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. 2014 Mar;35(3):2053-62.
doi: 10.1007/s13277-013-1272-3.

Characterization of CD44 variant expression in head and neck squamous cell carcinomas

D Spiegelberg, G Kuku, R Selvaraju, M Nestor

Characterization of CD44 variant expression in head and neck squamous cell carcinomas

D Spiegelberg et al. Tumour Biol. 2014 Mar.

Abstract

CD44 is a complex family of molecules, associated with aggressive malignancies and cancer stem cells. However, the role of CD44 variants in tumor progression and treatment resistance is not clear. In this study, the expression of CD44 and its variants was assessed in head and neck squamous cell carcinomas (HNSCC). Furthermore, subpopulations of cells expressing high amounts of CD44 variants were identified and characterized, for e.g., cell cycle phase and radioresistance. Results revealed high and homogenous CD44 and CD44v7 expression in four cell lines and CD44v4 and CD44v6 in three cell lines. CD44v3 was highly expressed in two cell lines, whereas CD44v5, CD44v7/8, CD44v10, CD133, and CD24 demonstrated no or moderate expression. Moreover, a subpopulation of very high CD44v4 expression was identified, which is independent of cell phase, demonstrating increased proliferation and radioresistance. In cell starvation experiments designed to enrich for cancer stem cells, a large population with dramatically increased expression of CD44, CD44v3, CD44v6, and CD44v7 was formed. Expression was independent of cell phase, and cells demonstrated increased radioresistance and migration rate. Our results demonstrate that the heterogeneity of tumor cells has important clinical implications for the treatment of HNSCC and that some of the CD44 variants may be associated with increased radioresistance. Highly expressed CD44 variants could make interesting candidates for selective cancer targeting.

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Figures

Fig. 1
Fig. 1
Example of FACS analysis of three markers differently expressed in the HNSCC cell line SCC-25. a Example of a marker, CD24, which displayed no or low expression. b Example of a marker, CD44v3, which displayed moderate expression. c Example of a marker, CD44v6, which displayed a high expression
Fig. 2
Fig. 2
a Dot plot and histogram of FACS analyzed UTSCC-7 and SCC-25 cells. All cell lines were positive for CD44v4 (purple population). Additionally, a distinct subpopulation with CD44v4 overexpressing cells was found (green population). b Clonogenic survival assay of FACS-sorted UT-SCC7 cells. CD44v4-positive and CD44v4 overexpression cells treated with a radiation dose of 2 Gy. CD44v4+ and CD44v4++ groups are normalized for plating efficiency (unirradiated controls). Analyses of variance was made using Student’s t test and was considered significant if P < 0.05. The error bars represent standard deviation (SD), N = 3
Fig. 3
Fig. 3
FACS analysis of UT-SCC7 and SCC-25 cells. Change of CD44, v3, v4/5, v6, and v7 marker expression under starvation condition, normalized to their controls. Marker expression of non-starved cells is set to 0 %. Error bars = SD, N ≥ 2–4
Fig. 4
Fig. 4
a FACS analysis of SCC-25 cells under normal growth condition and after serum starvation of 4 months (1 % FBS, 20 ng/ml EGF and bFGF) for CD44. Serum starvation increased the amount of cells highly expressing the marker. b Clonogenic survival assay of SCC-25 cells under normal growth condition and after serum starvation of 4 months (1 % FBS, 20 ng/ml EGF and bFGF). Normal SCC-25 cells are more sensitive to radiation than previously starved SCC-25 cells. Survival data was fit to a linear quadratic curve. The error bars represent SD. N ≥ 9
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