Authors' Affiliations: Department of Biotechnology and Biosciences, University of Milano-Bicocca; Department of Molecular Neuro-Oncology, Fondazione I.R.C.C.S. Istituto Neurologico C.Besta; Department of Experimental Oncology, European Institute of Oncology at IFOM-IEO Campus; Tissue Processing Unit, The FIRC Institute of Molecular Oncology Foundation-IFOM, IFOM-IEO Campus, Milano; and IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Cancer Res. 2014 Mar 15;74(6):1833-44. doi: 10.1158/0008-5472.CAN-13-1942. Epub 2014 Mar 5.
The stem cell-determining transcription factor Sox2 is required for the maintenance of normal neural stem cells. In this study, we investigated the requirement for Sox2 in neural cancer stem-like cells using a conditional genetic deletion mutant in a mouse model of platelet-derived growth factor-induced malignant oligodendroglioma. Transplanting wild-type oligodendroglioma cells into the brain generated lethal tumors, but mice transplanted with Sox2-deleted cells remained free of tumors. Loss of the tumor-initiating ability of Sox2-deleted cells was reversed by lentiviral-mediated expression of Sox2. In cell culture, Sox2-deleted tumor cells were highly sensitive to differentiation stimuli, displaying impaired proliferation, increased cell death, and aberrant differentiation. Gene expression analysis revealed an early transcriptional response to Sox2 loss. The observed requirement of oligodendroglioma stem cells for Sox2 suggested its relevance as a target for therapy. In support of this possibility, an immunotherapeutic approach based on immunization of mice with SOX2 peptides delayed tumor development and prolonged survival. Taken together, our results showed that Sox2 is essential for tumor initiation by mouse oligodendroglioma cells, and they illustrated a Sox2-directed strategy of immunotherapy to eradicate tumor-initiating cells.
干细胞决定转录因子 Sox2 对于维持正常神经干细胞是必需的。在这项研究中，我们使用血小板衍生生长因子诱导的恶性少突胶质细胞瘤的小鼠模型中的条件遗传缺失突变体，研究 Sox2 在神经癌干细胞样细胞中的需求。将野生型少突胶质细胞瘤细胞移植到大脑中会产生致命的肿瘤，但接受 Sox2 缺失细胞移植的小鼠没有肿瘤。通过慢病毒介导的 Sox2 表达，缺失的肿瘤起始能力恢复。在细胞培养中，Sox2 缺失的肿瘤细胞对分化刺激高度敏感，表现出增殖受损、细胞死亡增加和异常分化。基因表达分析显示 Sox2 缺失后的早期转录反应。观察到少突胶质细胞瘤干细胞对 Sox2 的需求表明其作为治疗靶点的相关性。支持这种可能性，基于用 SOX2 肽免疫小鼠的免疫治疗方法延迟了肿瘤的发展并延长了存活期。总之，我们的研究结果表明 Sox2 对于小鼠少突胶质细胞瘤细胞的肿瘤起始是必需的，并且说明了 Sox2 指导的免疫疗法策略来根除肿瘤起始细胞。
