Abstract
BackgroundExperimental and clinical data suggest that solid cancers contain treatment-resistant cancer stem cells that will impair treatment efficacy. The objective of this study was to investigate if head and neck squamous cell carcinoma (HNSCC) also contain cancer stem cells that can be identified by low 26S proteasome activity and if their presence correlates to clinical outcome.MethodsHuman HNSCC cells, engineered to report lack of proteasome activity based on accumulation of a fluorescent fusion protein, were separated based on high (ZsGreen-cODCneg) or low (ZsGreen-cODCpos) proteasome activity. Self-renewal capacity, tumorigenicity and radioresistance were assessed. Proteasome subunit expression was analyzed in tissue microarrays and correlated to survival and locoregional cancer control of 174 patients with HNSCC.ResultsHNSCC cells with low proteasome activity showed a significantly higher self-renewal capacity and increased tumorigenicity. Irradiation enriched for ZsGreen-cODCpos cells. The survival probability of 82 patients treated with definitive radio- or chemo-radiotherapy exhibiting weak, intermediate, or strong proteasome subunit expression were 21.2, 28.8 and 43.8 months (p = 0.05), respectively. Locoregional cancer control was comparably affected.ConclusionsSubpopulations of HNSCC display stem cell features that affect patients’ tumor control and survival. Evaluating cancer tissue for expression of the proteasome subunit PSMD1 may help identify patients at risk for relapse.
Highlights
Experimental and clinical data suggest that solid cancers contain treatment-resistant cancer stem cells that will impair treatment efficacy
We recently reported that lack of proteasome function and subunit expression is a feature of therapy-resistant, tumorigenic cells in breast cancer and glioma [16,21,25], we hypothesized that head and neck squamous cell carcinoma (HNSCC) could contain a similar cell population
HNSCC cells with low proteasome activity show increased self-renewal capacity We had previously shown that breast cancer and glioma cells with low proteasome activity had a cancer stem cell phenotype, exhibiting increased self-renewal capacity and tumorigenicity [21]
Summary
Experimental and clinical data suggest that solid cancers contain treatment-resistant cancer stem cells that will impair treatment efficacy. The objective of this study was to investigate if head and neck squamous cell carcinoma (HNSCC) contain cancer stem cells that can be identified by low 26S proteasome activity and if their presence correlates to clinical outcome. Radiotherapy is standard of care for advanced stage head and neck squamous cell carcinoma (HNSCC). A previous study suggested that CSCs in HNSCC could be prospectively identified using antibodies against the surface marker CD44 [22]. In combination with ALDH1 staining and use of the side population CD44 still seems to be a useful marker for the prospective identification of CSCs in HNSCC [24]
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