The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas
The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas
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DOI：
10.1158/0008-5472.can-04-1813
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发表时间：
2004-11-01
期刊：
影响因子：
11.2
通讯作者：
Olson, JM
中科院分区：
文献类型：
--
作者：
Hallahan, AR;Pritchard, JI;Olson, JM
为了开发一种与目前最佳模型相比肿瘤发病率增加的遗传上可靠的髓母细胞瘤模型，我们通过在小鼠小脑颗粒神经元前体（ND 2：SmoA1小鼠）中转基因表达Smoothened的组成型活性形式来激活Sonic Hedgehog（Shh）通路。这导致早期小脑颗粒细胞过度增殖和髓母细胞瘤形成的发生率为48%。基因表达研究表明，已知的Shh靶点Gli1和Nmyc的增加与增生和肿瘤形成的增加相关。Notch 2和Notch靶基因HES5在Smoothened诱导的肿瘤中也显著升高，表明Shh途径活化足以诱导Notch途径信号传导。在人髓母细胞瘤中，Shh和Notch靶点的逆转录-PCR显示，与正常小脑相比，大多数肿瘤中这两条通路都被激活。用可溶性δ配体或γ分泌酶抑制剂抑制Notch途径导致髓母细胞瘤细胞系和原代肿瘤培养物中活细胞数显著减少。用γ分泌酶抑制剂治疗D283成神经管细胞瘤异种移植物的小鼠导致增殖减少和凋亡增加，证实Notch信号传导有助于人成神经管细胞瘤增殖和存活。ND2：SmoA1小鼠和人类的髓母细胞瘤伴随Shh和Notch通路活性的增加，这两者都有助于肿瘤存活。
To develop a genetically faithful model of medulloblastoma with increased tumor incidence compared with the current best model we activated the Sonic Hedgehog (Shh) pathway by transgenically expressing a constitutively active form of Smoothened in mouse cerebellar granule neuron precursors (ND2:SmoA1 mice). This resulted in early cerebellar granule cell hyper-proliferation and a 48% incidence of medulloblastoma formation. Gene expression studies showed an increase in the known Shh targets Gli1 and Nmyc that correlated with increasing hyperplasia and tumor formation. Notch2 and the Notch target gene, HES5, were also significantly elevated in Smoothened-induced tumors showing that Shh pathway activation is sufficient to induce Notch pathway signaling. In human medulloblastomas reverse transcription-PCR for Shh and Notch targets revealed activation of both of these pathways in most tumors when compared with normal cerebellum. Notch pathway inhibition with soluble Delta ligand or gamma secretase inhibitors resulted in a marked reduction of viable cell numbers in medulloblastoma cell lines and primary tumor cultures. Treatment of mice with D283 medulloblastoma xenografts with a gamma secretase inhibitor resulted in decreased proliferation and increased apoptosis, confirming that Notch signaling contributes to human medulloblastoma proliferation and survival. Medulloblastomas in ND2:SmoA1 mice and humans have concomitant increase in Shh and Notch pathway activities, both of which contribute to tumor survival.