Cancer stem cells (CSCs) from various cancers are able to transdifferentiate into endothelial cells and further form functional blood vessels, indicating another possible resistance mechanism to antiangiogenic agents. However, it remains unclear whether CSCs from hepatocellular carcinoma have the ability to differentiate into endothelial cells, and thus resulting in resistance to antiangiogenic therapy targeting VEGF. Reactive oxygen species (ROS) are involved in the self-renewal and differentiation of CSCs, yet, their role in endothelial differentiation of CSCs has been poorly understood. In this study, we found that cancer stem-like sphere cells enriched from human hepatocellular carcinoma cell line Hep G2 could differentiate into endothelial cells morphologically and functionally, and this process could be blocked by Akt1/2 kinase inhibitor and IKK-β inhibitor BAY 11-7082 but not by Bevacizumab, a VEGFA-binding antibody, and DAPT, a γ-secretase inhibitor. Both hydrogen peroxide and BSO (an inhibitor of GSH biosynthesis) induce the differentiation of cancer stem-like sphere cells into endothelial cells, which can be canceled by the antioxidant N-Acetyl-L-cysteine (NAC). We also found that hydrogen peroxide or BSO induces the phosphorylation of Akt and IKK of endothelial differentiated sphere cells. Accordingly, both Akt1/2 kinase inhibitor and BAY 11-7082 inhibited hydrogen peroxide and BSO-mediated endothelial differentiation of cancer stem-like sphere cells. Collectively, the results of the present study demonstrate that cancer stem-like sphere cells from Hep G2 are able to differentiate into endothelial cells both morphologically and functionally, and this process is independent of VEGF and NOTCH signaling but dependent on the activation of Akt and IKK. ROS promote endothelial differentiation of cancer stem-like sphere cells through activation of Akt/IKK signaling pathway. Therefore, our study reveals a novel mechanism of resistance to conventional antiangiogenic therapy and may provide a potential therapeutic target for liver cancer treatment.

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