Cisplatin-resistant cells in malignant pleural mesothelioma cell lines show ALDHhighCD44+ phenotype and sphere-forming capacity

BMC Cancer

Golnaz Karoubi¹  Ralph Alexander Schmid¹  Ruben Boesch¹  Laurene Froment¹  Lourdes Cortes-Dericks¹ 

[1]Department of Clinical Research, Division of General Thoracic Surgery, University Hospital Berne, Berne, Switzerland

关键词: CD44;    ALDH;    Chemoresistance;    Malignant pleural mesothelioma;    Cancer stem cells;   

Others  :  858854
DOI  :  10.1186/1471-2407-14-304

 received in 2013-11-26, accepted in 2014-04-22,  发布年份 2014

【 摘 要 】

Background

Conventional chemotherapy in malignant pleural mesothelioma (MPM) has minimal impact on patient survival due to the supposed chemoresistance of cancer stem cells (CSCs). We sought to identify a sub-population of chemoresistant cells by using putative CSC markers, aldehyde dehydrogenase (ALDH) and CD44 in three MPM cell lines; H28, H2052 and Meso4.

Methods

The Aldefluor assay was used to measure ALDH activity and sort ALDH^high and ALDH^low cells. Drug-resistance was evaluated by cell viability, anchorage-independent sphere formation, flow-cytometry and qRT-PCR analyses.

Results

The ALDH^high - and ALDH^low -sorted fractions were able to demonstrate phenotypic heterogeneity and generate spheres, the latter being less efficient, and both showed an association with CD44. Cis- diamminedichloroplatinum (II) (cisplatin) treatment failed to reduce ALDH activity and conferred only a short-term inhibition of sphere generation in both ALDH^high and ALDH^low fractions of the three MPM cell lines. Induction of drug sensitivity by an ALDH inhibitor, diethylaminobenzaldehyde (DEAB) resulted in significant reductions in cell viability but not a complete elimination of the sphere-forming cells, suggestive of the presence of a drug-resistant subpopulation. At the transcript level, the cisplatin + DEAB-resistant cells showed upregulated mRNA expression levels for ALDH1A2, ALDH1A3 isozymes and CD44 indicating the involvement of these markers in conferring chemoresistance in both ALDH^high and ALDH^low fractions of the three MPM cell lines.

Conclusions

Our study shows that ALDH^high CD44⁺ cells are implicated in conveying tolerance to cisplatin in the three MPM cell lines. The combined use of CD44 and ALDH widens the window for identification and targeting of a drug-resistant population which may improve the current treatment modalities in mesothelioma.

【 授权许可】

   
2014 Cortes-Dericks et al.; licensee BioMed Central Ltd.

【 图 表 】

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