Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, SOX2, and CD44 through NFκB-signaling.

IF 6.5 2区医学 Q1 IMMUNOLOGY Oncoimmunology Pub Date : 2024-08-21 eCollection Date: 2024-01-01 DOI:10.1080/2162402X.2024.2393442

Kirsi Kainulainen, Einari A Niskanen, Johanna Kinnunen, Kaisa Mäki-Mantila, Kiia Hartikainen, Ville Paakinaho, Marjo Malinen, Kirsi Ketola, Sanna Pasonen-Seppänen

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Abstract

The inflammatory tumor microenvironment (TME) is a key driver for tumor-promoting processes. Tumor-associated macrophages are one of the main immune cell types in the TME and their increased density is related to poor prognosis in prostate cancer. Here, we investigated the influence of pro-inflammatory (M1) and immunosuppressive (M2) macrophages on prostate cancer lineage plasticity. Our findings reveal that M1 macrophage secreted factors upregulate genes related to stemness while downregulating genes associated with androgen response in prostate cancer cells. The expression of cancer stem cell (CSC) plasticity markers NANOG, KLF4, SOX2, OCT4, and CD44 was stimulated by the secreted factors from M1 macrophages. Moreover, AR and its target gene PSA were observed to be suppressed in LNCaP cells treated with secreted factors from M1 macrophages. Inhibition of NFκB signaling using the IKK16 inhibitor resulted in downregulation of NANOG, SOX2, and CD44 and CSC plasticity. Our study highlights that the secreted factors from M1 macrophages drive prostate cancer cell plasticity by upregulating the expression of CSC plasticity markers through NFκB signaling pathway.

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M1巨噬细胞分泌的因子通过NFκB信号上调NANOG、SOX2和CD44，驱动前列腺癌干细胞的可塑性。

炎性肿瘤微环境（TME）是肿瘤促发过程的关键驱动因素。肿瘤相关巨噬细胞是肿瘤微环境中的主要免疫细胞类型之一，其密度的增加与前列腺癌的不良预后有关。在这里，我们研究了促炎性（M1）和免疫抑制性（M2）巨噬细胞对前列腺癌血统可塑性的影响。我们的研究结果表明，M1巨噬细胞分泌的因子会上调前列腺癌细胞中与干性相关的基因，同时下调与雄激素反应相关的基因。癌症干细胞（CSC）可塑性标志物NANOG、KLF4、SOX2、OCT4和CD44的表达受到M1巨噬细胞分泌因子的刺激。此外，在使用 M1 巨噬细胞分泌因子处理的 LNCaP 细胞中，还观察到 AR 及其靶基因 PSA 受到抑制。使用IKK16抑制剂抑制NFκB信号传导会导致NANOG、SOX2和CD44的下调以及CSC的可塑性。我们的研究强调，M1巨噬细胞分泌的因子通过NFκB信号通路上调CSC可塑性标志物的表达，从而驱动前列腺癌细胞的可塑性。

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来源期刊

Oncoimmunology ONCOLOGYIMMUNOLOGY-IMMUNOLOGY

CiteScore

12.50

自引率

2.80%

发文量

276

审稿时长

24 weeks

期刊介绍： OncoImmunology is a dynamic, high-profile, open access journal that comprehensively covers tumor immunology and immunotherapy. As cancer immunotherapy advances, OncoImmunology is committed to publishing top-tier research encompassing all facets of basic and applied tumor immunology. The journal covers a wide range of topics, including: -Basic and translational studies in immunology of both solid and hematological malignancies -Inflammation, innate and acquired immune responses against cancer -Mechanisms of cancer immunoediting and immune evasion -Modern immunotherapies, including immunomodulators, immune checkpoint inhibitors, T-cell, NK-cell, and macrophage engagers, and CAR T cells -Immunological effects of conventional anticancer therapies.