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Developmental and oncogenic effects of Insulin-like Growth Factor-I in Ptc1+/- mouse cerebellum

机译：胰岛素样生长因子-I在Ptc1 +/-小鼠小脑中的发育和致癌作用

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Background Medulloblastoma is amongst the most common malignant brain tumors in childhood, arising from neoplastic transformation of granule neuron precursors (GNPs) of the cerebellum via deregulation of pathways involved in cerebellar development. Deregulation of the Sonic hedgehog/Patched1 (Shh/Ptc1) signaling pathway predisposes humans and mice to medulloblastoma. In the brain, insulin-like growth factor ( IGF-I ) plays a critical role during development as a neurotrophic and neuroprotective factor, and in tumorigenesis, as IGF-I receptor is often activated in medulloblastomas. Results To investigate the mechanisms of genetic interactions between Shh and IGF signaling in the cerebellum, we crossed nestin/ IGF-I transgenic ( IGF-I Tg) mice, in which transgene expression occurs in neuron precursors, with Ptc1 +/- knockout mice, a model of medulloblastoma in which cancer develops in a multistage process. The IGF-I transgene produced a marked brain overgrowth, and significantly accelerated tumor development, increasing the frequency of pre-neoplastic lesions as well as full medulloblastomas in Ptc1 +/- / IGF-I Tg mice. Mechanistically, tumor promotion by IGF-I mainly affected preneoplastic stages through de novo formation of lesions, while not influencing progression rate to full tumors. We also identified a marked increase in survival and proliferation, and a strong suppression of differentiation in neural precursors. Conclusions As a whole, our findings indicate that IGF-I overexpression in neural precursors leads to brain overgrowth and fosters external granular layer (EGL) proliferative lesions through a mechanism favoring proliferation over terminal differentiation, acting as a landscape for tumor growth. Understanding the molecular events responsible for cerebellum development and their alterations in tumorigenesis is critical for the identification of potential therapeutic targets.
机译：背景髓母细胞瘤是儿童时期最常见的恶性脑肿瘤之一，其源于小脑颗粒神经元前体（GNP）通过小脑发育相关通路的调控而发生的肿瘤转化。声波刺猬/ Patched1（Shh / Ptc1）信号通路的放松管制使人和小鼠容易患成髓母细胞瘤。在脑中，胰岛素样生长因子（IGF-I）在发育过程中作为神经营养和神经保护因子起着至关重要的作用，并且在肿瘤发生中也起着重要作用，因为髓母细胞瘤中经常会激活IGF-I受体。结果为了研究Shh和IGF信号在小脑之间的遗传相互作用的机制，我们将nestin / IGF-I转基因（IGF-I Tg）小鼠横渡，其中转基因在神经元前体中表达，Ptc1 +/- 敲除小鼠，一种髓母细胞瘤模型，其中癌症以多阶段过程发展。 IGF-I转基因产生了明显的脑过度生长，并显着加速了肿瘤的发展，增加了Ptc1肿瘤前病变以及全髓母细胞瘤的发生率 +/-

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