In vivo 5FU-exposed human medullary thyroid carcinoma cells contain a chemoresistant CD133+ tumor-initiating cell subset

Lucia Kucerova, Lucia Feketeova, Zuzana Kozovska, Martina Poturnajova, Miroslava Matuskova, Radim Nencka, Pavel Babal
Thyroid: Official Journal of the American Thyroid Association 2014, 24 (3): 520-32

BACKGROUND: The hierarchical model of solid tumor proposes the existence of rare tumor cell subpopulations with stem-cell properties. The glycoprotein prominin-1 (CD133) represents one of the cancer stem-cell markers in several tumor types. The CD133+ cell subpopulation was shown to be enriched for tumor-initiating and highly chemoresistant cells in human cancer(s).

METHODS: We investigated whether CD133+ cells derived from human medullary thyroid carcinoma (MTC) possess tumor-initiating properties in vivo and exhibit differential responses to chemotherapeutic agents. We demonstrated that separated CD133+ cells from the human MTC cell line TT are enriched for tumor-initiating cells as demonstrated by tumor formation in vivo. Nevertheless, TT CD133+ cells do not exhibit increased chemoresistance in comparison to parental cells. However, when MTC xenotransplants were treated with the chemotherapeutic drug 5-fluorouracil (5FU) in vivo, CD133 expression increased in MTC cells.

RESULTS: This cell line, designated FTTiv isolated from the drug-exposed xenotransplants, exhibits a significantly different response to 5FU associated with the substantial change in the expression profile of genes involved in 5FU metabolism and drug resistance. Moreover, the CD133+ tumor-initiating subpopulation derived from these drug-exposed FTTiv cells is significantly more resistant to 5FU and retains the chemoresistant properties upon FTTiv culture propagation.

CONCLUSIONS: These data suggest that the chemoresistant phenotype and the CD133+ MTC subpopulation emerged in response to chemotherapy in vivo.

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