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

Abstract

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.

miR-328-3p overexpression attenuates the malignant proliferation and invasion of liver cancer via targeting Endoplasmic Reticulum Metallo Protease 1 to inhibit AKT phosphorylation

“…Xu et al reported that growth differentiation factor 15 (GDF15) induces growth and metastasis of human liver cancer stem-like cells via AKT/GSK-3β/β-catenin signaling (31). Kim et al reported that irradiated endothelial cells triggered IL-4/ERK/AKT signaling axis activity, which enhanced the malignancy of liver cancer cells (32). Xu et al found that TGFβRII knockdown resulted in the suppression of cell proliferation, invasion, and induced cell apoptosis via inhibiting PI3K/ Akt and p38 MAPK pathways, as well as the expression of MMPs and ERMP1 in A549 cells (33).…”

Involvement of IL-4, IL-13 and Their Receptors in Pancreatic Cancer

“…The proline-rich box regions in the intracellular domain of the receptors thereby mediate association with the JAKs instead of exhibiting an intrinsic kinase activity [ 73 ]. Signal transducer and activator of transcription (STAT)6 [ 74 ], insulin receptor substrate (IRS)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) [ 75 ], IRS/extracellular signal-regulated kinase (ERK) [ 41 ], and the mechanistic target of rapamycin (mTOR) [ 62 ] are supposed to be the main downstream signaling pathways [ 52 , 76 ]. In addition, IL-13 appears to play its own distinct role in cancer cells through binding to IL-13Rα2 with high affinity [ 77 ] and mediating invasion and metastasis via IL-13Rα2, ERK/activator protein 1 (AP-1) signaling, and matrix metalloproteinases (MMPs) pathways [ 78 ].…”

Radiotherapy targeting cancer stem cells “awakens” them to induce tumour relapse and metastasis in oral cancer

“…118 In hepatocellular carcinoma, endothelial cells exposed to radiation express elevated IL-4 to activate the ERK and AKT pathways, which promotes the migration and invasion of cancer cells as well as increases the size of the CSC population. 119 Myofibroblasts in the CSC niche have also been found to activate the Wnt signalling pathway by expressing hepatocyte growth factor, thereby inducing cancer cell dedifferentiation into CSCs and expression of stemness-related genes. 27 In HNSCC, the majority of CSCs are located perivascularly within a radius of 100 μm, suggesting that a perivascular niche of CSCs exists.…”