Abstract
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.
Highlights
Chordomas are rare bone tumors of the axial skeleton that localize preferentially in the cranial and the sacral areas
Because the few available cellular models of chordoma do not fully recapitulate the structures of these tumors, we generated 3D cellular models of chordoma originating from three cell lines representative of the three different stages of the disease: (i) primary tumor U-CH12, (ii) locally relapsed tumor U-CH1, and (iii) metastatic tumor CH22
While EMA was strongly expressed by the three chordoma spheroid models, Brachyury and CD24 were highly expressed by the
Summary
Chordomas are rare bone tumors of the axial skeleton that localize preferentially in the cranial and the sacral areas. With an incidence of 700 new cases per year, chordomas account for 1–4% of bone tumors and 20% of spinal tumors [1]. They are slow growing tumors and are locally aggressive, invading surrounding structures including the bone and often compressing important structures such as cranial nerves or the spinal cord [4]. They are almost avascular, leading to strong hypoxia, and are composed of large, vacuolated, physaliphorous cells surrounded by an abundant mucoid extracellular matrix [5]
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