Respiratory Oncology Unit, Otto Wagner Hospital, Baumgartner Höhe, Vienna, Austria.
Department of Surgery, Medical University of Vienna, Spitalgasse, Vienna, Austria.
Invest New Drugs. 2020 Aug;38(4):946-955. doi: 10.1007/s10637-019-00847-8. Epub 2019 Aug 24.
Tumor dissemination and recurrence is attributed to highly resistant cancer stem cells (CSCs) which may constitute a fraction of circulating tumor cells (CTCs). Small cell lung cancer (SCLC) constitutes a suitable model to investigate the relation of CTCs and CSCs due to rapid tumor spread and a high number of CTCs. Expansion of five SCLC CTC lines (BHGc7, 10, 16, 26 and UHGc5) in vitro at our institution allowed for the analysis of CSC markers and cytotoxicity of the CSC-selective drugs salinomycin and niclosamide against CTC single cell suspensions or CTC spheroids/ tumorospheres (TOS). Salinomycin exerted dose-dependent cytotoxicity against the SCLC lines but, with exception of BHGc7 TOS, there was no markedly enhanced activity against TOS. Similarly, niclosamide exhibits high activity against BHGc7 TOS and UHGc5 TOS but not against the other CTC spheroids. High expression of the CSC marker CD133 was restricted to three SCLC tumor lines and the BHGc10 CTC line. All SCLC CTCs are CD24-positive but lack expression of CD44 and ABCG2 in contrast to the SCLC tumor lines which show a phenotype more similar to that of CSCs. The stem cell marker SOX2 was found in all CTC lines and SCLC GLC14/16, whereas elevated expression of Oct-3/4 and Nanog was restricted to BHGc26 and UHGc5. In conclusion, the SCLC CTCs established from patients with relapsed disease lack a typical CSC phenotype in respect to chemosensitivity to CSC-selective drugs, surface markers, expression of pluripotent stem cell and transcription factors.
肿瘤的扩散和复发归因于具有高耐药性的癌症干细胞（CSC），这些细胞可能构成循环肿瘤细胞（CTC）的一部分。小细胞肺癌（SCLC）是一种适合研究 CTC 和 CSC 之间关系的模型，因为它具有快速的肿瘤扩散和大量的 CTC。在我们机构中，体外扩增了五个 SCLC CTC 系（BHGc7、10、16、26 和 UHGc5），用于分析 CSC 标记物以及 CSC 选择性药物盐霉素和尼立达唑对 CTC 单细胞悬液或 CTC 球体/肿瘤球体（TOS）的细胞毒性。盐霉素对 SCLC 系表现出剂量依赖性细胞毒性，但除了 BHGc7 TOS 外，对 TOS 没有明显增强的活性。同样，尼立达唑对 BHGc7 TOS 和 UHGc5 TOS 表现出高活性，但对其他 CTC 球体没有活性。CSC 标记物 CD133 的高表达仅限于三个 SCLC 肿瘤系和 BHGc10 CTC 系。所有 SCLC CTC 均为 CD24 阳性，但缺乏 CD44 和 ABCG2 的表达，而 SCLC 肿瘤系表现出更类似于 CSC 的表型。所有 CTC 系和 SCLC GLC14/16 中均发现干细胞标记物 SOX2，而 Oct-3/4 和 Nanog 的高表达则仅限于 BHGc26 和 UHGc5。总之，从复发性疾病患者中建立的 SCLC CTC 缺乏对 CSC 选择性药物的化学敏感性、表面标记物、多能干细胞和转录因子表达的典型 CSC 表型。
