Abstract
Cancer stem cells (CSCs) are thought to be responsible for tumor initiation and recurrence after chemotherapy. Targeting CSCs and non-CSCs with specific compounds may be an effective approach to reduce lung cancer growth and metastasis. The aim of this study was to investigate the effect of salinomycin, a selective inhibitor of CSCs, with or without combination with paclitaxel, in a metastatic model. To evaluate the effect of these drugs in metastasis and tumor microenvironment we took advantage of the immunocompetent and highly metastatic LLC mouse model. Aldefluor assays were used to analyze the ALDH+/− populations in murine LLC and human H460 and H1299 lung cancer cells. Salinomycin reduced the proportion of ALDH+ CSCs in LLC cells, whereas paclitaxel increased such population. The same effect was observed for the H460 and H1299 cell lines. Salinomycin reduced the tumorsphere formation capacity of LLC by more than 7-fold, but paclitaxel showed no effect. In in vivo experiments, paclitaxel reduced primary tumor volume but increased the number of metastatic nodules (p<0.05), whereas salinomycin had no effect on primary tumors but reduced lung metastasis (p<0.05). Combination of both drugs did not improve the effect of single therapies. ALDH1A1, SOX2, CXCR4 and SDF-1 mRNA levels were higher in metastatic lesions than in primary tumors, and were significantly elevated in both locations by paclitaxel treatment. On the contrary, such levels were reduced (or in some cases did not change) when mice were administered with salinomycin. The number of F4/80+ and CD11b+ cells was also reduced upon administration of both drugs, but particularly in metastasis. These results show that salinomycin targets ALDH+ lung CSCs, which has important therapeutic effects in vivo by reducing metastatic lesions. In contrast, paclitaxel (although reducing primary tumor growth) promotes the selection of ALDH+ cells that likely modify the lung microenvironment to foster metastasis.
Highlights
Lung cancer is one of the leading causes of mortality worldwide and the most common cause of death from cancer in men and women [1]
We and others have previously shown that measurement of aldehyde dehydrogenases (ALDH) activity is an appropriate method for the identification of lung cancer stem cells (CSCs) [22,23], but whether this marker could be used to isolate and characterize the Lewis lung carcinoma (LLC) CSC population was unknown
To assess the presence of this population in the LLC cell line based on their ALDH enzymatic activity, Aldefluor assay followed by FACS analysis were carried out
Summary
Lung cancer is one of the leading causes of mortality worldwide and the most common cause of death from cancer in men and women [1]. In 2007, the 5-year survival rates for men and women diagnosed with lung cancer were 16% These percentages have not changed substantially over several decades despite significant advances in the diagnosis and therapeutic options [2]. Increased ALDH activity has been found in stem cell populations in different tumor types including human multiple myeloma, acute myeloid leukemia, brain, breast, liver, colon, pancreas [6,7] and, more recently, in lung, where ALDH1A1 expression is associated with poor survival in a cohort of stage I NSCLC patients [8]. The ALDH+ fraction is enriched in tumor initiating cells with increased migration, adhesion ability and metastatic potential [9] Together, these findings suggest that measurement of ALDH levels or enzymatic activity may serve as a lung CSC marker
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