Team Cell Death and Pediatric Cancer, Cancer Initiation and Tumor Cell Identity Department, INSERM1052, CNRS5286, Cancer Research Center of Lyon, F-69008 Lyon, France.
Department of Biopathology, Centre Leon Berard, F-69008 Lyon, France.
Cells. 2021 Feb 15;10(2):399. doi: 10.3390/cells10020399.
Chordomas are rare, slow-growing tumors of the axial skeleton. These tumors are locally aggressive and refractory to conventional therapies. Radical surgery and radiation remain the first-line treatments. Despite these aggressive treatments, chordomas often recur and second-line treatment options are limited. The mechanisms underlying chordoma radioresistance remain unknown, although several radioresistant cancer cells have been shown to respond favorably to aldehyde dehydrogenase (ALDH) inhibition. The study of chordoma has been delayed by small patient cohorts and few available models due to the scarcity of these tumors. We thus created cellular 3D models of chordoma by using low-adherence culture systems. Then, we evaluated their radiosensitivity using colony-forming and spheroid size assays. Finally, we determined whether pharmacologically inhibiting ALDH increased their radiosensitivity. We found that 3D cellular models of chordoma (derived from primary, relapse, and metastatic tumors) reproduce the histological and gene expression features of the disease. The metastatic, relapse, and primary spheroids displayed high, medium, and low radioresistance, respectively. Moreover, inhibiting ALDH decreased the radioresistance in all three models.
脊索瘤是一种罕见的、生长缓慢的中轴骨骼肿瘤。这些肿瘤具有局部侵袭性，对常规治疗方法有抗性。根治性手术和放疗仍然是一线治疗方法。尽管采用了这些积极的治疗方法，脊索瘤仍经常复发，二线治疗选择有限。脊索瘤放射抗性的机制尚不清楚，尽管已经证明几种放射抗性癌细胞对醛脱氢酶 (ALDH) 抑制反应良好。由于这些肿瘤的稀缺性，脊索瘤的研究因患者队列较小且可用模型较少而受到阻碍。因此，我们使用低附着培养系统创建了脊索瘤的细胞 3D 模型。然后，我们使用集落形成和球体大小测定法评估它们的放射敏感性。最后，我们确定是否通过药理学抑制 ALDH 来提高它们的放射敏感性。我们发现，脊索瘤的 3D 细胞模型（源自原发性、复发性和转移性肿瘤）再现了疾病的组织学和基因表达特征。转移性、复发性和原发性球体的放射抗性分别为高、中、低。此外，抑制 ALDH 降低了所有三种模型的放射抗性。
