Yokoo Hideaki, Tanaka Yuko, Nobusawa Sumihito, Nakazato Yoichi, Ohgaki Hiroko
Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Neuropathology. 2008 Dec;28(6):591-8. doi: 10.1111/j.1440-1789.2008.00923.x. Epub 2008 May 21.
Transgenic rats expressing v-erbB (viral form of the EGF receptor) under transcriptional regulation by the S100beta promoter develop brain tumors (Ohgaki et al. J Neuropathol Experimental Neurol 65: 1111-1117, 2006). In the present study, we carried out detailed immunohistochemical and ultrastructural characterization of the brain tumors that developed in these rats. Of 49 homozygous transgenic rats between 16 and 94 weeks of age (mean, 59 weeks), 31 rats were autopsied because they showed severe neurological symptoms and/or became moribund. Among these, 30 rats had brain tumors, which were classified histologically as malignant glioma, anaplastic oligodendroglioma, and low-grade oligodendroglioma. Six transgenic rats developed two different histologic types of brain tumor, which were considered to be of multiclonal origin, because of the lack of histological transitions. All brain tumors contained neoplastic cells immunoreactive for S100 and GFAP. Diffuse immunoreactivity for Olig2 and Nkx2.2 was observed in neoplastic cells in all seven anaplastic oligodendrogliomas and in all three low-grade oligodendrogliomas analyzed, but in none of 26 malignant gliomas. Electron microscopy, carried out on four malignant gliomas and four anaplastic oligodendrogliomas, revealed the presence of intermediate filament bundles devoid of side arms, indicating glial differentiation. There was no evidence of cilia, microvilli, neurosecretory granules, synaptic structures or neurofilaments, excluding the possibility of ependymal or neuronal tumors. The present study thus provides additional evidence that the brain tumors developing in S100beta-v-erbB transgenic rats are of glial origin, with or without oligodendroglial differentiation. Reproducible development of three distinct histologic types of brain tumor in unique localizations may be explained by activation of the v-erbB transgene driven by the S100beta promoter in specific precursor cells during development of the brain. Thus, S100beta-v-erbB transgenic rats may be useful to study the histogenesis and molecular mechanisms of development of glial tumors due to disruption of the EGFR pathway.
在S100β启动子的转录调控下表达v-erbB（表皮生长因子受体的病毒形式）的转基因大鼠会发生脑肿瘤（Ohgaki等人，《神经病理学与实验神经病学杂志》65: 1111 - 1117, 2006）。在本研究中，我们对这些大鼠所发生的脑肿瘤进行了详细的免疫组织化学和超微结构特征分析。在49只16至94周龄（平均59周）的纯合转基因大鼠中，31只因出现严重神经症状和/或濒死而进行了尸检。其中，30只大鼠患有脑肿瘤，组织学上分为恶性胶质瘤、间变性少突胶质细胞瘤和低级别少突胶质细胞瘤。6只转基因大鼠发生了两种不同组织学类型的脑肿瘤，由于缺乏组织学过渡变化，被认为是多克隆起源。所有脑肿瘤均含有对S100和GFAP呈免疫反应性的肿瘤细胞。在所有7例分析的间变性少突胶质细胞瘤和所有3例低级别少突胶质细胞瘤中的肿瘤细胞中观察到了Olig2和Nkx2.2的弥漫性免疫反应性，但在26例恶性胶质瘤中均未观察到。对4例恶性胶质瘤和4例间变性少突胶质细胞瘤进行的电子显微镜检查显示存在没有侧臂的中间丝束，表明为胶质细胞分化。没有发现纤毛、微绒毛、神经分泌颗粒、突触结构或神经丝的证据，排除了室管膜瘤或神经源性肿瘤的可能性。因此本研究提供了额外证据，表明S100β - v-erbB转基因大鼠所发生的脑肿瘤起源于胶质细胞，并伴有或不伴有少突胶质细胞分化。在独特定位处可重复性地发生三种不同组织学类型脑肿瘤，这可能是由于在脑发育过程中S...
