PDF(Pubmed)
Abstract：
The high-grade serous ovarian cancer (HG-SOC) tumor microenvironment (TME) is constellated by cellular elements and a network of soluble constituents that contribute to tumor progression. In the multitude of the secreted molecules, the endothelin-1 (ET-1) has emerged to be implicated in the tumor/TME interplay; however, the molecular mechanisms induced by the ET-1-driven feed-forward loops (FFL) and associated with the HG-SOC metastatic potential need to be further investigated. The tracking of the patient-derived (PD) HG-SOC cell transcriptome by RNA-seq identified the vascular endothelial growth factor (VEGF) gene and its associated signature among those mostly up-regulated by ET-1 and down-modulated by the dual ET-1R antagonist macitentan. Within the ligand-receptor pairs concurrently expressed in PD-HG-SOC cells, endothelial cells and activated fibroblasts, we discovered two intertwined FFL, the ET-1/ET-1R and VEGF/VEGF receptors, concurrently activated by ET-1 and shutting-down by macitentan, or by the anti-VEGF antibody bevacizumab. In parallel, we observed that ET-1 fine-tuned the tumoral and stromal secretome toward a pro-invasive pattern. Into the fray of the HG-SOC/TME double and triple co-cultures, the secretion of ET-1 and VEGF, that share a common co-regulation, was inhibited upon the administration of macitentan. Functionally, macitentan, mimicking the effect of bevacizumab, interfered with the HG-SOC/TME FFL-driven communication that fuels the HG-SOC invasive behavior. The identification of ET-1 and VEGF FFL as tumor and TME actionable vulnerabilities, reveals how ET-1R blockade, targeting the HG-SOC cells and the TME simultaneously, may represent an effective therapeutic option for HG-SOC patients.
摘要：
高级别浆液性卵巢癌（HG-SOC）肿瘤微环境（TME）由细胞元素和有助于肿瘤进展的可溶性成分网络组成。在大量的分泌分子中，内皮素-1（ET-1）已出现与肿瘤/TME相互作用有关，然而,由ET-1驱动的前馈环(FFL)诱导并与HG-SOC转移潜能相关的分子机制需要进一步研究.通过RNA-seq跟踪患者来源的（PD）HG-SOC细胞转录组，在主要由ET-1上调和由双重ET-1R拮抗剂Macitentan下调的那些基因中，确定了血管内皮生长因子（VEGF）基因及其相关特征。在PD-HG-SOC细胞中同时表达的配体-受体对中，内皮细胞和活化成纤维细胞，我们发现了两个交织在一起的FFL,ET-1/ET-1R和VEGF/VEGF受体，同时由ET-1激活并由Macitentan关闭，或抗VEGF抗体贝伐单抗。并行,我们观察到ET-1将肿瘤和基质分泌组朝一种前侵袭模式微调。进入HG-SOC/TME双重和三重共培养的竞争，ET-1和VEGF的分泌，拥有共同的共同监管，在服用Macitentan后被抑制。功能上,Macitentan,模仿贝伐单抗的效果，干扰了HG-SOC/TMEFFL驱动的通信，从而助长了HG-SOC的侵入性行为。ET-1和VEGFFFL作为肿瘤和TME可操作漏洞的鉴定，揭示了ET-1R的封锁，同时靶向HG-SOC细胞和TME，可能是HG-SOC患者的有效治疗选择。
