Lin Wensheng, Kemper April, McCarthy Ken D, Pytel Peter, Wang Jian-Ping, Campbell Iain L, Utset Manuel F, Popko Brian
Jack Miller Center for Peripheral Neuropathy, Department of Neurology, University of Chicago, Chicago, Illinois 60637, USA.
J Neurosci. 2004 Nov 10;24(45):10074-83. doi: 10.1523/JNEUROSCI.2604-04.2004.
We have generated a mouse model system with a high incidence of medulloblastoma, a malignant neoplasm believed to arise from immature precursors of cerebellar granule neurons. These animals ectopically express interferon-gamma (IFN-gamma) in astrocytes in the CNS in a controlled manner, exploiting the tetracycline-controllable system. More than 80% of these mice display severe ataxia and develop cerebellar tumors that express synaptophysin, the mouse atonal homolog MATH1, sonic hedgehog (SHH), and Gli1. IFN-gamma-induced tumorigenesis in these mice is associated with increased expression of SHH, and SHH induction and tumorigenesis are dependent on signal transducer and activator of transcription 1 (STAT1). When IFN-gamma expression is shut down with doxycycline at postnatal day 12 (P12), the clinical symptoms dissipate and the mice do not develop tumors, whereas if transgene expression is shut down at P16, the clinical symptoms and tumors progress to lethality, indicating that IFN-gamma is required for tumor induction but not progression. The tumors that occur in the continued presence of IFN-gamma display extensive necrosis and apoptosis as well as macrophage and lymphocytic infiltration, whereas the tumors that develop in mice in which IFN-gamma expression is shut down at P16 do not. Thus, IFN-gamma expression in the perinatal period can induce SHH expression and medulloblastoma in the cerebellum by a STAT1-dependent mechanism, and its continued presence appears to promote a host response to the tumor.
我们构建了一个髓母细胞瘤高发的小鼠模型系统，髓母细胞瘤是一种恶性肿瘤，被认为起源于小脑颗粒神经元的未成熟前体细胞。利用四环素可控系统，这些动物的中枢神经系统星形胶质细胞以可控方式异位表达干扰素-γ（IFN-γ）。超过80%的这些小鼠表现出严重共济失调，并发展出表达突触素、小鼠无调性同源物MATH1、音猬因子（SHH）和Gli1的小脑肿瘤。这些小鼠中IFN-γ诱导的肿瘤发生与SHH表达增加相关，并且SHH诱导和肿瘤发生依赖于信号转导及转录激活因子1（STAT1）。当在出生后第12天（P12）用强力霉素关闭IFN-γ表达时，临床症状消失，小鼠不会发生肿瘤，而如果在P16关闭转基因表达，临床症状和肿瘤会进展至致死，这表明IFN-γ是肿瘤诱导所必需的，但不是肿瘤进展所必需的。在IFN-γ持续存在的情况下发生的肿瘤表现出广泛的坏死和凋亡以及巨噬细胞和淋巴细胞浸润，而在P16时IFN-γ表达被关闭的小鼠中发生的肿瘤则没有这些表现。因此，围产期IFN-γ表达可通过STAT1依赖机制诱导小脑SHH表达和髓母细胞瘤，其持续存在似乎促进宿主对肿瘤的反应。
