Abstract
This study evaluated the effects of carbon ion and X-ray radiation and the tumor microenvironment on the migration of glioma and endothelial cells, a key process in tumorigenesis and angiogenesis during cancer progression. C6 glioma and human microvascular endothelial cells were treated with conditioned medium from cultures of glioma cells irradiated at a range of doses and the migration of both cell types, tube formation by endothelial cells, as well as the expression and secretion of migration-related proteins were evaluated. Exposure to X-ray radiation-conditioned medium induced dose-dependent increases in cell migration and tube formation, which were accompanied by an upregulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2 and -9 expression. However, glioma cells treated with conditioned medium of cells irradiated at a carbon ion dose of 4.0 Gy showed a marked decrease in migratory potential and VEGF secretion relative to non-irradiated cells. The application of recombinant VEGF165 stimulated migration in glioma and endothelial cells, which was associated with increased FAK phosphorylation at Tyr861, suggesting that the suppression of cell migration by carbon ion radiation could be via VEGF-activated FAK signaling. Taken together, these findings indicate that carbon ion may be superior to X-ray radiation for inhibiting tumorigenesis and angiogenesis through modulation of VEGF level in the glioma microenvironment.
Highlights
Malignant gliomas are the most common and lethal type of primary glioma in adults [1] due to its aggressivity and high propensity for invasion into surrounding normal tissue, which contribute to poor prognosis
High linear energy transfer (LET) heavy ions such as carbon ions have attracted attention as alternatives to conventional radiation for radiotherapy— for tumors that are radiation-resistant under hypoxic conditions—owing to their superior physical characteristics and high lethality for tumor cells compared to low-LET radiation such as X- and c-rays [3,4]
Endothelial cell migration is essential for angiogenesis, a process that is closely associated with tumorigenesis and cancer progression
Summary
Malignant gliomas are the most common and lethal type of primary glioma in adults [1] due to its aggressivity and high propensity for invasion into surrounding normal tissue, which contribute to poor prognosis. Our own studies have shown that carbon ion radiotherapy offers a high degree of control for targeting tumors and increases progressionfree survival rates without significant radiation-induced toxicity in skin carcinoma patients [5]. Due to the scarcity of particle accelerators that can produce heavy ion radiation, it has not yet been established whether carbon ions can modify the glioma microenvironment and affect the migratory behavior of cells during tumor progression and metastasis. To address this question, the present study evaluated the contribution of carbon ion radiation to the motility of glioma and endothelial cells using tumor-conditioned culture medium as an inducer
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