Background: Cancer progenitor/stem cells (CSCs), a small subpopulation with stem-like property, are known as a key factor for tumor initiation. We have reported that the turmeric derived volatile constitutes can inhibit mouse hepatoma cell growth in vivo and in vitro. Although the mechanism is largely unknown, the potential effects of the turmeric constitutes could come from either intervention of the tumor microenvironment, or directly abolishing the CSCs. This concept is supported by current studies in which the phyto-chemicals from natural products present a fundamentally different paradigm for cancer therapy though modulating the CSC and microenvironment signaling pathways thereby eliminating CSCs. The ingredient analysis of turmeric derived volatile constitutes by GCxGC/TOF-MS showed that there were more than twenty phyto-chemicals considered to be biologically active, including anti-inflammation, anti-virus, anti-oxidation and anticancer. Among these ingredients, the anti-cancer compounds known as turmerones are rich (46%). In this study, we are going to study the effects of turmerones on the CSCs from mouse hepatoma hepal-6 cells. Methods: A spheroid assay was performed to test the effect of turmericones on sphere formation of hepal-6 cells. The CSC surface antigens including EpCAM, CD133, CD90, and the functional marker aldehyde dehydrogenase were determined by flow cytometery. We further established a diabetic model in C57L/J mouse to create the metabolic disorder microenvironment in the liver to facilitate hepatocellular carcinoma (HCC) initiation. The hepal-6 spheres were pretreated with turmerones and inoculated into the liver lobs of diabetic mouse. The animals were continued to treat with turmerones by i.p. every 3 days for 6 weeks. The liver weights, tumor volume and histology were determined. The cells from tumor tissues were isolated and CSCs were identified by the surface/functional markers. To investigate the diabetes compromised liver microenvironment, IL-6, IGF-1, TGF-β, TNF-α, and FGF-21 were determined in the liver tissues. To investigate the CSC signaling, CSC self-renewal and Wnt signaling pathway (β-catenin, EpCAM, E-Cadherin, TGF-β1, FZD-7, and LRP5/6) are analyzed by RT-PCR and Western blot. Results: Turmerones inhibits hepal-6 cells sphere formation and abolish the CSCs in vitro. The tumor size was significantly decreasd by turmerones treatment compare to control. Although turmerones did not change the serum levels of glucose and insulin, the increased levels (interleukin-6, IGF-1, TGF-β, TNF-α, and FGF-21) and aberrant Wnt pathway components in diabetic liver tissues were ameliorated by turmerones at varying extents. Conclusion: Turmerones treatment can inhibit the HCC formation in diabetic liver. The intervention of tumor microenvironment and Wnt pathway components by turmerones may contribute to the inactivation of CSCs thereby inhibiting the HCC formation.

Citation Format: Yan Li, Harshul Pandit, Xuanyi Li, Suping Li, Jingwen Zhang, Guozhen Cui, Robert C. Martin. Abolish cancer progenitor cells in a mouse model of diabetes associated hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4069. doi:10.1158/1538-7445.AM2015-4069