MYCN Promotes the Expansion of Phox2B-Positive Neuronal Progenitors to Drive Neuroblastoma Development
MYCN Promotes the Expansion of Phox2B-Positive Neuronal Progenitors to Drive Neuroblastoma Development
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DOI：
10.2353/ajpath.2009.090019
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发表时间：
2009-08-01
影响因子：
6
通讯作者：
Ding, Han-Fei
中科院分区：
文献类型：
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作者：
Alam, Goleeta;Cui, Hongjuan;Ding, Han-Fei
癌基因MYCN扩增是神经母细胞瘤亚群发展中的致瘤事件，通常由未分化或低分化的神经母细胞组成；临床结果不佳。这些神经母细胞的细胞起源尚不清楚。此外，MYCN在神经母细胞瘤中的细胞功能和靶细胞。发展仍未确定。在这里，我们研究了驱动TH-MYCN转基因小鼠（人类疾病的动物模型）神经母细胞瘤发展的细胞类型。神经母细胞瘤。这些小鼠的发育始于出生后早期交感神经节的增生性病变。我们发现增生和原发性肿瘤主要由高度增殖的Phox2B（+）神经元祖细胞组成。MYCN通过促进这些祖细胞的增殖和阻止它们的分化来诱导它们的增殖。我们进一步在增生性病变和原发性肿瘤中发现少量未分化的巢蛋白（+）细胞，它们可能是Phox2B（+）神经元祖细胞的前体。这些发现确定了表征肿瘤表型的神经母细胞的身份，并提示MYCN可以通过细胞途径促进神经母细胞瘤的发展。（美国病理杂志2009,175:856-866;DOI: 10.2353/ajpath.2009.090019）
Amplification of the oncogene MYCN is a tumorigenic event in the development of a subset of neuroblastomas that commonly consist of undifferentiated or poorly differentiated neuroblasts; with unfavorable clinical outcome. The cellular origin of these neuroblasts is unknown. Additionally, the cellular functions and target cells of MYCN in neuroblastoma. development remain undefined. Here we examine the cell types that drive neuroblastoma development in TH-MYCN transgenic mice, an animal model of the human disease. Neuroblastoma. development in these mice begins with hyperplastic lesions in early postnatal sympathetic ganglia. We show that both hyperplasia and primary tumors are composed predominantly of highly proliferative Phox2B(+) neuronal progenitors. MYCN induces the expansion of these progenitors by both promoting their proliferation and preventing their differentiation. We further identify a minor population of undifferentiated nestin(+) cells in both hyperplastic lesions and primary tumors that may serve as precursors of Phox2B(+) neuronal progenitors. These findings establish the identity of neuroblasts that characterize the tumor phenotype and suggest a cellular pathway by which MYCN can promote neuroblastoma development. (Am J Pathol 2009, 175:856-866; DOI: 10.2353/ajpath.2009.090019)