Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma
Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma
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DOI：
10.1073/pnas.1101657108
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发表时间：
2011-03-15
影响因子：
11.1
通讯作者：
Beachy, Philip A.
中科院分区：
文献类型：
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作者：
Monje, Michelle;Mitra, Siddhartha S.;Beachy, Philip A.
弥漫性内在脑桥胶质瘤（dipg）是一种高度侵袭性的儿童肿瘤，几乎是普遍致命的。由于缺乏可用的研究组织和缺乏忠实的动物模型，我们对这种毁灭性癌症的了解受到限制。有趣的是，dipg局限于脑桥腹侧，发生在童年中期的一个狭窄窗口，表明出生后神经发育过程失调。在这里，我们报告了先前在人类和小鼠脑干中发现的免疫表型神经前体细胞群，其时间和空间分布与DIPG的发病率密切相关，并强调了一个候选细胞的起源。利用早期死后的DIPG肿瘤组织，我们建立了体外和异种移植模型，发现参与许多发育和致癌过程的Hedgehog （Hh）信号通路在DIPG肿瘤细胞中是活跃的。Hh通路活性的调节对神经球培养中DIPG自我更新能力具有功能性影响。Hh通路在小鼠正常的腹侧脑桥前体样细胞中似乎也很活跃，不受调节的通路活性导致腹侧脑桥肥大。总之，这些发现为理解DIPG的细胞和分子起源提供了基础，并表明Hh通路代表了这种破坏性儿童肿瘤的潜在治疗靶点。
Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG self-renewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.