Assanah Marcela, Lochhead Richard, Ogden Alfred, Bruce Jeffrey, Goldman James, Canoll Peter
Department of Pathology, Columbia University, New York, New York 10032, USA.
J Neurosci. 2006 Jun 21;26(25):6781-90. doi: 10.1523/JNEUROSCI.0514-06.2006.
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.
为了测试成年神经胶质祖细胞的致胶质瘤潜能，我们用一种表达高水平血小板衍生生长因子（PDGF）和绿色荧光蛋白（GFP）的逆转录病毒感染成年大鼠的白质。感染后14天，100%的动物体内形成了与人类胶质母细胞瘤极为相似的肿瘤。令人惊讶的是，这些肿瘤由异质性细胞群体组成，其中表达逆转录病毒报告基因（GFP）的细胞不到20%。绝大多数GFP+和GFP-肿瘤细胞都表达神经胶质祖细胞的标志物。因此，这些肿瘤源于受感染和未受感染的神经胶质祖细胞的大量增殖，这表明PDGF通过自分泌和旁分泌刺激神经胶质祖细胞来驱动肿瘤形成。为了进一步探究这种可能性，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同注射。所形成的肿瘤包含红细胞（表达PDGF的/肿瘤起始细胞）和绿色细胞（募集的祖细胞）的混合物。这两种细胞群体都具有高度增殖性和浸润性。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，并且大多数受感染细胞沿着少突胶质细胞谱系分化。这些结果共同表明，成年白质祖细胞不仅具有产生胶质瘤的能力，而且驻留祖细胞会被募集到肿瘤的促有丝分裂环境中进行增殖，从而对构成恶性胶质瘤的异质性细胞团有显著贡献。
