文章：

探索对横纹肌肉瘤的更深层次的理解：来自互补模型系统的见解

Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems

原文发布日期：2015-06-24

DOI: 10.1038/nrc3961

类型: Review Article

开放获取: 否

要点：

1. Rhabdomyosarcoma (RMS) is a soft tissue malignancy composed of neoplastic cells that morphologically resemble skeletal muscle-lineage precursor cells. High-risk RMS has a dismal prognosis, and treatments for this condition have not improved for three decades now.
2. RMS is a heterogeneous disease composed of four subtypes. Embryonal RMS (ERMS), the most common subtype, associates with various tumour-promoting signalling pathways (for example, RAS and Hedgehog) and/or loss of tumour surveillance (for example, TP53 mutations). Pleomorphic RMS is very aggressive and occurs during the sixth and seventh decades of life. Spindle cell/sclerosing RMS affects both children and adults, with favourable and unfavourable prognoses, respectively. Alveolar RMS (ARMS), which is notoriously aggressive, is a genetically distinct disease driven by the PAX3–FOXO1 and PAX7–FOXO1 chimeric oncoproteins that are unique to ARMS.
3. Understanding the cell (or cells) of origin for RMS is complex, reflecting the fact that multiple precursor cells can give rise to RMS in mouse models.
4. To relieve a bottleneck that has existed in the design of new RMS therapies, an impressive array of new RMS model systems, spanning the evolutionary spectrum from flies to fish to mammals, have recently been developed; these new models have proven successful in uncovering new pathogenic mechanisms of RMS.
5. Moreover, RMS gene discovery prompted by these diverse yet remarkably complementary model systems is inspiring new possibilities for targeted RMS therapy.
6. These models also point to viable approaches for the genetic and molecular dissection of other clinically problematic non-RMS sarcomas.

要点翻译：

1. 横纹肌肉瘤（RMS）是一种软组织恶性肿瘤，由形态上类似骨骼肌谱系前体细胞的肿瘤细胞组成。高危型RMS预后极差，且三十年来该疾病的治疗方法未见改善。
2. RMS是一种异质性疾病，包含四种亚型。胚胎型横纹肌肉瘤（ERMS）作为最常见亚型，与多种肿瘤促进信号通路（如RAS和Hedgehog）和/或肿瘤免疫监视缺失（如TP53突变）相关。多形性横纹肌肉瘤侵袭性极强，好发于六十至七十岁人群。梭形细胞/硬化性横纹肌肉瘤可影响儿童和成人，其预后分别为良好和不良。肺泡型横纹肌肉瘤（ARMS）以侵袭性著称，是一种由ARMS特有的PAX3–FOXO1和PAX7–FOXO1嵌合癌蛋白驱动的遗传学独特疾病。
3. 理解RMS的起源细胞具有复杂性，这反映了在小鼠模型中多种前体细胞均可诱发RMS的事实。
4. 为突破新型RMS疗法设计长期存在的瓶颈，近期已开发出涵盖从果蝇到鱼类再到哺乳动物的进化谱系的一系列新型RMS模型系统；这些新模型在揭示RMS新致病机制方面已取得显著成效。
5. 此外，通过这些多样化且具有显著互补性的模型系统推动的RMS基因发现，正在为靶向RMS治疗激发新的可能性。
6. 这些模型也为其他临床疑难非RMS肉瘤的遗传学和分子解析指明了可行路径。

英文摘要：

Rhabdomyosarcoma (RMS) is a mesenchymal malignancy composed of neoplastic primitive precursor cells that exhibit histological features of myogenic differentiation. Despite intensive conventional multimodal therapy, patients with high-risk RMS typically suffer from aggressive disease. The lack of directed therapies against RMS emphasizes the need to further uncover the molecular underpinnings of the disease. In this Review, we discuss the notable advances in the model systems now available to probe for new RMS-targetable pathogenetic mechanisms, and the possibilities for enhanced RMS therapeutics and improved clinical outcomes.

摘要翻译： 

横纹肌肉瘤（RMS）是一种间叶性恶性肿瘤，由表现出肌源性分化组织学特征的肿瘤性原始前体细胞组成。尽管接受强化的传统多模式治疗，高风险RMS患者仍常遭受侵袭性疾病。缺乏针对RMS的定向治疗突显了进一步揭示该疾病分子基础的必要性。在本综述中，我们探讨了现有模型系统的显著进展，这些系统可用于探究新的RMS可靶向致病机制，以及增强RMS治疗和改善临床结果的可能性。

原文链接：

Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems