The malignancy of liver cancer cells is increased by IL-4/ERK/AKT signaling axis activity triggered by irradiated endothelial cells.

The malignant traits involved in tumor relapse, metastasis and the expansion of cancer stem-like cells are acquired via the epithelial-mesenchymal transition (EMT) process in the tumor microenvironment. In addition, the tumor microenvironment strongly supports the survival and growth of malignant tumor cells and further contributes to the reduced efficacy of anticancer therapy. Ionizing radiation can influence the tumor microenvironment, because it alters the biological functions of endothelial cells composing tumor vascular systems. However, to date, studies on the pivotal role of these endothelial cells in mediating the malignancy of cancer cells in the irradiated tumor microenvironment are rare. We previously evaluated the effects of irradiated endothelial cells on the malignant traits of human liver cancer cells and reported that endothelial cells irradiated with 2 Gy reinforce the malignant properties of these cancer cells. In this study, we investigated the signaling mechanisms underlying these events. We revealed that the increased expression level of IL-4 in endothelial cells irradiated with 2 Gy eventually led to enhanced migration and invasion of cancer cells and further expansion of cancer stem-like cells. In addition, this increased level of IL-4 activated the ERK and AKT signaling pathways to reinforce these events in cancer cells. Taken together, our data indicate that ionizing radiation may indirectly modulate malignancy by affecting endothelial cells in the tumor microenvironment. Importantly, these indirect effects on malignancy are thought to offer valuable clues or targets for overcoming the tumor recurrence after radiotherapy.