Expression of MYCN in Multipotent Sympathoadrenal Progenitors Induces Proliferation and Neural Differentiation, but Is Not Sufficient for Tumorigenesis.
Expression of MYCN in Multipotent Sympathoadrenal Progenitors Induces Proliferation and Neural Differentiation, but Is Not Sufficient for Tumorigenesis.
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DOI：
10.1371/journal.pone.0133897
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Carter BD
中科院分区：
文献类型：
--
作者：
Mobley BC;Kwon M;Kraemer BR;Hickman FE;Qiao J;Chung DH;Carter BD
神经母细胞瘤是小儿交感神经节和肾上腺的恶性肿瘤，假设起源于发育中的交感神经系统的祖细胞。MYCN癌基因的扩增是这种疾病风险的遗传标记。了解癌基因表达对交感肾上腺祖细胞发育的影响可能会提高我们对神经母细胞瘤发生和进展的认识。我们从出生后的小鼠肾上腺中分离出交感肾上腺祖细胞，通过球体培养，发现它们是多能的，产生分化的神经元、雪旺细胞和肌成纤维细胞集落。MYCN在球体中的过表达促进了对神经谱系的承诺，这由含神经元集落的频率增加证明。MYCN促进交感肾上腺祖细胞球和来自这些球的分化神经元的增殖，但也有凋亡的增加。MYCN诱导的增殖、凋亡和神经谱系定型具有肿瘤样特征，从而支持多能肾上腺髓质祖细胞是神经母细胞瘤起源细胞的假设。然而，我们发现MYCN过表达不足以使这些细胞在裸鼠中形成肿瘤，这表明额外的转化突变是肿瘤发生所必需的。
Neuroblastoma is a pediatric malignancy of the sympathetic ganglia and adrenal glands, hypothesized to originate from progenitors of the developing sympathetic nervous system. Amplification of the MYCN oncogene is a genetic marker of risk in this disease. Understanding the impact of oncogene expression on sympathoadrenal progenitor development may improve our knowledge of neuroblastoma initiation and progression. We isolated sympathoadrenal progenitor cells from the postnatal murine adrenal gland by sphere culture and found them to be multipotent, generating differentiated colonies of neurons, Schwann cells, and myofibroblasts. MYCN overexpression in spheres promoted commitment to the neural lineage, evidenced by an increased frequency of neuron-containing colonies. MYCN promoted proliferation of both sympathoadrenal progenitor spheres and differentiated neurons derived from these spheres, but there was also an increase in apoptosis. The proliferation, apoptosis, and neural lineage commitment induced by MYCN are tumor-like characteristics and thereby support the hypothesis that multipotent adrenal medullary progenitor cells are cells of origin for neuroblastoma. We find, however, that MYCN overexpression is not sufficient for these cells to form tumors in nude mice, suggesting that additional transforming mutations are necessary for tumorigenesis.