神经胶质瘤干细胞中骨化三醇信号传导和敏感性的分子决定因素。
Molecular Determinants of Calcitriol Signaling and Sensitivity in Glioma Stem-like Cells.
发表日期:2023 Oct 31
作者:
Sarah Rehbein, Anna-Lena Possmayer, Süleyman Bozkurt, Catharina Lotsch, Julia Gerstmeier, Michael Burger, Stefan Momma, Claudia Maletzki, Carl Friedrich Classen, Thomas M Freiman, Daniel Dubinski, Katrin Lamszus, Brett W Stringer, Christel Herold-Mende, Christian Münch, Donat Kögel, Benedikt Linder
来源:
Experimental Hematology & Oncology
摘要:
胶质母细胞瘤是成人中最常见的原发性脑癌,也是对患者来说最糟糕的癌症诊断之一。由于预后不良和治疗选择有限,肿瘤复发几乎是不可避免的。此外,这种疾病的治疗耐药性很常见,并使预后恶化。据推测,这些因素和其他因素很大程度上是由于已知胶质母细胞瘤细胞能够获得干细胞样特征,从而驱动这些表型。最近,我们已经证明,用激素活性形式的维生素 D3、骨化三醇(1α,25(OH)2-维生素 D3)对胶质母细胞瘤干样细胞进行体外和离体治疗可以阻断部分细胞系的干细胞性并减少肿瘤生长。在这里,我们将细胞组扩展到 40 多种不同的培养物,并且可以表明,虽然一半的测试细胞系是敏感的,但四分之一可以归类为高反应细胞。通过遗传和蛋白质组学分析,我们进一步确定治疗成功可以部分地通过维生素 D3 受体的特定多态性来解释,并且高反应者表现出暗示干性阻断的蛋白质组以及迁移潜力。
Glioblastoma is the most common primary brain cancer in adults and represents one of the worst cancer diagnoses for patients. Suffering from a poor prognosis and limited treatment options, tumor recurrences are virtually inevitable. Additionally, treatment resistance is very common for this disease and worsens the prognosis. These and other factors are hypothesized to be largely due to the fact that glioblastoma cells are known to be able to obtain stem-like traits, thereby driving these phenotypes. Recently, we have shown that the in vitro and ex vivo treatment of glioblastoma stem-like cells with the hormonally active form of vitamin D3, calcitriol (1α,25(OH)2-vitamin D3) can block stemness in a subset of cell lines and reduce tumor growth. Here, we expanded our cell panel to over 40 different cultures and can show that, while half of the tested cell lines are sensitive, a quarter can be classified as high responders. Using genetic and proteomic analysis, we further determined that treatment success can be partially explained by specific polymorphism of the vitamin D3 receptor and that high responders display a proteome suggestive of blockade of stemness, as well as migratory potential.