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. 2013 Jan;40(1):61-71.
doi: 10.1007/s00259-012-2242-5. Epub 2012 Oct 19.

CD133-expressing thyroid cancer cells are undifferentiated, radioresistant and survive radioiodide therapy

Chien-Chih Ke  1 , Ren-Shyan Liu, An-Hang Yang, Ching-Sheng Liu, Chin-Wen Chi, Ling-Ming Tseng, Yi-Fan Tsai, Jennifer H Ho, Chen-Hsen Lee, Oscar K Lee
Affiliations

CD133-expressing thyroid cancer cells are undifferentiated, radioresistant and survive radioiodide therapy

Chien-Chih Ke et al. Eur J Nucl Med Mol Imaging. 2013 Jan.

Abstract

Purpose: (131)I therapy is regularly used following surgery as a part of thyroid cancer management. Despite an overall relatively good prognosis, recurrent or metastatic thyroid cancer is not rare. CD133-expressing cells have been shown to mark thyroid cancer stem cells that possess the characteristics of stem cells and have the ability to initiate tumours. However, no studies have addressed the influence of CD133-expressing cells on radioiodide therapy of the thyroid cancer. The aim of this study was to investigate whether CD133(+) cells contribute to the radioresistance of thyroid cancer and thus potentiate future recurrence and metastasis.

Methods: Thyroid cancer cell lines were analysed for CD133 expression, radiosensitivity and gene expression.

Results: The anaplastic thyroid cancer cell line ARO showed a higher percentage of CD133(+) cells and higher radioresistance. After γ-irradiation of the cells, the CD133(+) population was enriched due to the higher apoptotic rate of CD133(-) cells. In vivo (131)I treatment of ARO tumour resulted in an elevated expression of CD133, Oct4, Nanog, Lin28 and Glut1 genes. After isolation, CD133(+) cells exhibited higher radioresistance and higher expression of Oct4, Nanog, Sox2, Lin28 and Glut1 in the cell line or primarily cultured papillary thyroid cancer cells, and lower expression of various thyroid-specific genes, namely NIS, Tg, TPO, TSHR, TTF1 and Pax8.

Conclusion: This study demonstrates the existence of CD133-expressing thyroid cancer cells which show a higher radioresistance and are in an undifferentiated status. These cells possess a greater potential to survive radiotherapy and may contribute to the recurrence of thyroid cancer. A future therapeutic approach for radioresistant thyroid cancer may focus on the selective eradication of CD133(+) cells.

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Figures

Fig. 1
Fig. 1
CD133+ population and radiosensitivity in thyroid cancer cell lines. a Four thyroid cancer cell lines, ARO, WRO, CG3 and CGTH were analysed to explore their CD133+ population using flow cytometry. CD133+ populations were determined according to the binding of the isotype-matched control in each cell line. Similar results were observed in two independent experiments. b Radiosensitivity was assessed by clonogenic survival assays after the cells had been γ-irradiated at different doses. The surviving fractions are shown as means ± SD (n = 3)
Fig. 2
Fig. 2
Radiosensitivity and gene expression of CD133+ and CD133− populations of the ARO thyroid cancer cell line. a The CD133+ and CD133− populations were isolated by FACS. The proportion of CD133+ cells was determined by flow cytometry before and after cell sorting. b The surviving fractions of isolated CD133+ and CD133− populations were assessed by clonogenic assays after irradiation. The surviving fractions are shown as means ± SD (n = 3) c The sorted CD133+ and CD133− cells were analysed for CD133, Oct4, Lin28 and Glut1 mRNA expression using real-time quantitative PCR. Expression of each gene was normalized to that of GAPDH mRNA and is presented as 2−ΔCt. The relative mRNA expression levels are shown as means ± SD (n = 2)
Fig. 3
Fig. 3
Effect of radiation on the CD133 populations. a ARO, WRO and CG3 cells were analysed for CD133+ populations by flow cytometry before and 48 h after γ-irradiation. b Apoptosis in the CD133+ and CD133− populations was determined by analysis of annexin V binding. Similar results were observed in two independent experiments
Fig. 4
Fig. 4
Gene expression profile after in vivo 131I treatment of an ARO-hNIS tumour. a ARO cells stably expressing hNIS (ARO-hNIS, established in our previous study) were injected subcutaneously into the right shoulder of SCID mice. Radioiodine uptake by the ARO-hNIS tumours was verified by intravenous injection of 1.85 MBq (50 µCi) 123I followed by in vivo imaging using a microPET/SPECT/CT. b The mice bearing the ARO-hNIS tumours received an intraperitoneal injection of 37 MBq (1 mCi) 131I. Mice injected with normal saline formed the control group. Each group consisted of five mice. Tumour volume was measured on various days. On day 11, the mice were killed and the tumours were excised for subsequent gene expression analysis. c After tumours had been minced and digested, total RNA was isolated, reverse-transcribed and the expression levels of CD133, Glut1, Oct4, Nanog and Lin28 mRNA were determined by real-time quantitative PCR using designed primers. Expression of each gene was normalized to that of GAPDH mRNA and is presented as 2−ΔCt. The relative mRNA expression levels are shown as means ± SD (n = 2)
Fig. 5
Fig. 5
Immunohistochemical staining for CD133 in clinical. CD133 expression was detected in paraffin-embedded sections of two UTCs (Poor) and two PTCs (Papillary)
Fig. 6
Fig. 6
Gene expression profiles of CD133+ and CD133− cells from primarily cultured PTCs. a Clinical PTCs removed from patients were minced, digested and then subjected to primary culture. After total RNA isolation, the thyroid origin of the cells was confirmed by examining Tg and TPO expression using RT-PCR and ethidium bromide-stained agarose gel electrophoresis. ARO cells are known to lack thyroid-specific gene expression and served as the negative control. b CD133+ and CD133− populations isolated from primarily cultured cells by FACS were subjected to total RNA isolation and first-strand cDNA transcription. Expression levels of CD133 mRNA by the isolated populations were analysed by real-time quantitative PCR and normalized to that of GAPDH mRNA. c Expression levels of Oct4, Nanog, Lin28 and Sox2 were assessed in the CD133+ and CD133− cell populations by real-time quantitative PCR. d Expression levels of NIS, Tg, TPO, TSHR, TTF1 and Pax8 were assessed in CD133+ and CD133− cell populations by real-time quantitative PCR. All experiments were performed at least in duplicate and normalized to GAPDH mRNA expression. Data shown are the ratios of gene expression levels in the CD133+ population to those in the CD133− population
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