Oncolytic vaccinia virus GLV-1h68 strain shows enhanced replication in human breast cancer stem-like cells in comparison to breast cancer cells

Journal of Translational Medicine

Aladar A Szalay²  Boris R Minev¹  Nanhai G Chen³  Huiqiang Wang⁴ 

[1] UCSD Division of Neurosurgery, University of California, San Diego, La Jolla, CA, 92093, USA;Rudolf Virchow Center for Experimental Biomedicine and Institute for Molecular Infection Biology, University of Würzburg, Am hubland, D-97074, Würzburg, Germany;Department of Radiation Oncology, Rebecca & John Moores Comprehensive Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA;Genelux Corporation, San Diego Science Center, 3030 Bunker Hill Street, Suite 310, San Diego, CA, 92109, USA

关键词: EMT;    Vaccinia virus;    Oncolytic virotherapy;    Cancer stem cells;    Aldehyde dehydrogenase 1;   

Others  :  1205914
DOI  :  10.1186/1479-5876-10-167

 received in 2012-04-07, accepted in 2012-08-02,  发布年份 2012

【 摘 要 】

Background

Recent data suggest that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are responsible for relapses after apparently curative therapies have been undertaken. Hence, novel cancer therapies will be needed to test for both tumor regression and CSC targeting. The use of oncolytic vaccinia virus (VACV) represents an attractive anti-tumor approach and is currently under evaluation in clinical trials. The purpose of this study was to demonstrate whether VACV does kill CSCs that are resistant to irradiation and chemotherapy.

Methods

Cancer stem-like cells were identified and separated from the human breast cancer cell line GI-101A by virtue of increased aldehyde dehydrogenase 1 (ALDH1) activity as assessed by the ALDEFLUOR assay and cancer stem cell-like features such as chemo-resistance, irradiation-resistance and tumor-initiating were confirmed in cell culture and in animal models. VACV treatments were applied to both ALDEFLUOR-positive cells in cell culture and in xenograft tumors derived from these cells. Moreover, we identified and isolated CD44⁺CD24⁺ESA⁺ cells from GI-101A upon an epithelial-mesenchymal transition (EMT). These cells were similarly characterized both in cell culture and in animal models.

Results

We demonstrated for the first time that the oncolytic VACV GLV-1h68 strain replicated more efficiently in cells with higher ALDH1 activity that possessed stem cell-like features than in cells with lower ALDH1 activity. GLV-1h68 selectively colonized and eventually eradicated xenograft tumors originating from cells with higher ALDH1 activity. Furthermore, GLV-1h68 also showed preferential replication in CD44⁺CD24⁺ESA⁺ cells derived from GI-101A upon an EMT induction as well as in xenograft tumors originating from these cells that were more tumorigenic than CD44⁺CD24^-ESA⁺ cells.

Conclusions

Taken together, our findings indicate that GLV-1h68 efficiently replicates and kills cancer stem-like cells. Thus, GLV-1h68 may become a promising agent for eradicating both primary and metastatic tumors, especially tumors harboring cancer stem-like cells that are resistant to chemo and/or radiotherapy and may be responsible for recurrence of tumors.

【 授权许可】

   
2012 Wang et al.; licensee BioMed Central Ltd.

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