肿瘤微环境内皮-间质转化促进前列腺癌神经内分泌分化。

IF 4.3 2区 医学 Q1 ONCOLOGY
Cancer Science Pub Date : 2025-07-24 DOI:10.1111/cas.70144
Takumi Kageyama, Manabu Kato, Shiori Miyachi, Xin Bao, Sho Sekito, Yusuke Sugino, Shinichiro Higashi, Takeshi Sasaki, Kouhei Nishikawa, Yasuhiro Murakawa, Masatoshi Watanabe, Takahiro Inoue
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引用次数: 0

摘要

神经内分泌前列腺癌(NEPC)是去势抵抗性前列腺癌(CRPC)的一种高度侵袭性和治疗耐药亚型,通常在雄激素受体(AR)途径抑制的进展过程中出现。虽然癌细胞的谱系可塑性已被认为是耐药性的关键机制,但肿瘤微环境在驱动这种转变中的作用仍不清楚。在其细胞成分中,血管内皮细胞可以经历内皮-间充质转化(EndoMT),这是一种与肿瘤进展和纤维化相关的表型转变。在这里,我们调查了EndoMT是否有助于NEPC的发展。利用IL-1β和TGF-β2诱导人脐静脉内皮细胞(HUVEC)进行EndoMT,以下简称EndoMTed HUVEC。EndoMTed HUVEC促进LNCaP细胞的神经内分泌特征和功能改变。转录组分析显示,在EndoMTed HUVEC中,粒细胞-巨噬细胞集落刺激因子(GM-CSF)显著上调。使用靶向GM-CSF受体α (CSF2RA)的单克隆抗体mavrilimumab中和GM-CSF信号,以及sirna介导的CSF2RA敲低均抑制LNCaP细胞的神经内分泌表型和STAT3信号传导。相反,单独刺激GM-CSF可再现这些变化。enzalutamide处理的LNCaP细胞分泌IL-1β和TGF-β2,进而触发EndoMT,提示相互循环。这些研究结果表明,抗雄激素治疗可能通过涉及肿瘤源性细胞因子和内皮GM-CSF分泌的旁分泌环无意中促进NEPC,强调EndoMT是治疗耐药的微环境驱动因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Endothelial-Mesenchymal Transition in Tumor Microenvironment Promotes Neuroendocrine Differentiation of Prostate Cancer

Endothelial-Mesenchymal Transition in Tumor Microenvironment Promotes Neuroendocrine Differentiation of Prostate Cancer

Neuroendocrine prostate cancer (NEPC) is a highly aggressive and treatment-resistant subtype of castration-resistant prostate cancer (CRPC) that often emerges during progression under androgen-receptor (AR) pathway inhibition. While lineage plasticity in cancer cells has been recognized as a key mechanism of resistance, the role of the tumor microenvironment in driving this transition remains unclear. Among its cellular components, vascular endothelial cells can undergo endothelial-mesenchymal transition (EndoMT), a phenotypic shift associated with tumor progression and fibrosis. Here, we investigated whether EndoMT contributes to NEPC development. Human umbilical vein endothelial cells (HUVEC) were induced to undergo EndoMT using IL-1β and TGF-β2, and are hereafter referred to as EndoMTed HUVEC. EndoMTed HUVEC promoted neuroendocrine features and functional changes in LNCaP cells. Transcriptome analysis revealed marked upregulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in EndoMTed HUVEC. Neutralization of GM-CSF signaling using mavrilimumab, a monoclonal antibody targeting the GM-CSF receptor alpha (CSF2RA), and siRNA-mediated CSF2RA knockdown both suppressed the neuroendocrine phenotype and STAT3 signaling of LNCaP cells. Conversely, GM-CSF stimulation alone reproduced these changes. Enzalutamide-treated LNCaP cells secreted IL-1β and TGF-β2, which in turn triggered EndoMT, suggesting a reciprocal loop. These findings indicate that anti-androgen therapy may inadvertently promote NEPC through a paracrine loop involving tumor-derived cytokines and endothelial GM-CSF secretion, highlighting EndoMT as a microenvironmental driver of treatment resistance.

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来源期刊
Cancer Science
Cancer Science 医学-肿瘤学
自引率
3.50%
发文量
406
审稿时长
2 months
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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