Mesenchymal stem/stromal cells (MSCs) are a promising resource for cell-based therapy because of their high immunomodulation ability, tropism towards inflamed and injured tissues, and their easy access and isolation. Currently, there are more than 1200 registered MSC clinical trials globally. However, a lack of standardized methods to characterize cell safety, efficacy, and biodistribution dramatically hinders the progress of MSC utility in clinical practice. In this review, we summarize the current state of MSC-based cell therapy, focusing on the systemic safety and biodistribution of MSCs. MSC-associated risks of tumor initiation and promotion and the underlying mechanisms of these risks are discussed. In addition, MSC biodistribution methodology and the pharmacokinetics and pharmacodynamics of cell therapies are addressed. Better understanding of the systemic safety and biodistribution of MSCs will facilitate future clinical applications of precision medicine using stem cells.

Purpose: To determine the role of insulin-like growth factor (IGF)-I receptor (IGF-IR) in alpha 9 nicotinic acetylcholine receptor (α9-nAChR)-induced stemness-related properties and to assess the therapeutic potential for preventing early tumor relapse and metastasis of TNBCs. Experimental Design: Expression levels of stemness-related genes, α9-nAChR and IGF-IR in tissues (n = 67) were analyzed by real-time Q-PCR and the correlation of different gene levels were calculated by the Pearson correlation analysis. The effects of either α9-nAChR activation or IGF-1R transactivation on stemness expression in TNBC were examined using ALDEFLUOR assay with flow cytometry, RNA interference, wound closure/migration/invasion assay, and animal models. The α9-nAChR, OCT4 and IGF-1R protein, p-IGF-1R in tissues were detected by immunohistochemical staining. Results: A high positive correlation between the gene expression levels of OCT4/NANOG/CD24/CD44 and α9-nAChR/IGF-IR in human breast cancer tissues was observed. Nicotine induced α9-nAChR activation trans-activates an IGF-IR expression and a phosphorylation of STAT3, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of either α9-nAChR or IGF-IR activation by RNA interference significantly suppressed the nicotine-induced stemness-related properties and cell metastasis both in vitro and in vivo. Conclusions: IGF-1R signal regulates the nicotine/α9-nAChR-induced stemness properties and cell metastasis therefore convene poor prognosis in TNBCs. Citation Format: Yung-Che Kuo, Jan-Show Chu, Kha-Liang Lee, Victor James Drew, Wei-Zhan Zhuang, Chi-Long Chen, Yuan-Soon Ho, Yen-Hua Huang. Nicotine promotes stemness-related properties and cell migration/metastasis through IGF-1R regulation in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5739. doi:10.1158/1538-7445.AM2017-5739

Purpose: To assess the potential therapeutic target on the alpha 9 nicotinic acetylcholine receptor (α9-nAChR) and the insulin-like growth factor (IGF)-I receptor (IGF-IR) for preventing distant metastasis in TNBC patients. Experimental Design: Expression levels of stemness-related genes, α9-nAChR and IGF-IR in clinical tissues (n = 67) were analyzed by RT-qPCR and the Pearson correlation analysis. The α9-nAChR, OCT4, IGF-1R, and p-IGF-1R protein in tissues were detected by immunohistochemical staining (n = 200). The effects of either α9-nAChR activation or IGF-1R transactivation on stemness expression in TNBC were examined using Western blot, ALDH activity assay with flow cytometry, shRNA silencing, wound closure/migration/invasion assay, as well as microCT scanning and IVIS assay for animal models. Results: A high positive correlation between the gene expression levels of OCT4/NANOG/CD24/CD44 and α9-nAChR/IGF-IR in human breast cancer tissues was observed. IGF-1R and OCT4 highly expressed in tumor part compared than that of in normal part. Moreover, IGF-1R positively correlated with OCT4 in tumor tissues. We also show that nicotine induced α9-nAChR activation trans-activates the expression of IGF-1R and pluripotent protein OCT4, which mediated stemness-related properties in TNBC cell lines. Our results reveal that knockdown α9nAChR and IGF-1R diminish the pernicious effects of nicotine, inhibit stemness activities, and suppress metastasis both in vitro and in vivo. Conclusions: A crosstalk between α9-nAChR and IGF-IR signal mediates the stemness-related properties and metastasis therefore convene poor prognosis in TNBCs. Citation Format: Yung-Che Kuo, Jan-Show Chu, Kha-Liang Lee, Hsiao-Feng Wang, Victor James Drew, Wei-Zhan Zhuang, Chi-Long Chen, Yuan-Soon Ho, Yen-Hua Huang. Alpha 9 nicotinic acetylcholine receptor promotes tumor progression in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4203.