Targeted inhibition of the Hedgehog pathway in established malignant glioma xenografts enhances survival.
Targeted inhibition of the Hedgehog pathway in established malignant glioma xenografts enhances survival.
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DOI：
10.1038/onc.2009.208
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发表时间：
2009-10-01
期刊：
影响因子：
8
通讯作者：
Cooper, M. K.
中科院分区：
文献类型：
--
作者：
Sarangi, A.;Valadez, J. G.;Rush, S.;Abel, T. W.;Thompson, R. C.;Cooper, M. K.
Hedgehog通路活性已在恶性胶质瘤中得到证实。然而，其在肿瘤生长中的作用尚未确定。在这里，我们证明了在已建立的原位恶性胶质瘤异种移植物中，Hedgehog通路的药理学抑制赋予了生存优势。在移植的人肿瘤细胞中而不是在宿主小鼠脑中测量通路抑制。相应地，仅在具有操作性Hedgehog通路的肿瘤中观察到生存益处。这些数据表明Hedgehog信号传导调节选定恶性胶质瘤的生长。我们还证明了Hedgehog途径组分和基因靶向表达分离到CD133+肿瘤起始细胞。经治疗的小鼠最终死于疾病，因此靶向CD133+细胞中的Hedgehog途径产生显著但不完全的肿瘤消退。因此，我们的研究表明，更完全的肿瘤消退可能需要包括其他治疗靶点，包括CD133−细胞。
Hedgehog pathway activity has been demonstrated in malignant glioma. However, its role in tumor growth has not been determined. Here we demonstrate that pharmacological inhibition of the Hedgehog pathway in established orthotopic malignant glioma xenografts confers a survival advantage. Pathway inhibition is measured in transplanted human tumor cells and not in host mouse brain. Correspondingly, survival benefit is observed only in tumors with an operational Hedgehog pathway. These data indicate that Hedgehog signaling regulates the growth of select malignant gliomas. We also demonstrate that Hedgehog pathway component and gene target expression segregate to CD133+ tumor initiating cells. Treated mice eventually succumb to disease, thus targeting the Hedgehog pathway in CD133+ cells produces significant, but incomplete tumor regression. Therefore, our studies suggest that more complete tumor regression may require the inclusion of other therapeutic targets, including CD133− cells.
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