Balça-Silva Joana, Matias Diana, Dubois Luiz Gustavo, Carneiro Brenno, do Carmo Anália, Girão Henrique, Ferreira Fernanda, Ferrer Valeria Pereira, Chimelli Leila, Filho Paulo Niemeyer, Tão Hermínio, Rebelo Olinda, Barbosa Marcos, Sarmento-Ribeiro Ana Bela, Lopes Maria Celeste, Moura-Neto Vivaldo
Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences (CNC.IBILI), Coimbra, Portugal; Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal; Instituto Estadual do Cérebro Paulo Niemeyer (IECPN)-Secretaria de Estado de Saúde, Rio de Janeiro, Brazil.
Instituto Estadual do Cérebro Paulo Niemeyer (IECPN)-Secretaria de Estado de Saúde, Rio de Janeiro, Brazil; Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Transl Oncol. 2017 Aug;10(4):555-569. doi: 10.1016/j.tranon.2017.04.005. Epub 2017 Jun 24.
Glioblastoma (GBM) is the most malignant primary brain tumor, with an average survival rate of 15 months. GBM is highly refractory to therapy, and such unresponsiveness is due, primarily, but not exclusively, to the glioma stem-like cells (GSCs). This subpopulation express stem-like cell markers and is responsible for the heterogeneity of GBM, generating multiple differentiated cell phenotypes. However, how GBMs maintain the balance between stem and non-stem populations is still poorly understood. We investigated the GBM ability to interconvert between stem and non-stem states through the evaluation of the expression of specific stem cell markers as well as cell communication proteins. We evaluated the molecular and phenotypic characteristics of GSCs derived from differentiated GBM cell lines by comparing their stem-like cell properties and expression of connexins. We showed that non-GSCs as well as GSCs can undergo successive cycles of gain and loss of stem properties, demonstrating a bidirectional cellular plasticity model that is accompanied by changes on connexins expression. Our findings indicate that the interconversion between non-GSCs and GSCs can be modulated by extracellular factors culminating on differential expression of stem-like cell markers and cell-cell communication proteins. Ultimately, we observed that stem markers are mostly expressed on GBMs rather than on low-grade astrocytomas, suggesting that the presence of GSCs is a feature of high-grade gliomas. Together, our data demonstrate the utmost importance of the understanding of stem cell plasticity properties in a way to a step closer to new strategic approaches to potentially eliminate GSCs and, hopefully, prevent tumor recurrence.
胶质母细胞瘤（GBM）是最恶性的原发性脑肿瘤，平均生存率为15个月。GBM对治疗具有高度难治性，而这种无反应性主要但并非唯一地归因于胶质瘤干细胞样细胞（GSCs）。这一亚群表达干细胞样细胞标志物，并导致GBM的异质性，产生多种分化的细胞表型。然而，GBM如何维持干细胞和非干细胞群体之间的平衡仍知之甚少。我们通过评估特定干细胞标志物以及细胞通讯蛋白的表达，研究了GBM在干细胞和非干细胞状态之间相互转换的能力。我们通过比较其干细胞样细胞特性和连接蛋白的表达，评估了源自分化GBM细胞系的GSCs的分子和表型特征。我们发现非GSCs以及GSCs都可以经历干细胞特性的获得和丧失的连续循环，证明了一种双向细胞可塑性模型，该模型伴随着连接蛋白表达的变化。我们的研究结果表明，非GSCs和GSCs之间的相互转换可以由细胞外因子调节，最终导致干细胞样细胞标志物和细胞间通讯蛋白的差异表达。最终，我们观察到干细胞标志物大多在GBM上表达，而不是在低级别星形细胞瘤上表达，这表明GSCs的存在是高级别胶质瘤的一个特征。总之，我们的数据表明，理解干细胞可塑性特性对于接近潜在消除GSCs并有望预防肿瘤复发的新战略方法至关重要。
