Genetic modeling of human rhabdomyosarcoma
Genetic modeling of human rhabdomyosarcoma
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DOI：
10.1158/0008-5472.can-04-3194
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发表时间：
2005-06-01
期刊：
影响因子：
11.2
通讯作者：
Counter, CM
中科院分区：
文献类型：
--
作者：
Linardic, CM;Downie, DL;Counter, CM
横纹肌肉瘤是一种以骨骼肌分化为特征的恶性肿瘤，是儿童最常见的软组织肉瘤。不同的临床表现模式、组织学肿瘤类型和危险人群的识别表明横纹肌肉瘤是高度相关的肉瘤的集合，而不是单一的实体。为了了解这种看似异质性的恶性肿瘤，我们通过靶向横纹肌肉瘤中改变的通路，将分化程度较低的人类骨骼肌细胞前体（SkMC）和固定的人类骨骼肌成肌细胞（HSMM）转化为恶性细胞，构建了一个遗传定义但具有可塑性的横纹肌肉瘤模型。虽然这两种细胞类型都具有致瘤性，但SkMCs产生高度异质性的肿瘤，偶尔表现出横纹肌肉瘤的特征，而HSMMs形成具有胚胎形态的横纹肌肉瘤样肿瘤，具有侵袭和转移能力。因此，尽管引入了相同的遗传改变，但改变起源的骨骼肌细胞导致了不同的肿瘤形态，这表明起源细胞可能决定了横纹肌肉瘤的肿瘤组织学。现在基因诱导人类横纹肌肉瘤样肿瘤的能力为解剖这种癌症的分子机制提供了一个有代表性的模型。
Rhabdomyosarcoma, a malignancy showing features of skeletal muscle differentiation, is the most common soft tissue sarcoma of childhood. The identification of distinct clinical presentation patterns, histologic tumor types, and risk groups suggests that rhabdomyosarcoma is a collection of highly related sarcomas rather than a single entity. In an effort to understand this seemingly heterogeneous malignancy, we constructed a genetically defined but malleable model of rhabdomyosarcoma by converting less differentiated human skeletal muscle cell precursors (SkMC) and committed human skeletal muscle myoblasts (HSMM) into their malignant counterparts by targeting pathways altered in rhabdomyosarcoma. Whereas the two cell types were both tumorigenic, SkMCs gave rise to highly heterogeneous tumors occasionally displaying features of rhabdomyosarcoma, whereas HSMMs formed rhabdomyosarcoma-like tumors with an embryonal morphology, capable of invasion and metastasis. Thus, despite introducing the same panel of genetic changes, altering the skeletal muscle cell of origin led to different tumor morphologies, suggesting that cell of origin may dictate rhabdomyosarcoma tumor histology. The ability to now genetically induce human rhabdomyosarcoma-like tumors provides a representative model to dissect the molecular mechanisms underlying this cancer.