# Diabetic Retinopathy and Ocular Melanoma: How Far We Are?
## 4 Uveal Melanoma, Angiogenesis and Anti-Angiogenic Therapy
Melanocytes have the ability to suppress increased ROS levels, however melanoma cells do not have the same capacity [172]. Additionally, uveal melanocytes seem to a have a higher level of enzymatic antioxidant activity than normal melanocytes, the superoxide dismutase (SOD) activity being more evident. This can be explained by the high oxygen tension found in the choroid [173]. Moreover, other antioxidant enzymes have a reduced activity in melanoma cells, such as catalase, glutathione-S-transferase (GST) and manganese superoxide dismutase (MnSOD), associated with low levels of glutathione (GSH) [174; 175; 176]. An important achievement in melanoma cells is related to the enhancement of superoxide anion levels and also the decrease of hydrogen peroxide levels. The pro-oxidant intracellular environment and the activation of redox-sensitive transcription factors, which increase the high proliferative rate and drug resistance in these cells, are thought to justify these levels [177]. Another reason for the increased ROS levels is related to the ultraviolet (UV) light exposure, which is also associated with uveal melanoma development. Since melanoma results from abnormalities in melanocytes, the most harmful factor affecting these cells is UV exposure, for skin and also for ocular melanomas [178]. In uveal melanoma, UVB radiation is related to the high risk of tumour development [179]. Figure 2 illustrates the mechanism of oxidative stress and its effect in angiogenesis. Several researchers have investigated the role of blood vessels in uveal melanoma growth and metastasis [40]. For metastases to occur it is necessary for uveal melanoma cells to spread beyond the primary site and to enter the surrounding tissues and then the nearby blood vessels, where they circulate to other parts of the body. Several studies show a strong association between tumour cell growth in blood vessels and extraocular extension, indicating a high risk of death [180,181]. Malignant cells circulate in the blood and reach an organ to form a metastatic tumour (in uveal melanoma it is usually the liver) [182,183]. Certainly, there is a microenvironment that allows the uveal melanoma cells to spread faster. The poor prognosis can be explained by the expression of insulin growth factor 1 receptor (IGF-1R) in this melanoma. IGF-1 leads to phosphorylation of IGF-1R, activating signal molecules involved in cell proliferation. This growth factor is mainly produced in the liver, which explains liver metastases in uveal melanoma [184,185]. It was been proven that IGF-1 promotes VEGF release in RPE cells and is also involved in tumour proliferation in liver metastases [186]. Uveal melanoma is defined by slow progression and dormant periods, which are related to the avascular phase. However, the conversion to the angiogenic phenotype has not been determined yet, and this \"angiogenic change\" is a consequence of the change in the balance of inhibitory/stimulating factors [187]. It is known that the VEGF gene and protein expression is observed in retinal epithelium and pigment and is controlled in retinopathies associated with angiogenic proliferation [188]. Local treatment of this melanoma allows the eye to be saved in most patients, but some of them develop other complications (neovascularization of the iris), and therefore, eye removal is required. [PERSON] et al. proved that melanoma patients had higher VEGF-A concentrations compared to patients with routine cataract extraction [142]. No relationship was found between aqueous VEGF levels and retinal detachment, tumour size, vascularization or immunohistochemistry. High levels of VEGF are explained by anterior radiotherapy and also by neovascularization of the iris or optic nerve head. These results show that anti-VEGF therapy can be used to treat some patients with iris neovascularization secondary to uveal melanoma [142]. Tumour microvascularity, as referred to previously, is crucial for prior knowledge of uveal melanoma diagnosis and therapy.