Almazán-Moga Ana, Zarzosa Patricia, Vidal Isaac, Molist Carla, Giralt Irina, Navarro Natalia, Soriano Aroa, Segura Miguel F, Alfranca Arantza, Garcia-Castro Javier, Sánchez de Toledo José, Roma Josep, Gallego Soledad
Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain.
Stem Cells Int. 2017;2017:7507380. doi: 10.1155/2017/7507380. Epub 2017 Jan 24.
Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children and can be divided into two main subtypes: embryonal (eRMS) and alveolar (aRMS). Among the cellular heterogeneity of tumors, the existence of a small fraction of cells called cancer stem cells (CSC), thought to be responsible for the onset and propagation of cancer, has been demonstrated in some neoplasia. Although the existence of CSC has been reported for eRMS, their existence in aRMS, the most malignant subtype, has not been demonstrated to date. Given the lack of suitable markers to identify this subpopulation in aRMS, we used cancer stem cell-enriched supracellular structures (spheres and holoclones) to study this subpopulation. This strategy allowed us to demonstrate the capacity of both aRMS and eRMS cells to form these structures and retain self-renewal capacity. Furthermore, cells contained in spheres and holoclones showed significant Hedgehog pathway induction, the inhibition of which (pharmacologic or genetic) impairs the formation of both holoclones and spheres. Our findings point to a crucial role of this pathway in the maintenance of these structures and suggest that Hedgehog pathway targeting in CSC may have great potential in preventing local relapses and metastases.
横纹肌肉瘤（RMS）是儿童最常见的软组织肉瘤类型，可分为两个主要亚型：胚胎型（eRMS）和肺泡型（aRMS）。在肿瘤的细胞异质性中，一小部分被称为癌症干细胞（CSC）的细胞被认为与癌症的发生和扩散有关，在一些肿瘤中已得到证实。尽管已有报道称eRMS中存在CSC，但迄今为止，在最恶性的亚型aRMS中尚未证实其存在。鉴于缺乏合适的标志物来识别aRMS中的这一亚群，我们使用富含癌症干细胞的超细胞结构（球体和全克隆）来研究这一亚群。这一策略使我们能够证明aRMS和eRMS细胞形成这些结构并保持自我更新能力的能力。此外，球体和全克隆中包含的细胞显示出明显的Hedgehog信号通路激活，抑制该通路（药物或基因抑制）会损害全克隆和球体的形成。我们的研究结果表明该信号通路在维持这些结构中起关键作用，并提示靶向CSC中的Hedgehog信号通路在预防局部复发和转移方面可能具有巨大潜力。
