Phenotype plasticity rather than repopulation from CD90-CK14 cancer stem cells leads to cisplatin resistance of urothelial carcinoma cell linesReportar como inadecuado

Phenotype plasticity rather than repopulation from CD90-CK14 cancer stem cells leads to cisplatin resistance of urothelial carcinoma cell lines - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal of Experimental and Clinical Cancer Research

, 34:144

First Online: 25 November 2015Received: 10 July 2015Accepted: 14 November 2015DOI: 10.1186-s13046-015-0259-x

Cite this article as: Skowron, M.A., Niegisch, G., Fritz, G. et al. J Exp Clin Cancer Res 2015 34: 144. doi:10.1186-s13046-015-0259-x


BackgroundTumour heterogeneity and resistance to systemic treatment in urothelial carcinoma UC may arise from cancer stem cells CSC. A recent model describes cellular differentiation states within UC based on corresponding expression of surface markers CD and cytokeratins CK with CD90 and CK14 positive cells representing the least differentiated and most tumourigenic population. Based on the fact that this population is postulated to constitute CSCs and the origin of cisplatin resistance, we enriched urothelial carcinoma cell lines UCCs for CD90 and studied the tumour-initiating potential of these separated cells in vitro.

MethodsMagnetic- and fluorescence-activated- cell sorting were used for separation of CD90 and CD90 UCCs. Distribution of cell surface markers CD90, CD44, and CD49f and cytokeratins CK14, CK5, and CK20 as well as the effects of short- and long-term treatment with cisplatin were assessed in vitro and measured by qRT-PCR, immunocytochemistry, reporter assay and flow cytometry in 11 UCCs.

ResultsWe observed cell populations with surface markers according to those reported in tumour xenografts. However, expression of cytokeratins did not concord regularly with that of the surface markers. In particular, expression of CD90 and CK14 diverged during enrichment of CD90 cells by immunomagnetic sorting or following cisplatin treatment. Enriched CD90 cells did not exhibit CSC-like characteristics like enhanced clonogenicity and cisplatin resistance. Moreover, selection of cisplatin-resistant sublines by long-term drug treatment did not result in enrichment of CD90 cells. Rather, these sublines displayed significant phenotypic plasticity expressing EMT markers, an altered pattern of CKs, and WNT-pathway target genes.

ConclusionsOur findings indicate that the correspondence between CD surface markers and cytokeratins reported in xenografts is not maintained in commonly used UCCs and that CD90 may not be a stable marker of CSC in UC. Moreover, UCCs cells are capable of substantial phenotypic plasticity that may significantly contribute to the emergence of cisplatin resistance.

KeywordsUrothelial carcinoma Cancer stem cells Cisplatin CD90 CK14 Epithelial-mesenchymal-transition WNT-signalling AbbreviationsCSCCancer stem cell


LTTLong-term cisplatin treatment

SDHASuccinate Dehydrogenase Complex, Subunit A, Flavoprotein Variant

STTShort-term cisplatin treatment

TBPTATA-binding protein

UCCUrothelial carcinoma cell line

Electronic supplementary materialThe online version of this article doi:10.1186-s13046-015-0259-x contains supplementary material, which is available to authorized users.

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