在这里，据报道，粒细胞髓系来源的抑制细胞（MDSC）是在无胸腺裸鼠中建立的前列腺癌异种移植瘤中主要浸润的肿瘤细胞。MDSC 的数量随着异种移植瘤的生长而显著增加，并通过 Gr-1 抗体治疗成功耗尽。重要的是，MDSC 的耗竭显著降低了异种移植瘤的生长。我们假设粒细胞 MDSC 可能通过中性粒细胞弹性蛋白酶（NE）发挥其促肿瘤作用，这是一种粒细胞激活时释放的丝氨酸蛋白酶。事实上，已经确定 NE 由浸润的免疫细胞表达，并在前列腺癌异种移植瘤和前列腺特异性 -null 小鼠的前列腺肿瘤中具有酶活性。重要的是，使用特异性针对 NE 的小分子抑制剂 sivelestat 治疗可显著降低异种移植瘤的生长，再现了 Gr-1 MDSC 耗竭的表型。在机制上，NE 激活 MAPK 信号通路并诱导 MAPK 依赖性前列腺癌细胞中增殖基因 的转录。功能上，NE 刺激前列腺癌细胞的增殖、迁移和侵袭。对人前列腺癌临床活检的免疫组织化学分析显示，NE 与浸润的 CD33 MDSC 共表达。本报告表明 MDSC 和 NE 是前列腺癌进展的生理上重要的介质，可能作为潜在的生物标志物和治疗靶点。
