Glial progenitors in adult white matter are driven to form malignant gliomas by platelet-derived growth factor-expressing retroviruses
Glial progenitors in adult white matter are driven to form malignant gliomas by platelet-derived growth factor-expressing retroviruses
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DOI：
10.1523/jneurosci.0514-06.2006
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发表时间：
2006-06-21
影响因子：
5.3
通讯作者：
Canoll, Peter
中科院分区：
文献类型：
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作者：
Assanah, Marcela;Lochhead, Richard;Canoll, Peter
为了测试成年神经胶质前体细胞的神经胶质生成潜能，我们用一种高水平表达PDGF和绿色荧光蛋白(GFP)的逆转录病毒感染成年大鼠白质。在感染14d后，100%的动物形成了与人类胶质母细胞瘤非常相似的肿瘤。令人惊讶的是，肿瘤是由不同种类的细胞组成的，其中20%表达逆转录病毒报告基因(GFP)。绝大多数GFP+和GFP-肿瘤细胞都表达神经胶质前体细胞的标志物。因此，肿瘤发生于感染和未感染的神经胶质前体细胞的大量扩张，这表明PDGF通过自分泌和旁分泌刺激神经胶质前体细胞而推动肿瘤的形成。为了进一步探索这种可能性，我们将表达PDGF-IRES-DsRed的逆转录病毒与仅表达GFP的对照逆转录病毒共注射。由此产生的肿瘤含有红细胞(表达PDGF/肿瘤启动细胞)和绿色细胞(招募的祖细胞)的混合物。两个种群都是高度增殖和浸润性的。相比之下，当单独注射对照GFP逆转录病毒时，动物从未形成肿瘤，大多数感染细胞沿着少突胶质细胞谱系分化。综上所述，这些结果表明，成年白质祖细胞不仅有能力产生胶质瘤，而且常驻祖细胞被招募在肿瘤的有丝分裂环境中增殖，并以这种方式显著促进构成恶性胶质瘤的异质细胞团。
To test the gliomagenic potential of adult glial progenitors, we infected adult rat white matter with a retrovirus that expresses high levels of PDGF and green fluorescent protein (GFP). Tumors that closely resembled human glioblastomas formed in 100% of the animals by 14 d postinfection. Surprisingly, the tumors were composed of a heterogeneous population of cells, < 20% of which expressed the retroviral reporter gene (GFP). The vast majority of both GFP+ and GFP- tumor cells expressed markers of glial progenitors. Thus, the tumors arose from the massive expansion of both infected and uninfected glial progenitors, suggesting that PDGF was driving tumor formation via autocrine and paracrine stimulation of glial progenitor cells. To explore this possibility further, we coinjected a retrovirus expressing PDGF-IRES-DsRed with a control retrovirus expressing only GFP. The resulting tumors contained a mixture of red cells (PDGF-expressing/tumor-initiating cells) and green cells (recruited progenitors). Both populations were highly proliferative and infiltrative. In contrast, when the control GFP retrovirus was injected alone, the animals never formed tumors and the majority of infected cells differentiated along the oligodendrocyte lineage. Together, these results reveal that adult white matter progenitors not only have the capacity to give rise to gliomas, but resident progenitors are recruited to proliferate within the mitogenic environment of the tumor and in this way contribute significantly to the heterogeneous mass of cells that compose a malignant glioma.