The tumor microenvironment is closely associated with tumor malignancy, and includes tumor relapse and metastasis trigged by epithelial-mesenchymal transition (EMT), which leads to the expansion of cancer stem-like cells. Radiotherapy is known to acutely and persistently affect changes in this tumor microenvironment by altering the vascular functions of tumor endothelial cells. However, the precise role of endothelial cells in tumor malignancy following treatment with irradiation has not been completely elucidated. The present study investigated the differences in malignant behavior of liver cancer cells in response to irradiated endothelial cells. To achieve this, a co-cultivation system was established to identify the potential role of endothelial cells in malignant liver cancer cells using medium conditioned with endothelial cells. It was observed that the medium conditioned by endothelial cells when irradiated with a single dose (2 Gy), greatly increased the migratory and invasive properties of liver cancer cells, as well as inducing mesenchymal markers, and enhancing the sphere-forming ability of liver cancer cells, The mRNA levels of genes regulating the self-renewal of cancer stem cells were increased in liver cancer cells by treatment with medium conditioned with endothelial cells. However, neither the medium conditioned by endothelial cells irradiated with fractionated doses (2 Gy × 3; 2 Gy/day for 3 days) or with a single dose (6 Gy) greatly influenced the malignancy of liver cancer cells. In conclusion, the data obtained by the present study indicated that 2 Gy irradiation of endothelial cells influenced the increase in tumor malignancy in liver cancer cells. Furthermore, the distinct differences in the indirect effects of ionizing radiation on tumor malignancy may provide valuable information for the improvement in the efficacy of radiotherapy.
Keywords: cancer stem-like cells; endothelial cells; epithelial-mesenchymal transition; invasion; ionizing radiation; migration.