Abstract 1392: Differential effects of Cancer Stem Cells (CSCs) and non-CSCs-targeted therapies on lung primary tumors and metastasis

Abstract

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. Salinomycin was recently identified as a selective inhibitor of CSCs. The aim of this study was to investigate the effect of salinomycin with or without combination with paclitaxel in the Lewis lung carcinoma (LLC) metastatic model. Salinomycin reduced the proportion of ALDH+ CSCs in LLC cells, whereas paclitaxel increased such population. The same effect was observed for the human H460, H1299 and H272 lung cancer cell lines. Salinomycin reduced the tumorsphere formation capacity of LLC by more than 7-fold, but paclitaxel showed no effect. For in vivo experiments, LLC cells were injected subcutaneously and, after surgical removal of the primary tumors, animals were checked for lung metastasis. 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 metastasis (p<0.05). Combination of both drugs did not improve the effect of single therapies. mRNA levels of ALDH, CXCR4 and SDF-1 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+ (macrophages) was also decreased upon administration of paclitaxel or salinomycin in both primary tumors and metastasis. The number of mast cells was only reduced in primary and metastatic lesions of paclitaxel-treated mice. These results show that salinomycin targets ALDH+ lung CSCs, which has important therapeutic effects in vivo by reducing metastatic lesions. On the contrary, paclitaxel (although reducing primary tumor growth) promotes the selection of ALDH+ cells that likely modify the lung microenvironment to foster metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1392. doi:1538-7445.AM2012-1392