Developmental origins and oncogenic pathways in malignant brain tumors.

Q1 Biochemistry, Genetics and Molecular Biology
Q Richard Lu, Lily Qian, Xianyao Zhou
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引用次数: 34

Abstract

Brain tumors such as adult glioblastomas and pediatric high-grade gliomas or medulloblastomas are among the leading causes of cancer-related deaths, exhibiting poor prognoses with little improvement in outcomes in the past several decades. These tumors are heterogeneous and can be initiated from various neural cell types, contributing to therapy resistance. How such heterogeneity arises is linked to the tumor cell of origin and their genetic alterations. Brain tumorigenesis and progression recapitulate key features associated with normal neurogenesis; however, the underlying mechanisms are quite dysregulated as tumor cells grow and divide in an uncontrolled manner. Recent comprehensive genomic, transcriptomic, and epigenomic studies at single-cell resolution have shed new light onto diverse tumor-driving events, cellular heterogeneity, and cells of origin in different brain tumors. Primary and secondary glioblastomas develop through different genetic alterations and pathways, such as EGFR amplification and IDH1/2 or TP53 mutation, respectively. Mutations such as histone H3K27M impacting epigenetic modifications define a distinct group of pediatric high-grade gliomas such as diffuse intrinsic pontine glioma. The identification of distinct genetic, epigenomic profiles and cellular heterogeneity has led to new classifications of adult and pediatric brain tumor subtypes, affording insights into molecular and lineage-specific vulnerabilities for treatment stratification. This review discusses our current understanding of tumor cells of origin, heterogeneity, recurring genetic and epigenetic alterations, oncogenic drivers and signaling pathways for adult glioblastomas, pediatric high-grade gliomas, and medulloblastomas, the genetically heterogeneous groups of malignant brain tumors. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion Signaling Pathways > Cell Fate Signaling.

Abstract Image

恶性脑肿瘤的发育起源和致癌途径。
脑肿瘤,如成人胶质母细胞瘤和儿童高级别胶质瘤或髓母细胞瘤是癌症相关死亡的主要原因之一,在过去的几十年里表现出预后差,结果几乎没有改善。这些肿瘤是异质的,可以从不同的神经细胞类型开始,有助于治疗抵抗。这种异质性是如何产生的与肿瘤细胞的起源和它们的基因改变有关。脑肿瘤的发生和发展概括了与正常神经发生相关的关键特征;然而,潜在的机制是相当失调的,因为肿瘤细胞生长和分裂的方式不受控制。最近在单细胞分辨率下的全面基因组学、转录组学和表观基因组学研究为不同脑肿瘤的不同驱动事件、细胞异质性和细胞起源提供了新的视角。原发性和继发性胶质母细胞瘤通过不同的遗传改变和途径发生,如EGFR扩增和IDH1/2或TP53突变。影响表观遗传修饰的组蛋白H3K27M等突变定义了一组独特的儿科高级胶质瘤,如弥漫性内在脑桥胶质瘤。不同的遗传、表观基因组谱和细胞异质性的鉴定导致了成人和儿童脑肿瘤亚型的新分类,为治疗分层提供了分子和谱系特异性脆弱性的见解。这篇综述讨论了我们目前对肿瘤细胞的起源、异质性、复发性遗传和表观遗传改变、成人胶质母细胞瘤、儿童高级别胶质瘤和髓母细胞瘤(恶性脑肿瘤的遗传异质性群体)的致癌驱动因素和信号通路的理解。本文分类如下:基因表达和转录层次>基因网络和基因组学成体干细胞,组织更新和再生>干细胞分化和逆转信号通路>细胞命运信号传导。
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期刊介绍: Developmental biology is concerned with the fundamental question of how a single cell, the fertilized egg, ultimately produces a complex, fully patterned adult organism. This problem is studied on many different biological levels, from the molecular to the organismal. Developed in association with the Society for Developmental Biology, WIREs Developmental Biology will provide a unique interdisciplinary forum dedicated to fostering excellence in research and education and communicating key advances in this important field. The collaborative and integrative ethos of the WIREs model will facilitate connections to related disciplines such as genetics, systems biology, bioengineering, and psychology. The topical coverage of WIREs Developmental Biology includes: Establishment of Spatial and Temporal Patterns; Gene Expression and Transcriptional Hierarchies; Signaling Pathways; Early Embryonic Development; Invertebrate Organogenesis; Vertebrate Organogenesis; Nervous System Development; Birth Defects; Adult Stem Cells, Tissue Renewal and Regeneration; Cell Types and Issues Specific to Plants; Comparative Development and Evolution; and Technologies.
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