Ocular melanoma is a rare but deadly cancer. Despite treatment for primary tumors, about 50% of patients develop metastasis with poor prognosis, mostly in the liver. How do they spread? Can we prevent their escaping from the eyes?
Ocular melanoma patients have highly vascularized tumors with elevated expression of vascular endothelial growth factor (VEGF). VEGF is known to induce vascular leakage and angiogenesis. The anti-VEGF strategy was first developed against tumor angiogenesis and is currently used in clinics to reduce vascular leakage in eye diseases. However, the effects of injecting anti-VEGF in the eyes with ocular melanoma are controversial in mice and humans. Here, using an in vitro study, an organ-on-a-chip, and an in vivo animal model of ocular melanoma, we investigated whether ocular melanoma uses VEGF to metastasize.
Nhàn, N. T. T., Ganesh, S., Maidana, D. E., Heiferman, M. J. & Yamada, K. H. Uveal melanoma with a GNA11/GNAQ mutation secretes VEGF for systemic spread. Signal Transduct. Target. Ther. 10, 51 (2025).https://www.nature.com/articles/s41392-025-02144-8
Ocular melanoma cells with a GNA11/GNAQ mutation secrete VEGF to its conditioned medium, thus, treatment of ocular endothelial cells with an ocular melanoma-conditioned medium induces leakage of the endothelial barrier. To escape from the eyes, ocular melanoma cells need to go through the endothelial barrier. Inhibition of the VEGF signaling pathway by anti-VEGF treatment or a peptide inhibitor KAI prevents ocular melanoma migration across the endothelial barrier. Ocular melanoma that is injected at the back of the eyes escapes from the eyes and circulates through the bloodstream. Treatment of tumor-bearing mice with KAI eyedrop daily reduced the number of animals that have circulating tumor cells in their blood, suggesting that targeting VEGF could be a potential therapeutic strategy.
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