Abstract
SummaryTumor 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.
Highlights
The high mortality rate of cancer patients is due to the refractoriness of metastatic cells to current treatments
Tumor dissemination is accomplished by circulating tumor cells (CTCs) which may show cancer stem cells (CSCs) characteristics provided that these cells play a decisive role in cancer metastasis [7]
Chemosensitivity of the Small cell lung cancer (SCLC) cell lines to salinomycin The cytotoxic activity of salinomycin against SCLC CTC and tumor cell lines was tested in MTT proliferation assays
Summary
The high mortality rate of cancer patients is due to the refractoriness of metastatic cells to current treatments. Tumors seem to contain a small subpopulation of cancer stem cells (CSCs) which sustain primary tumors and metastases [1,2,3,4]. Conventional chemotherapy eliminates the bulk of the tumor cells but CSCs survive and reconstitute the tumor as well as metastases [6]. Targeting CSCs in combination with standard chemotherapy may improve outcomes of cancer patients and procure long-lasting responses. Attempts to target and eliminate CSC by suitable drugs were clinically not successful so far [8]. CSCs have been identified in most solid tumors and this subpopulation has been found to be enriched after chemotherapy [4, 9,10,11,12]. Altered developmental pathways such as Notch, Wnt and Hedgehog drive CSC growth, progression and drug resistance
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