向肿瘤募集成纤维细胞并将其激活为癌症相关成纤维细胞 (CAF) 是肿瘤细胞用于指导细胞外基质 (ECM) 重塑、侵袭和转移的策略，这凸显了研究驱动 CAF 功能的分子机制的必要性。内皮素-1 (ET-1) 调节癌症与间质之间的通讯，促进浆液性卵巢癌 (SOC) 的进展。通过与内皮素 A (ETA) 和 B (ETB) 受体结合，ET-1 能够募集 β-arrestin1 (β-arr1) 并形成协调肿瘤进展的信号复合物。然而，ET-1 受体如何“教育”人类卵巢成纤维细胞 (HOF) 产生改变的 ECM 并促进转移仍有待阐明。这项研究确定 ET-1 是激活能够进行蛋白水解 ECM 重塑的 CAF 以及生成含有具有转移倾向的癌细胞的异型球体的关键因素。自分泌/旁分泌 ET-1/ETA/BR/β-arr1 环可增强 HOF 增殖，上调 CAF 标记物表达，分泌促炎细胞因子，并增加胶原收缩性和细胞运动性。此外，ET-1 通过促进侵袭体的裂解活性和整合素 β1 的激活来促进 ECM 重塑。此外，ET-1信号传导支持异型HOF/SOC球体的形成，其具有增强的穿过间皮单层迁移和侵袭的能力，代表转移单位。阻断 ETA/BR 或 β-arr1 沉默可防止 CAF 激活、侵袭体功能、间皮清除和异型球体的侵袭能力。在体内，使用波生坦 (BOS) 治疗性抑制 ETA/BR 可显着降低 HOF/SOC 组合细胞的转移潜力，这与增强肿瘤细胞和基质成分的凋亡作用有关。这些发现支持一个模型，其中 ET-1/β-arr1 通过 CAF 激活增强肿瘤/基质相互作用，并促进 SOC 细胞的存活和转移特性，而 ETA/BR 拮抗剂可以抵消这种作用。© 2024。 ）。

Recruitment of fibroblasts to tumors and their activation into cancer-associated fibroblasts (CAFs) is a strategy used by tumor cells to direct extracellular matrix (ECM) remodeling, invasion, and metastasis, highlighting the need to investigate the molecular mechanisms driving CAF function. Endothelin-1 (ET-1) regulates the communication between cancer and stroma and facilitates the progression of serous ovarian cancer (SOC). By binding to Endothelin A (ETA) and B (ETB) receptors, ET-1 enables the recruitment of β-arrestin1 (β-arr1) and the formation of signaling complexes that coordinate tumor progression. However, how ET-1 receptors might "educate" human ovarian fibroblasts (HOFs) to produce altered ECM and promote metastasis remains to be elucidated. This study identifies ET-1 as a pivotal factor in the activation of CAFs capable of proteolytic ECM remodeling and the generation of heterotypic spheroids containing cancer cells with a propensity to metastasize. An autocrine/paracrine ET-1/ETA/BR/β-arr1 loop enhances HOF proliferation, upregulates CAF marker expression, secretes pro-inflammatory cytokines, and increases collagen contractility, and cell motility. Furthermore, ET-1 facilitates ECM remodeling by promoting the lytic activity of invadosome and activation of integrin β1. In addition, ET-1 signaling supports the formation of heterotypic HOF/SOC spheroids with enhanced ability to migrate through the mesothelial monolayer, and invade, representing metastatic units. The blockade of ETA/BR or β-arr1 silencing prevents CAF activation, invadosome function, mesothelial clearance, and the invasive ability of heterotypic spheroids. In vivo, therapeutic inhibition of ETA/BR using bosentan (BOS) significantly reduces the metastatic potential of combined HOFs/SOC cells, associated with enhanced apoptotic effects on tumor cells and stromal components. These findings support a model in which ET-1/β-arr1 reinforces tumor/stroma interaction through CAF activation and fosters the survival and metastatic properties of SOC cells, which could be counteracted by ETA/BR antagonists.© 2024. The Author(s).