CD133+ Anaplastic Thyroid Cancer Cells Initiate Tumors in Immunodeficient Mice and Are Regulated by Thyrotropin

Abstract

BackgroundAnaplastic thyroid cancer (ATC) is one of the most lethal human malignancies. Its rapid onset and resistance to conventional therapeutics contribute to a mean survival of six months after diagnosis and make the identification of thyroid-cancer-initiating cells increasingly important.Methodology/Principal FindingsIn prior studies of ATC cell lines, CD133+ cells exhibited stem-cell-like features such as high proliferation, self-renewal and colony-forming ability in vitro. Here we show that transplantation of CD133+ cells, but not CD133− cells, into immunodeficient NOD/SCID mice is sufficient to induce growth of tumors in vivo. We also describe how the proportion of ATC cells that are CD133+ increases dramatically over three months of culture, from 7% to more than 80% of the total. This CD133+ cell pool can be further separated by flow cytometry into two distinct populations: CD133+/high and CD133+/low. Although both subsets are capable of long-term tumorigenesis, the rapidly proliferating CD133+/high cells are by far the most efficient. They also express high levels of the stem cell antigen Oct4 and the receptor for thyroid stimulating hormone, TSHR. Treating ATC cells with TSH causes a three-fold increase in the numbers of CD133+ cells and elicits a dose-dependent up-regulation of the expression of TSHR and Oct4 in these cells. More importantly, immunohistochemical analysis of tissue specimens from ATC patients indicates that CD133 is highly expressed on tumor cells but not on neighboring normal thyroid cells.Conclusions/SignificanceTo our knowledge, this is the first report indicating that CD133+ ATC cells are solely responsible for tumor growth in immunodeficient mice. Our data also give a unique insight into the regulation of CD133 by TSH. These highly tumorigenic CD133+ cells and the activated TSH signaling pathway may be useful targets for future ATC therapies.

Normal vs cancer thyroid stem cells: the road to transformation

“…65 Different research groups reported controversial results regarding CD133 (also known as Prominin-1) in TC. In anaplastic KAT18 and FRO cell lines, Zito et al 76 did not find CD133 + cells; Friedman et al 71 identified CD133 + in 6.32% FRO cells, but not in the papillary TPC cell line. Recently, Ke et al 77 described o 5% CD133 + cells in papillary CG3 and follicular WRO and CGTH cell lines.…”

“…By using primary tumours, Malaguarnera et al 75 and Tseng et al 73 identified a CD133 + subpopulation in PTC samples, while it was absent in thyroid spheres derived from PTC, FTC and ATC samples analysed by Todaro's research group. 63 Immunohistochemical examinations reported an elevated expression of CD133 in ATC paraffin-embedded tissue sections, 71,78 but only a low variable expression in FTC and PTC adjacent to ATC samples. 78 Besides the inconsistencies in the reported results, another limit of this marker is that its expression is greatly influenced by the cell cycle phase.…”

“…70 Detection of high levels of these transcription factors, together with low or absent markers of thyroid differentiation, can help identify putative thyroid CSCs ( Figure 6). 30,63,64,[71][72][73] Such identification can be supported by the analysis of biomarker expression belonging to self-renewing control pathways, such as Wnt/ β-catenin, Sonic hedgehog protein and Notch1 (classified also as epithelial-mesenchymal transition (EMT)-inducing signalling pathways). 74 Malaguarnera et al 75 reported that the selfrenewal capacity of thyrospheres is also sustained by the overexpression of the insulin receptor and IGF signalling pathway genes (IGF-I receptor, IGF-I, IGF-II) promoting their volume, growth and survival.…”

Cancer stem cells as a potential therapeutic target in thyroid carcinoma

“…Subsequently, Friedman et al (66) demonstrated that the transplantation of CD133+ cells into immunodeficient NOD/SCID mice was sufficient to induce tumor growth in vivo. However, these results were considered controversial, as Schweppe et al (67) evaluated 40 thyroid cancer cell lines using short tandem repeat and single nucleotide polymorphism array analyses, and reported that a number of the cell lines tested were redundant or did not originate from the thyroid.…”

Doxorubicin fails to eradicate cancer stem cells derived from anaplastic thyroid carcinoma cells: Characterization of resistant cells

“…Until recently, there are only very few studies on adult thyroid stem/progenitor cells and thyroid CSC (11)(12)(13). We and others have recently described and characterized adult stem cells in human thyroid tissues (14)(15)(16).…”