Olson Melissa V, Johnson David G, Jiang Hong, Xu Jing, Alonso Marta M, Aldape Kenneth D, Fuller Gregory N, Bekele B Nebiyou, Yung W K Alfred, Gomez-Manzano Candelaria, Fueyo Juan
Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Res. 2007 May 1;67(9):4005-9. doi: 10.1158/0008-5472.CAN-06-2973.
The Rb/E2F pathway is deregulated in most human brain tumors, and the finding that loss of E2F1 reduced pituitary tumorigenesis in Rb(+/-) mice suggests that loss of pRb induces brain tumors by activating E2F1. We therefore investigated the role of E2F1 in the development and maintenance of brain cancer using a transgenic mouse model engineered to express E2F1 specifically within glial cells (GFAP-tgE2F1). GFAP-tgE2F1 mice developed a highly penetrant phenotype characterized by neurologic defects, and examination of the brains revealed the presence of brain tumors in 20% of these animals. Importantly, the distribution of tumors according to mouse age suggests the existence of a bimodal pattern of tumor development, forcing a comparison with the human disease. Mice, at an early age, with deregulated E2F1 show the formation of embryonal brain tumors such as medulloblastoma, choroid plexus carcinoma, and primary neuroectodermal tumor. Conversely, at an older age, mice escaping embryonal tumor formation present with malignant gliomas, which are typically identified in the human adult population. Thus, this study offers the first evidence for a global role of E2F1 in the formation and maintenance of multilineage brain tumors, irrefutably establishing E2F1 as an oncogene in the brain.
在大多数人类脑肿瘤中，Rb/E2F信号通路失调，并且E2F1缺失可降低Rb(+/-)小鼠垂体肿瘤发生的这一发现表明，pRb缺失通过激活E2F1诱导脑肿瘤发生。因此，我们利用一种经过基因工程改造的转基因小鼠模型（GFAP-tgE2F1）来研究E2F1在脑癌发生和维持过程中的作用，该模型可在神经胶质细胞中特异性表达E2F1。GFAP-tgE2F1小鼠表现出一种高度显性的表型，其特征为神经功能缺陷，对这些小鼠的脑部检查发现，其中20%的动物存在脑肿瘤。重要的是，根据小鼠年龄的肿瘤分布情况表明存在肿瘤发生的双峰模式，这促使人们将其与人类疾病进行比较。幼年时E2F1失调的小鼠会形成胚胎性脑肿瘤，如髓母细胞瘤、脉络丛癌和原发性神经外胚层肿瘤。相反，在老年时，未发生胚胎性肿瘤的小鼠会出现恶性胶质瘤，这在人类成年人群中较为常见。因此，本研究首次证明了E2F1在多谱系脑肿瘤形成和维持过程中的全局性作用，无可辩驳地确立了E2F1作为脑内癌基因的地位。
