In vivo 5FU-exposed human medullary thyroid carcinoma cells contain a chemoresistant CD133+ tumor-initiating cell subset.
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.
1 Laboratory of Molecular Oncology, Cancer Research Institute , Slovak Academy of Sciences, Bratislava, Slovakia .
Lucia
L
Kucerova
Lucia
L
Feketeova
Zuzana
Z
Kozovska
Martina
M
Poturnajova
Miroslava
M
Matuskova
Radim
R
Nencka
Pavel
P
Babal
D000071916:AC133 Antigen; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D018276:Carcinoma, Medullary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018278:Carcinoma, Neuroendocrine; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005472:Fluorouracil / Q000494:pharmacology; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D005472:Fluorouracil