RESUMEN
BACKGROUND: Crosstalk between neoplastic and stromal cells fosters prostate cancer (PCa) progression and dissemination. Insight in cell-to-cell communication networks provides new therapeutic avenues to mold processes that contribute to PCa tumor microenvironment (TME) alterations. Here we performed a detailed characterization of PCa tumor endothelial cells (TEC) to delineate intercellular crosstalk between TEC and the PCa TME. METHODS: TEC isolated from 67 fresh radical prostatectomy (RP) specimens underwent multi-omic ex vivo characterization as well as orthogonal validation of both TEC functions and key markers by immunohistochemistry (IHC) and immunofluorescence (IF). To identify cell-cell interaction targets in TEC, we performed single-cell RNA sequencing (scRNA-seq) in four PCa patients who underwent a RP to catalogue cellular TME composition. Targets were cross-validated using IHC, publicly available datasets, cell culture expriments as well as a PCa xenograft mouse model. RESULTS: Compared to adjacent normal endothelial cells (NEC) bulk RNA-seq analysis revealed upregulation of genes associated with tumor vasculature, collagen modification and extracellular matrix remodeling in TEC. PTGIR, PLAC9, CXCL12 and VDR were identified as TEC markers and confirmed by IF and IHC in an independent patient cohort. By scRNA-seq we identified 27 cell (sub)types, including endothelial cells (EC) with arterial, venous and immature signatures, as well as angiogenic tip EC. A focused molecular analysis revealed that arterial TEC displayed highest CXCL12 mRNA expression levels when compared to all other TME cell (sub)populations and showed a negative prognostic role. Receptor-ligand interaction analysis predicted interactions between arterial TEC derived CXCL12 and its cognate receptor CXCR4 on angiogenic tip EC. CXCL12 was in vitro and in vivo validated as actionable TEC target by highlighting the vessel number- and density- reducing activity of the CXCR4-inhibitor AMD3100 in murine PCa as well as by inhibition of TEC proliferation and migration in vitro. CONCLUSIONS: Overall, our comprehensive analysis identified novel PCa TEC targets and highlights CXCR4/CXCL12 interaction as a potential novel target to interfere with tumor angiogenesis in PCa.
Asunto(s)
Próstata , Neoplasias de la Próstata , Animales , Línea Celular Tumoral , Proliferación Celular , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Células Endoteliales/metabolismo , Humanos , Masculino , Ratones , Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Receptores de Epoprostenol , Microambiente TumoralRESUMEN
A 21-year-old athletic woman had been suffering from flank pain during fluid intake after sports for some time. Urological work-up revealed hydronephrosis with a "fishhook" shape and medial displacement of the ureter. This ureteral narrowing was studied ureterorenoscopically, bioptically and endoscopic-radiologically without the correct diagnosis of a retrocaval ureter being made. Therapeutically, a DJ stent was inserted several times, a balloon dilatation was performed under anaesthesia three times and finally a permanent DJ catheter was inserted. Due to the patient's dissatisfaction, an endoscopic endopyelotomy using Acucise was offered.
Asunto(s)
Hidronefrosis , Uréter , Obstrucción Ureteral , Femenino , Humanos , Adulto Joven , Adulto , Uréter/cirugía , Endoscopía , Cateterismo , StentsRESUMEN
We report on a 66-year-old neuro-urological female patient who, three years after implantation of a neurostimulator, experienced cecal necrosis due to strangulation caused by the cable of the device.