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This study shows that inducing endothelial-mesenchymal transition (EndoMT) in human endothelial cells promotes neuroendocrine features and functional changes in prostate cancer cells. Transcriptome profiling links this effect to endothelial GM-CSF, which activates STAT3 signaling. Neutralizing GM-CSF signaling or knocking down CSF2RA suppresses the neuroendocrine phenotype, while GM-CSF stimulation reproduces it. Enzalutamide-treated cancer cells secrete IL-1β and TGF-β2 that trigger EndoMT, revealing a reciprocal paracrine loop.",{"@graph":14,"@context":71},[15,34,54],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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role does endothelial-mesenchymal transition (EndoMT) play in neuroendocrine prostate cancer development?","Question",{"text":61,"@type":62},"The study investigates whether EndoMT contributes to NEPC development by inducing EndoMT in endothelial cells and assessing subsequent neuroendocrine features in prostate cancer cells.","Answer",{"name":64,"@type":59,"acceptedAnswer":65},"How is GM-CSF connected to the observed neuroendocrine differentiation?",{"text":66,"@type":62},"Transcriptome analysis shows marked upregulation of GM-CSF in EndoMTed endothelial cells, and blocking GM-CSF signaling or knocking down CSF2RA suppresses the neuroendocrine phenotype and STAT3 signaling.",{"name":68,"@type":59,"acceptedAnswer":69},"Why can anti-androgen therapy promote NEPC according to this work?",{"text":70,"@type":62},"Enzalutamide-treated cancer cells secrete IL-1β and TGF-β2 that trigger EndoMT, creating a reciprocal paracrine loop involving tumor-derived cytokines and endothelial GM-CSF secretion.","https://schema.org",{"og:url":32,"og:type":73,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":75,"canonical":32},"index,follow",{"doc_id":77,"site_id":7},376365,1790241387,{"code":4,"msg":80,"data":81},"success",[82,86,90,94,99,104,109,113,118,121,125],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":83,"show_sort_weight":84,"slug":85},"Story & 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Neuroendocrine Differentiation of Prostate Cancer  \nTakumi Kageyama1  | Manabu Kato1 | Shiori Miyachi1 | Xin Bao1 | Sho Sekito1,2 | Yusuke Sugino1 | Shinichiro Higashi1 | Takeshi Sasaki1 | Kouhei Nishikawa1 | Yasuhiro Murakawa2 | Masatoshi Watanabe3 | Takahiro Inoue1   \n1Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Tsu, Japan | 2Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan | 3Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Japan Correspondence: Takahiro Inoue ([tinoue28@med.mie-u.ac.jp](tinoue28@med.mie-u.ac.jp))  \nReceived: 17 December 2024 | Revised: 3 July 2025 | Accepted: 9 July 2025  \nFunding: This work was supported by Japan Society for the Promotion of Science, 24K02576, 24K12434 .  \nKeywords: androgen deprivation therapy | endothelial-mesenchymal transition | granulocyte-macrophage colony-stimulating factor | neuroendocrine differentiation | prostate cancer  \nABSTRACT  \nNeuroendocrine 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.  \n\n| Abbreviations: αSMA, Alpha smooth muscle actin; AR, Androgen receptor; CAF, Cancer-associated fibroblast; CD31, Platelet endothelial cell adhesion molecule-1\u003Cbr>(PECAM-1); CgA, Chromogranin A; CRPC, Castration-resistant prostate cancer; CSF2, Colony-stimulating factor 2 (gene encoding GM-CSF); CSF2RA, Colonystimulating factor 2 receptor alpha subunit; EMT, Epithelial-mesenchymal transition; EndoMT, Endothelial-mesenchymal transition; GM-CSF, Granulocytemacrophage colony-stimulating Factor; HUVEC, Human umbilical vein endothelial cell; NE, Neuroendocrine; NED, Neuroendocrine differentiation; NEPC, Neuroendocrine prostate cancer; PSA, Prostate-specific antigen; TME, Tumor microenvironment. |\n| --- |\n| This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.\u003Cbr>© 2025 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. |\n\n2712 Cancer Science, 2025; 116:27","cbCaijLZf1U7WIfG","https://ap.wps.com/l/cbCaijLZf1U7WIfG","pdf",4481942,11,"English","# Introduction\n## Tumor microenvironment and therapy resistance\n## EndoMT in cancer progression\n## Neuroendocrine differentiation in prostate cancer","[{\"question\":\"What role does endothelial-mesenchymal transition (EndoMT) play in neuroendocrine prostate cancer development?\",\"answer\":\"The study investigates whether EndoMT contributes to NEPC development by inducing EndoMT in endothelial cells and assessing subsequent neuroendocrine features in prostate cancer cells.\"},{\"question\":\"How is GM-CSF connected to the observed neuroendocrine differentiation?\",\"answer\":\"Transcriptome analysis shows marked upregulation of GM-CSF in EndoMTed endothelial cells, and blocking GM-CSF signaling or knocking down CSF2RA suppresses the neuroendocrine phenotype and STAT3 signaling.\"},{\"question\":\"Why can anti-androgen therapy promote NEPC according to this work?\",\"answer\":\"Enzalutamide-treated cancer cells secrete IL-1β and TGF-β2 that trigger EndoMT, creating a reciprocal paracrine loop involving tumor-derived cytokines and endothelial GM-CSF secretion.\"}]","Endothelial-Mesenchymal Transition in Tumor Microenvironment Promotes Neuroendocrine Differentiation of Prostate Cancer | PDF",1790218401,28]