Changes in metabolism and metastatic properties of melanoma cells after X-ray irradiation

Background: Malignant melanoma has the ability to form metastases at very early stages and in addition to surgical resection treatment involves immunotherapy, chemotherapy and also radiotherapy. As it is known that irradiation can influence cellular metabolism it is conceivable that it can induce metabolic changes which lead to a predisposition of certain cells to show enhanced survival, migratory activity and metastasis. The aim of this study was to investigate short term and long term irradiation effects on metabolism and proliferation of irradiated melanoma cells in vitro and their ability to form metastases in vivo.
Material and methods: B16-F10 melanoma cells were irradiated with different doses of X-ray irradiation in the range of 1 to 20 Gy. One, two, and three days (short term effects) and, furthermore, 7, 14 and 21 days (long term effects) after treatment cells were analyzed concerning cell growth, viability, proliferation, cell cycle distribution, glucose and amino acid transport. Additionally, we performed in vivo studies in a syngeneic mouse model to analyze the capability of irradiated melanoma cells to form lung metastases.
Results: The analysis of short term effects showed decreased cell growth, viability and arrest in the G2/M phase of the cell cycle. Long term effects involve increase in proliferation, cell growth and glucose uptake but still decreased viability and amino acid transport. Our in vivo studies showed no formation of lung metastases when cells were irradiated before injection. If irradiated cells were allowed to recover for 2 weeks before injection, mice again developed lung metastases although to a lesser extent than control mice.
Conclusions: We conclude that melanoma cells as short term response to irradiation show cell cycle arrest and decrease in cell viability, growth and metabolic properties. One to three weeks after irradiation, the re-start of proliferation and recurrence of metabolic properties such as glucose uptake indicate that a subpopulation of surviving melanoma cells compensate for the initial irradiation-dependent damage possibly by metabolic modulations such as increase in glycolysis. Furthermore, in vivo studies reveal that irradiated melanoma cells are able to resume their metastatic potential within two weeks. As lung metastasis is lower when using recovered cells versus untreated cells, the role of additional mechanisms is strongly suggested.