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Open Access Research article

Tumor cells with low proteasome subunit expression predict overall survival in head and neck cancer patients

Chann Lagadec1, Erina Vlashi1, Sunita Bhuta2, Chi Lai2, Paul Mischel3, Martin Werner4, Michael Henke5 and Frank Pajonk16*

Author Affiliations

1 Department of Radiation Oncology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA

2 Department of Pathology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA

3 Ludwig Institute for Cancer Research, San Diego Branch, 9500 Gilman Drive, La Jolla, CA 92039, USA

4 Department of Pathology, University Hospital Freiburg, Breisacher Str. 115a, 79106 Freiburg, Germany

5 Section Clinical Studies, Department of Radiation Oncology, University Hospital Freiburg, Robert-Koch-Strasse 3, D-79106 Freiburg, Germany

6 Jonsson Comprehensive Cancer Center at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA

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BMC Cancer 2014, 14:152  doi:10.1186/1471-2407-14-152

Published: 5 March 2014

Abstract

Background

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) also contain cancer stem cells that can be identified by low 26S proteasome activity and if their presence correlates to clinical outcome.

Methods

Human 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.

Results

HNSCC 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.

Conclusions

Subpopulations 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.

Keywords:
Cancer stem cells; Head and neck cancer; Proteasome; Radiotherapy