Grimmer Matthew R, Weiss William A
Department of Neurology, University of California, San Francisco, CA 94143, USA.
Curr Opin Pediatr. 2006 Dec;18(6):634-8. doi: 10.1097/MOP.0b013e32801080fe.
Advances in tumor genetics have increasingly linked pediatric neoplasms with disordered mechanisms of normal development, supporting the model of embryonal tumorigenesis. We provide a detailed discussion of two pediatric neural tumors, medulloblastoma and neuroblastoma, addressing tumorigenic causality and similarities within a pharmacological context.
Expression profiling, elegant murine models, and chemical blockades of oncogenic signaling pathways have encouraged a new generation of therapeutic approaches for tumor treatment. Recent data have further clarified regulation of neural developmental and factors triggering malignancy.
Medulloblastoma and neuroblastoma exemplify the current embryonal tumor model. Sonic hedgehog signaling is required for cerebellar development and its dysregulation is implicated in formation of medulloblastoma. The transcription factor Mycn orchestrates proliferation and differentiation of the developing peripheral neural crest. Amplification of the MYCN gene is the predominant marker for aggressive neuroblastoma, and correlates with poor prognosis. Current evidence suggests that Mycn is also the primary executor of Sonic hedgehog signaling in the cerebellum and that the Sonic hedgehog pathway regulates levels of both MYCN mRNA and Mycn protein product independently. Destabilization of Myc through inhibition of phosphoinositide 3-kinase signaling exhibits promise not only in medulloblastoma and neuroblastoma, but in a wide range of Myc-driven tumors.
肿瘤遗传学的进展越来越多地将儿童肿瘤与正常发育的紊乱机制联系起来，支持胚胎肿瘤发生模型。我们详细讨论两种儿童神经肿瘤——髓母细胞瘤和神经母细胞瘤，在药理学背景下探讨致瘤因果关系及相似性。
表达谱分析、精妙的小鼠模型以及致癌信号通路的化学阻断推动了新一代肿瘤治疗方法的发展。近期数据进一步阐明了神经发育的调控以及引发恶性肿瘤的因素。
髓母细胞瘤和神经母细胞瘤是当前胚胎肿瘤模型的典型代表。音猬因子信号通路对小脑发育至关重要，其失调与髓母细胞瘤的形成有关。转录因子Mycn协调发育中的外周神经嵴的增殖和分化。MYCN基因扩增是侵袭性神经母细胞瘤的主要标志物，与预后不良相关。目前的证据表明，Mycn也是小脑音猬因子信号通路的主要执行者，且音猬因子通路独立调节MYCN mRNA和Mycn蛋白产物的水平。通过抑制磷酸肌醇3激酶信号通路使Myc失稳不仅在髓母细胞瘤和神经母细胞瘤中显示出前景，在多种由Myc驱动的肿瘤中也有前景。
