PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo
PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo
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DOI：
10.1101/gad.903001
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发表时间：
2001-08-01
影响因子：
10.5
通讯作者：
Holland, EC
中科院分区：
文献类型：
--
作者：
Dai, C;Celestino, JC;Holland, EC
我们提供的证据表明，一些低级别少突胶质细胞瘤可能由增殖的神经胶质祖细胞组成，这些细胞的分化能力受阻，而恶性胶质瘤还获得了其他突变，例如因Ink4a - Arf缺失导致细胞周期停滞通路中断。我们通过血小板衍生生长因子受体（PDGFR）产生神经胶质的自分泌刺激，在细胞培养和小鼠中模拟了这些效应。在细胞培养中，PDGF信号传导诱导神经胶质前体细胞增殖，并阻止它们分化为少突胶质细胞和星形胶质细胞。此外，在人类胶质瘤中已证实PDGF和PDGF受体共表达，这意味着自分泌刺激可能参与胶质瘤的形成。在这项研究中，利用体细胞类型特异性基因转移，我们通过在细胞培养和体内将PDGF - β的过表达转移到表达巢蛋白的神经祖细胞或表达胶质纤维酸性蛋白（GFAP）的星形胶质细胞中，研究了PDGF自分泌信号在胶质瘤发生中的作用。在培养的星形胶质细胞中，PDGF - β的过表达导致星形胶质细胞和神经祖细胞的增殖率显著增加。此外，PDGF基因转移将培养的星形胶质细胞转化为具有神经胶质前体细胞形态和基因表达特征的细胞。在体内，将PDGF基因转移到神经祖细胞中，在约60%的小鼠12周龄时诱导形成少突胶质细胞瘤；在同一时期，将PDGF转移到星形胶质细胞中，在约40%的小鼠中诱导形成少突胶质细胞瘤或混合性少突 - 星形细胞瘤。Ink4a - Arf的缺失是在高级别人类胶质瘤中经常发现的一种突变，它导致胶质瘤潜伏期缩短和恶性程度增加。PDGF诱导的恶性胶质瘤比例最高的来自Ink4a - Arf缺失的祖细胞。这些数据表明，慢性自分泌PDGF信号传导可促进神经胶质前体细胞的增殖群体，并且可能足以诱导胶质瘤发生。Ink4a - Arf的缺失对于PDGF诱导的胶质瘤形成不是必需的，但可促进肿瘤向更恶性的表型进展。
We present evidence that some low-grade oligodendrogliomas may be comprised of proliferating glial progenitor cells that are blocked in their ability to differentiate, whereas malignant gliomas have additionally acquired other mutations such as disruption of cell cycle arrest pathways by loss of Ink4a-Arf. We have modeled these effects in cell culture and in mice by generating autocrine stimulation of glia through the platelet-derived growth factor receptor (PDGFR). In cell culture, PDGF signaling induces proliferation of glial precursors and blocks their differentiation into oligodendrocytes and astrocytes. In addition, coexpression of PDGF and PDGF receptors has been demonstrated in human gliomas, implying that autocrine stimulation may be involved in glioma formation. In this study, using somatic cell type-specific gene transfer we investigated the functions of PDGF autocrine signaling in gliomagenesis by transferring the overexpression of PDGF-beta into either nestin-expressing neural progenitors or glial fibrillary acidic protein (GFAP)-expressing astrocytes both in cell culture and in vivo. In cultured astrocytes, overexpression of PDGF-beta caused significant increase in proliferation rate of both astrocytes and neural progenitors. Furthermore, PDGF gene transfer converted cultured astrocytes into cells with morphologic and gene expression characteristics of glial precursors. In vivo, gene transfer of PDGF to neural progenitors induced the formation of oligodendrogliomas in about 60% of mice by 12 wk of age; PDGF transfer to astrocytes induced the formation of either oligodendrogliomas or mixed oligoastrocytomas in about 40% of mice in the same time period. Loss of Ink4a-Arf, a mutation frequently found in high-grade human gliomas, resulted in shortened latency and enhanced malignancy of gliomas. The highest percentage of PDGF-induced malignant gliomas arose from of Ink4a-Arf null progenitor cells. These data suggest that chronic autocrine PDGF signaling can promote a proliferating population of glial precursors and is potentially sufficient to induce gliomagenesis. Loss of Ink4a-Arf is not required for PDGF-induced glioma formation but promotes tumor progression toward a more malignant phenotype.