Lindberg Nanna, Jiang Yiwen, Xie Yuan, Bolouri Hamid, Kastemar Marianne, Olofsson Tommie, Holland Eric C, Uhrbom Lene
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, SE-75185 Uppsala, Sweden, Department of Cancer Biology and Genetics, and The Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, Human Biology Division and Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, SE-75185 Uppsala, Sweden.
J Neurosci. 2014 Oct 29;34(44):14644-51. doi: 10.1523/JNEUROSCI.2977-14.2014.
Stem cells, believed to be the cellular origin of glioma, are able to generate gliomas, according to experimental studies. Here we investigated the potential and circumstances of more differentiated cells to generate glioma development. We and others have shown that oligodendrocyte precursor cells (OPCs) can also be the cell of origin for experimental oligodendroglial tumors. However, the question of whether OPCs have the capacity to initiate astrocytic gliomas remains unanswered. Astrocytic and oligodendroglial tumors represent the two most common groups of glioma and have been considered as distinct disease groups with putatively different origins. Here we show that mouse OPCs can give rise to both types of glioma given the right circumstances. We analyzed tumors induced by K-RAS and AKT and compared them to oligodendroglial platelet-derived growth factor B-induced tumors in Ctv-a mice with targeted deletions of Cdkn2a (p16(Ink4a-/-), p19(Arf-/-), Cdkn2a(-/-)). Our results showed that glioma can originate from OPCs through overexpression of K-RAS and AKT when combined with p19(Arf) loss, and these tumors displayed an astrocytic histology and high expression of astrocytic markers. We argue that OPCs have the potential to develop both astrocytic and oligodendroglial tumors given loss of p19(Arf), and that oncogenic signaling is dominant to cell of origin in determining glioma phenotype. Our mouse data are supported by the fact that human astrocytoma and oligodendroglioma display a high degree of overlap in global gene expression with no clear distinctions between the two diagnoses.
根据实验研究，干细胞被认为是胶质瘤的细胞起源，能够生成胶质瘤。在此，我们研究了分化程度更高的细胞产生胶质瘤发展的可能性及条件。我们和其他人已经表明，少突胶质前体细胞（OPCs）也可能是实验性少突胶质细胞瘤的起源细胞。然而，OPCs是否有能力引发星形胶质细胞瘤这一问题仍未得到解答。星形胶质细胞瘤和少突胶质细胞瘤是胶质瘤中最常见的两类，一直被认为是起源可能不同的不同疾病组。在此我们表明，在合适的条件下，小鼠OPCs能够产生这两种类型的胶质瘤。我们分析了由K-RAS和AKT诱导的肿瘤，并将其与Ctv-a小鼠中靶向缺失Cdkn2a（p16(Ink4a-/-)、p19(Arf-/-)、Cdkn2a(-/-)）的少突胶质血小板衍生生长因子B诱导的肿瘤进行比较。我们的结果表明，当与p19(Arf)缺失相结合时，胶质瘤可通过K-RAS和AKT的过表达起源于OPCs，并且这些肿瘤表现出星形胶质细胞组织学特征和星形胶质细胞标志物的高表达。我们认为，在p19(Arf)缺失的情况下，OPCs有产生星形胶质细胞瘤和少突胶质细胞瘤的潜力，并且在确定胶质瘤表型方面，致癌信号比起源细胞更具主导性。我们的小鼠实验数据得到了以下事实的支持：人类星形细胞瘤和少突胶质细胞瘤在整体基因表达上有高度重叠，两种诊断之间没有明显区别。
