Neuronal differentiation and synaptogenesis in retinoblastoma
Neuronal differentiation and synaptogenesis in retinoblastoma
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DOI：
10.1158/0008-5472.can-06-3754
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发表时间：
2007-03-15
期刊：
影响因子：
11.2
通讯作者：
Dyer, Michael A.
中科院分区：
文献类型：
--
作者：
Johnson, Dianna A.;Zhang, Jiakun;Dyer, Michael A.
视网膜母细胞瘤起源于子宫内发育中的视网膜，在生命的头几年被诊断出来。我们最近建立了一系列视网膜母细胞瘤基因敲除小鼠模型，概括了人类视网膜母细胞瘤的时间、位置和进展。这些临床前模型最重要的好处之一是我们可以研究肿瘤起始和扩张的最早阶段。这在人类视网膜母细胞瘤中是不可能的，因为肿瘤起源于子宫，直到晚期才被诊断出来。我们发现，小鼠视网膜母细胞瘤细胞表现出令人惊讶的分化程度，这在以往任何神经肿瘤中都没有报道过。早期小鼠视网膜母细胞瘤细胞表达正常存在于视网膜网状层的蛋白质。它们还延伸神经突起，形成突触。免疫组织化学染色、高尔基-考克斯染色、扫描电子显微镜和透射电子显微镜的特征表明，小鼠视网膜母细胞瘤细胞类似于视网膜的无长突/水平细胞。随着晚期视网膜母细胞瘤细胞的扩张和侵袭周围组织，它们失去了分化的形态，变得与人类视网膜母细胞瘤难以区分。综上所述，我们的数据表明，神经元分化是早期视网膜母细胞瘤的一个特征，随着细胞变得更具侵袭性和侵袭性而消失。我们还表明，玫瑰花环的形成并不像以前认为的那样是视网膜母细胞瘤分化的标志。相反，玫瑰花环的形成反映了早期(分化)和晚期(去分化)肿瘤中视网膜母细胞瘤细胞之间广泛的细胞-细胞接触。
Retinoblastomas initiate in the developing retina in utero and are diagnosed during the first few years of life. We have recently generated a series of knockout mouse models of retinoblastoma that recapitulate the timing, location, and progression of human retinoblastoma. One of the most important benefits of these preclinical models is that we can study the earliest stages of tumor initiation and expansion. This is not possible in human retinoblastoma because tumors initiate in utero and are not diagnosed until they are at an advanced stage. We found that mouse retinoblastoma cells exhibit a surprising degree of differentiation, which has not been previously reported for any neural tumor. Early-stage mouse retinoblastoma cells express proteins found normally in retinal plexiform layers. They also extend neurites and form synapses. All of these features, which were characterized by immunostaining, Golgi-Cox staining, scanning electron microscopy, and transmission electron microscopy, suggest that mouse retinoblastoma cells resemble amacrine/horizontal cells from the retina. As late-stage retinoblastoma cells expand and invade the surrounding tissue, they lose their differentiated morphology and become indistinguishable from human retinoblastomas. Taken together, our data suggest that neuronal differentiation is a hallmark of early-stage retinoblastoma and is lost as cells become more aggressive and invasive. We also show that rosette formation is not a hallmark of retinoblastoma differentiation, as previously believed. Instead, rosette formation reflects extensive cell-cell contacts between retinoblastoma cells in both early-stage (differentiated) and late-stage (dedifferentiated) tumors.