Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma
Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma
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DOI：
10.1634/stemcells.2007-0166
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发表时间：
2007-01-01
期刊：
影响因子：
5.2
通讯作者：
Eberharta, Charles G.
中科院分区：
文献类型：
--
作者：
Bar, Eli E.;Chaudhry, Aneeka;Eberharta, Charles G.
脑肿瘤可以在脑发育期间正常激活的信号通路失调后产生，并且可能来自神经干细胞。鉴于非肿瘤干细胞对Hedgehog的需求，我们研究了Hedgehog阻断是否可以靶向多形性胶质母细胞瘤（GBM）中的干细胞样群体。我们发现，Gli 1，一个关键的刺猬途径的目标，是高度表达的19个主要GBM中的5个和7个GBM细胞系中的4个。Shh配体在一些原发性肿瘤和GBM衍生的神经球中表达，表明了通路激活的潜在机制。Hedgehog通路阻断环巴胺导致40%-60%的生长减少粘附胶质瘤细胞系高表达Gli 1，但不是在那些缺乏证据的通路活性。当GBM衍生的神经球用环巴胺处理，然后解离并接种在缺乏抑制剂的培养基中时，没有新的神经球形成，表明克隆源性癌症干细胞已经耗尽。与这一假设一致，胶质瘤中的干样部分标记的醛脱氢酶活性和Hoechst染料排泄（侧人口）显着减少或消除环巴胺。相反，我们发现GBM神经球的放射治疗增加了这些干细胞样细胞的百分比，这表明这种标准疗法优先靶向分化较好的肿瘤细胞。最重要的是，在Hedgehog阻断后颅内注射的活GBM细胞不再能够在无胸腺小鼠中形成肿瘤，这表明对持续生长至关重要的癌症干细胞群已经被去除。
Brain tumors can arise following deregulation of signaling pathways normally activated during brain development and may derive from neural stem cells. Given the requirement for Hedgehog in non-neoplastic stem cells, we investigated whether Hedgehog blockade could target the stem-like population in glioblastoma multiforme ( GBM). We found that Gli1, a key Hedgehog pathway target, was highly expressed in 5 of 19 primary GBM and in 4 of 7 GBM cell lines. Shh ligand was expressed in some primary tumors, and in GBM-derived neurospheres, suggesting a potential mechanism for pathway activation. Hedgehog pathway blockade by cyclopamine caused a 40%-60% reduction in growth of adherent glioma lines highly expressing Gli1 but not in those lacking evidence of pathway activity. When GBM-derived neurospheres were treated with cyclopamine and then dissociated and seeded in media lacking the inhibitor, no new neurospheres formed, suggesting that the clonogenic cancer stem cells had been depleted. Consistent with this hypothesis, the stem-like fraction in gliomas marked by both aldehyde dehydrogenase activity and Hoechst dye excretion ( side population) was significantly reduced or eliminated by cyclopamine. In contrast, we found that radiation treatment of our GBM neurospheres increased the percentage of these stemlike cells, suggesting that this standard therapy preferentially targets better-differentiated neoplastic cells. Most importantly, viable GBM cells injected intracranially following Hedgehog blockade were no longer able to form tumors in athymic mice, indicating that a cancer stem cell population critical for ongoing growth had been removed.