Doxorubicin resistance in a novel in vitro model of human pleomorphic liposarcoma associated with alternative lengthening of telomeres.
Doxorubicin resistance in a novel in vitro model of human pleomorphic liposarcoma associated with alternative lengthening of telomeres.
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DOI：
10.1158/1535-7163.mct-09-0705
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发表时间：
2010-03
影响因子：
5.7
通讯作者：
Broccoli D
中科院分区：
文献类型：
--
作者：
Mitchell MA;Johnson JE;Pascarelli K;Beeharry N;Chiourea M;Gagos S;Lev D;von Mehren M;Kipling D;Broccoli D
软组织肉瘤是一组多样的致命性人类肿瘤，其中很少有药物具有可证实的临床疗效，多柔比星和异环磷酰胺的标准治疗组合在大型多机构试验中仅显示25-30%的缓解率。虽然脂肪肉瘤是成人软组织肉瘤中最常见的组织学形式，但由于缺乏易于实验处理的体外模型系统，这一领域的研究受到严重阻碍。为此，我们在这里描述了一种新的人多形性脂肪肉瘤体外模型。该细胞系（LS 2）来源于多形性脂肪肉瘤，其利用端粒替代延长（ALT）的端粒维持机制，这可能在调节这种肿瘤类型对DNA损伤剂的反应中很重要。我们提出了详细的基线分子和基因组数据，包括全基因组拷贝数和转录组概况，为这个模型相比，其亲本肿瘤和一组脂肪肉瘤涵盖多种组织学。该模型基本上保留了在亲代肿瘤中观察到的所有可检测的拷贝数变化，并显示出与多形性脂肪肉瘤一致的分子核型和表达谱。我们还证明了该模型的实用性，连同两个额外的人脂肪肉瘤细胞系，研究拓扑异构酶2A表达和ALT阳性脂肪肉瘤对阿霉素的敏感性之间的关系。该模型及其相关的基线数据提供了一个强大的新工具，用于开发这种临床上难以处理的肿瘤的治疗方法，并研究ALT对调节阿霉素敏感性的贡献。
Soft tissue sarcomas are a diverse set of fatal human tumors where few agents have demonstrable clinical efficacy, with the standard therapeutic combination of doxorubicin and ifosfamide showing only a 25–30% response rate in large multi-institutional trials. Although liposarcomas are the most common histological form of adult soft tissue sarcomas, research in this area is severely hampered by the lack of experimentally tractable in vitro model systems. To this end, here we describe a novel in vitro model for human pleomorphic liposarcoma. The cell line (LS2) is derived from a pleomorphic liposarcoma that utilizes the Alternative Lengthening of Telomeres (ALT) mechanism of telomere maintenance, which may be important in modulating the response of this tumor type to DNA damaging agents. We present detailed baseline molecular and genomic data, including genome wide copy number and transcriptome profiles, for this model compared to its parental tumor and a panel of liposarcomas covering multiple histologies. The model has retained essentially all of the detectable alterations in copy number that are seen in the parental tumor, and shows molecular karyotypic and expression profiles consistent with pleomorphic liposarcomas. We also demonstrate the utility of this model, together with two additional human liposarcoma cell lines, to investigate the relationship between topoisomerase 2A expression and the sensitivity of ALT-positive liposarcomas to doxorubicin. This model, together with its associated baseline data, provide a powerful new tool to develop treatments for this clinically poorly-tractable tumor, and to investigate the contribution that ALT makes to modulating sensitivity to doxorubicin.