Radiation-induced VEGF-C expression and endothelial cell proliferation in lung cancer

Abstract

BackgroundThe present study was undertaken to investigate whether radiation induces the expression of vascular endothelial growth factor C (VEGF-C) through activation of the PI3K/Akt/mTOR pathway,subsequently affecting endothelial cells.Materials and methodsRadiotherapy-induced tumor micro-lymphatic vessel density (MLVD) was determined in a lung cancer xenograft model established in SCID mice. The protein expression and phosphorylation of members of the PI3K/Akt/mTOR pathway and VEGF-C secretion and mRNA expression in irradiated lung cancer cells were assessed by Western blot analysis, enzyme-linked immunosorbent assays (ELISAs), and reverse transcriptase–polymerase chain reaction (RT-PCR). Moreover, specific chemical inhibitors were used to evaluate the role of the PI3K/Akt/mTOR signaling pathway. Conditioned medium (CM) from irradiated control-siRNA or VEGF-C-siRNA-expressing A549 cells was used to evaluate the proliferation of endothelial cells by the MTT assay.ResultsRadiation increased VEGF-C expression in a dose-dependent manner over time at the protein but not at the mRNA level. Radiation also up-regulated the phosphorylation of Akt, mTOR, 4EBP, and eIF4E, but not of p70S6K. Radiation-induced VEGF-C expression was down-regulated by LY294002 and rapamycin (both p < 0.05). Furthermore, CM from irradiated A549 cells enhanced human umbilical vein endothelial cell (HUVEC) and lymphatic endothelial cell (LEC) proliferation, which was not observed with CM from irradiated VEGF-C-siRNA-expressing A549 cells.ConclusionsRadiation-induced activation of the PI3K/Akt/mTOR signaling pathway increases VEGF-C expression in lung cancer cells, thereby promoting endothelial cell proliferation.

Effects of proton versus photon irradiation on (lymph)angiogenic, inflammatory, proliferative and anti-tumor immune responses in head and neck squamous cell carcinoma

“…It has been reported that gamma rays irradiation induced VEGF-C expression and endothelial cell proliferation in lung cancer. 30 These observations, corroborated with ours, suggest that VEGF-C may be an important therapeutic target for HNSCC patients who relapse after radiotherapy with either P or X.…”

Relationship between four tumor-associated bio-markers and prognosis of gastric cancer

“…VEGF is highly expressed in most of human malignant tumors; it promotes endothelial cell proliferation and increases vascular permeability [18]. In the present study, the expression of VEGF was 55.9 %, which indicated that the VEGF expression can be used as an indicator for evaluating prognosis GC.…”

Deletion of Atm in Tumor but not Endothelial Cells Improves Radiation Response in a Primary Mouse Model of Lung Adenocarcinoma

“…It is possible that these radiation-induced vascular changes may be insufficient to impact tumor control because of vasculogenesis from bone marrow-derived cells that can reconstitute tumor vasculature after radiotherapy (30). It has also been reported that radiation activates VEGF expression, which can promote endothelial cell proliferation (31). Therefore, tumors may be able to redevelop their blood supply after highdose radiotherapy.…”