IL-4 Receptor Blockade Abrogates Satellite Cell: Rhabdomyosarcoma Fusion and Prevents Tumor Establishment
IL-4 Receptor Blockade Abrogates Satellite Cell: Rhabdomyosarcoma Fusion and Prevents Tumor Establishment
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DOI：
10.1002/stem.1491
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发表时间：
2013-11-01
期刊：
影响因子：
5.2
通讯作者：
Keller, Charles
中科院分区：
文献类型：
--
作者：
Li, Guangheng;Kikuchi, Ken;Keller, Charles
与肌肉相关的肺泡型横纹肌肉瘤(ARMS)的肿瘤细胞具有终末成肌分化异常，其特征是持续增殖，表达终末分化标志物的能力降低，并且肿瘤细胞不能像正常成肌细胞那样相互融合。目前尚不清楚手臂肿瘤细胞能否与骨骼肌干细胞(卫星细胞)或成肌细胞等正常的肌祖细胞融合，如果发生这种现象，融合事件的生物学效应也是未知的。为了研究这种可能性，我们分离了携带LacZ Cre-loxP报告基因的原代卫星细胞，用于与表达Cre的小鼠ARM原代肿瘤细胞共培养。体外和体内实验结果表明，在同种异体原位移植模型中，卫星细胞和衍生肌祖细胞与肿瘤细胞共注射时，肿瘤细胞肌祖细胞融合事件以及肿瘤的建立和进展速度加快。白介素4受体(IL-4R)阻断抗体治疗在体外逆转融合事件，并在体内阻止肿瘤的启动和进展。综上所述，这项研究支持了肿瘤细胞宿主细胞融合的潜在作用和IL-4R阻断阻止RMS肿瘤在新的解剖位置建立的强大治疗潜力。干细胞2013；31：2304-2312
Tumor cells of the muscle-related cancer alveolar rhabdomyosarcoma (aRMS) have dysregulated terminal myogenic differentiation that is characterized by continuous proliferation, decreased capacity to express markers of terminal differentiation, and inability of tumor cells to fuse to one another in the manner seen for normal myoblasts. Whether aRMS tumor cells can fuse with normal myogenic progenitors such as skeletal muscle stem cells (satellite cells) or myoblasts is unknown, as is the biological effect of fusion events if the phenomenon occurs. To study this possibility, we isolated primary satellite cells harboring a lacZ Cre-LoxP reporter gene for coculture with murine aRMS primary tumor cells expressing Cre. Results of in vitro and in vivo experiments demonstrated tumor cellmuscle cell progenitor fusion events as well as accelerated rates of tumor establishment and progression when satellite cells and derived muscle progenitors were coinjected with tumor cells in an orthotopic allograft model. Interleukin 4 receptor (IL-4R) blocking antibody treatment reversed fusion events in vitro and blocked tumor initiation and progression in vivo. Taken together, this study supports a potential role of tumor cellhost cell fusion and the strong therapeutic potential of IL-4R blockade to prevent the establishment of RMS tumors at new anatomical sites. Stem Cells2013;31:2304-2312