Temperature-dependent vascular endothelial growth factor (VEGF) induction in human retinal pigment epithelium – implications for transpupillary thermotherapy in uveal melanoma

Purpose Transpupillary thermotherapy is a hyperthermia treatment for small uveal melanomas but its use is controversially discussed. In uveal melanomas, vascular endothelial growth factor (VEGF) increase is correlated with metastases, and VEGF increase can be found in treated melanomas. In this study, the effect of hyperthermia on the VEGF secretion in human RPE cells was studied. Methods Immortal human retinal pigment epithelium (RPE) cell line Arpe-19 was exposed to 40°, 42°, 45° and 50°C for 1 min, 5 min and 15 min. Toxicity was evaluated using trypan blue exclusion assay and VEGF secretion was evaluated by ELISA. Involvement of Mitogen activated protein kinase (MAPK) pathways and Transient Receptor Potential Vanilloid (TRPV) channels on VEGF induction was investigated using commercially available inhibitors. Results Hyperthermia induces cell death in a time and temperature dependent manner. VEGF expression and secretion is strongly induced by hyperthermia in a time and temperature dependent manner. VEGF induction is mediated by p38 and to a lesser degree by JNK. TRPV channels are only involved in VEGF secretion at lower temperatures. Conclusion Hyperthermia induces a temperature dependent secretion of VEGF in human RPE, which is mediated by p38. As VEGF may be involved in the development of micrometastases, these findings indicate that thermotherapy for the treatment of uveal melanomas should be regarded with caution.