PDF(Pubmed)
Abstract：
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.
摘要：
将成纤维细胞募集到肿瘤中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）重塑的策略。入侵,和转移，强调需要研究驱动CAF功能的分子机制。内皮素-1（ET-1）调节癌症与基质之间的联系，并促进浆液性卵巢癌（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（HOFs）产生改变的ECM并促进转移仍有待阐明。这项研究确定ET-1是能够蛋白水解ECM重塑的CAF活化和含有具有转移倾向的癌细胞的异型球体产生的关键因素。自分泌/旁分泌ET-1/ETA/BR/β-arr1环增强HOF增殖,上调CAF标记表达，分泌促炎细胞因子，并增加胶原蛋白的收缩力，和细胞运动。此外，ET-1通过促进侵袭小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球状体的形成，具有增强的迁移通过间皮单层的能力，入侵，代表转移单位。ETA/BR或β-arr1沉默的阻断可防止CAF活化，invadosome函数，间皮间隙,异型球状体的侵袭能力。在体内,使用波生坦（BOS）的ETA/BR的治疗性抑制显着降低了组合HOFs/SOC细胞的转移潜力，与增强对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，这可以被ETA/BR拮抗剂抵消。
