Medulloblastoma growth inhibition by Hedgehog pathway blockade
Medulloblastoma growth inhibition by Hedgehog pathway blockade
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DOI：
10.1126/science.1073733
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发表时间：
2002-08-30
期刊：
影响因子：
56.9
通讯作者：
Beachy, PA
中科院分区：
文献类型：
--
作者：
Berman, DM;Karhadkar, SS;Beachy, PA
组成性刺猬（Hh）信号通路活性与肿瘤形成的起始相关，但其在已形成肿瘤的持续生长中所起的作用尚不明确。在此，我们研究了Hh信号通路拮抗剂环巴胺在髓母细胞瘤临床前模型中的治疗效果，髓母细胞瘤是儿童中最常见的恶性脑肿瘤。环巴胺对小鼠髓母细胞瘤细胞的处理在体外抑制了增殖，并诱导了基因表达的变化，这些变化与神经元分化的起始以及神经元干细胞样特性的丧失相一致。这种化合物还在体内导致小鼠肿瘤同种异体移植物消退，并诱导新鲜切除的人髓母细胞瘤细胞快速死亡，但对其他脑肿瘤细胞无此作用，从而确定了Hh信号通路活性在髓母细胞瘤生长中的特定作用。
Constitutive Hedgehog (Hh) pathway activity is associated with initiation of neoplasia, but its role in the continued growth of established tumors is unclear. Here, we investigate the therapeutic efficacy of the Hh pathway antagonist cyclopamine in preclinical models of medulloblastoma, the most common malignant brain tumor in children. Cyclopamine treatment of murine medulloblastoma cells blocked proliferation in vitro and induced changes in gene expression consistent with initiation of neuronal differentiation and loss of neuronal stem cell like character. This compound also caused regression of murine tumor allografts in vivo and induced rapid death of cells from freshly resected human medulloblastomas, but not from other brain tumors, thus establishing a specific role for Hh pathway activity in medulloblastoma growth.