Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, 1600 7th Ave. South, Lowder Building, Suite 300, Birmingham, AL 35233, USA.
Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
J Pediatr Surg. 2021 Jun;56(6):1165-1173. doi: 10.1016/j.jpedsurg.2021.02.041. Epub 2021 Feb 24.
The poor therapeutic efficacy seen with current treatments for neuroblastoma may be attributed to stem cell-like cancer cells (SCLCCs), a subpopulation of cancer cells associated with poor prognosis and disease recurrence. Retinoic acid (RA) is a differentiating agent used as maintenance therapy for high-risk neuroblastoma but nearly half of children treated with RA relapse. We hypothesized that 6-Methyl-UAB30 (6-Me), a second-generation rexinoid recently developed with a favorable toxicity profile compared to RA, would reduce cancer cell stemness in human neuroblastoma patient-derived xenografts (PDXs).
Cells from three neuroblastoma PDXs were treated with 6-Me and proliferation, viability, motility, and cell-cycle progression were assessed. CD133 expression, sphere formation, and mRNA abundance of stemness and differentiation markers were evaluated using flow cytometry, in vitro extreme limiting dilution analysis, and real-time PCR, respectively.
Treatment with 6-Me decreased proliferation, viability, and motility, and induced cell-cycle arrest and differentiation in all three neuroblastoma PDXs. In addition, 6-Me treatment led to decreased CD133 expression, decreased sphere-forming ability, and decreased mRNA abundance of Oct4, Nanog, and Sox2, indicating decreased cancer cell stemness.
6-Me decreased oncogenicity and reduced cancer cell stemness of neuroblastoma PDXs, warranting further exploration of 6-Me as potential novel therapy for neuroblastoma.
目前神经母细胞瘤的治疗效果不佳，这可能归因于具有干细胞样特性的癌细胞（SCLCCs），这是一种与预后不良和疾病复发相关的癌细胞亚群。维甲酸（RA）是一种分化剂，用于高危神经母细胞瘤的维持治疗，但近一半接受 RA 治疗的儿童会复发。我们假设与 RA 相比，具有良好毒性特征的第二代视黄醇受体激动剂 6-甲基-UAB30（6-Me）将降低人神经母细胞瘤患者来源异种移植瘤（PDX）中的癌细胞干性。
用 6-Me 处理来自三个神经母细胞瘤 PDX 的细胞，评估增殖、活力、迁移和细胞周期进程。使用流式细胞术、体外极限稀释分析和实时 PCR 分别评估 CD133 表达、球体形成以及干性和分化标志物的 mRNA 丰度。
6-Me 处理可降低三种神经母细胞瘤 PDX 的增殖、活力和迁移，并诱导细胞周期停滞和分化。此外，6-Me 处理导致 CD133 表达降低、球体形成能力降低和 Oct4、Nanog 和 Sox2 的 mRNA 丰度降低，表明癌细胞干性降低。
6-Me 降低了神经母细胞瘤 PDX 的致癌性并减少了癌细胞干性，这使得进一步探索 6-Me 作为神经母细胞瘤的潜在新型治疗方法成为必要。
