Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China.
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York.
Clin Cancer Res. 2019 Feb 1;25(3):1070-1086. doi: 10.1158/1078-0432.CCR-18-0586. Epub 2018 Nov 5.
Cancer stem-like cells (CSCs) contribute to bladder cancer chemotherapy resistance and progression, but the associated mechanisms have not been elucidated. This study determined whether blocking an autocrine signaling loop in CSCs improves the therapeutic effects of -platinum on bladder cancer.
The expression of the epithelial marker OV6 and other markers in human bladder cancer specimens was examined by IHC. The CSC properties of magnetic-activated cell sorting (MACS)-isolated OV6 and OV6 bladder cancer cells were examined. Molecular mechanisms were assessed through RNA-Seq, cytokine antibody arrays, co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP) and other assays. An orthotopic bladder cancer mouse model was established to evaluate the effects of a YAP inhibitor (verteporfin) and a PDGFR inhibitor (CP-673451) on the -platinum resistance of OV6 CSCs in bladder cancer.
Upregulated OV6 expression positively associated with disease progression and poor prognosis for bladder cancer patients. Compared with OV6 cells, OV6 bladder cancer cells exhibited strong CSC characteristics, including self-renewal, tumor initiation in NOD/SCID mice, and chemotherapy resistance. YAP, which maintains the stemness of OV6 CSCs, triggered PDGFB transcription by recruiting TEAD1. Autocrine PDGF-BB signaling through its receptor PDGFR stabilized YAP and facilitated YAP nuclear translocation. Furthermore, blocking the YAP/TEAD1/PDGF-BB/PDGFR loop with verteporfin or CP-673451 inhibited the -platinum resistance of OV6 bladder cancer CSCs in an orthotopic bladder cancer model.
OV6 could be a helpful indicator of disease progression and prognosis for patients with bladder cancer, and targeting the autocrine YAP/TEAD1/PDGF-BB/PDGFR loop might serve as a remedy for -platinum resistance in patients with advanced bladder cancer.
癌症干细胞样细胞（CSCs）导致膀胱癌化疗耐药和进展，但相关机制尚未阐明。本研究旨在确定阻断 CSCs 中的自分泌信号环是否能提高 -铂类药物治疗膀胱癌的疗效。
通过免疫组化检查人膀胱癌标本中上皮标志物 OV6 及其他标志物的表达。通过磁激活细胞分选（MACS）分离 OV6 和 OV6 膀胱癌细胞，检测其 CSC 特性。通过 RNA-Seq、细胞因子抗体阵列、共免疫沉淀（co-IP）、染色质免疫沉淀（ChIP）和其他检测评估分子机制。建立原位膀胱癌小鼠模型，评估 YAP 抑制剂（verteporfin）和 PDGFR 抑制剂（CP-673451）对 OV6 CSCs 对 -铂类药物耐药性的影响。
上调的 OV6 表达与膀胱癌患者疾病进展和预后不良呈正相关。与 OV6 细胞相比，OV6 膀胱癌细胞表现出强烈的 CSC 特征，包括自我更新、在 NOD/SCID 小鼠中引发肿瘤和化疗耐药性。YAP 通过募集 TEAD1 维持 OV6 CSCs 的干性，触发 PDGFB 转录。通过其受体 PDGFR 自分泌 PDGF-BB 信号稳定 YAP 并促进 YAP 核转位。此外，用 verteporfin 或 CP-673451 阻断 YAP/TEAD1/PDGF-BB/PDGFR 环抑制了原位膀胱癌模型中 OV6 膀胱癌 CSCs 的 -铂类药物耐药性。
OV6 可能是膀胱癌患者疾病进展和预后的有用指标，靶向自分泌 YAP/TEAD1/PDGF-BB/PDGFR 环可能是治疗晚期膀胱癌 -铂类药物耐药的一种方法。
