# Diabetic Retinopathy and Ocular Melanoma: How Far We Are?
## 4 Uveal Melanoma, Angiogenesis and Anti-Angiogenic Therapy
Thus, the endothelial factor VEGF-A is the main element governing angiogenesis in ocular diseases, promoting a higher permeability and neovascularization, but it is not the only one. Recent studies reported that, when VEGF-A is down-expressed, VEGF-C is involved in the initiation and potentiation of neovascularization [152]. However, both VEGF-A and VEGF-C are overexpressed in certain physiological situations, such a hypoxia, oxidative stress, inflammation and hyperglyaemia. Paradoxically, other studies suggest that VEGF-C also incites lymphangiogenesis [153, 154]. In vitro studies have shown that tumour-associated macrophages are involved in all stages of melanomagenesis [155], in addition to the increased levels of lymphocytesand macrophages which are correlated with increased mortality. In order to stimulate angiogenesis, VEGF-C is activated by VEGFR-2 and VEGFR-3, specifically in retinal epithelial cells. [PERSON] et al. showed that VEGF-A supplementation stabilizes VEGF-C expression levels [156]. In DR, VEGF-C is also overexpressed by vascular endothelial cells and pericytes. Under constant hyperglyaemia levels in retinal cells, VEGF-C has been shown to promote survival of retinal vascular endothelial cells, especially via VEGFR-2 [157]. VEGF-C has been reported to control the display of VEGF-A, but the mechanisms of expression are not fully described yet [154]. VEGF is known to bind to cell surface tyrosine kinase receptors (VEGF-1 and VEGFR-2) [158]. Some studies documented the expression of VEGF-1 by pericytes in iris capillaries [146]. Furthermore, the secretion of VEGF and placental growth factor (PIGF) is believed to be mediated by VEGFR-1, which affects the perivascular cells directly, contributing to pericyte reduction and also to an increase of vascular leakage. Additionally, VEGFR-1 ligands have been investigated as potential therapeutic targets for cancer therapy due to their importance in the mediation of angiogenesis [158]. As mentioned previously, VEGF levels are elevated in uveal melanoma patients with metastases, in comparison to those without metastatic disease [159; 160]. Tumour vasculature is crucial in uveal melanoma, because metastasis only happens through the hematogenous pathway [161]. The first VEGF-directed angiogenesis inhibitor (bevacizumab) was developed for intravenous administration to be used for the treatment of several malignancies and is being studied for other primary tumours, together with other antiangiogenic drugs [162]. These antiangiogenic agents are already widely used to treat the secondary effects of radiotherapy in uveal melanoma patients [135]. Reactive oxygen species (ROS) are products of normal cellular metabolism; however, oxidative stress occurs when the capacity to regulate their overproduction is limited. Oxidative stress damages cellular lipids, proteins and DNA. The down-regulation of ROS is instrumental, especially in tumour development, since this process maintains homeostasis and thus controls oxidative stress [163]. The role of ROS in some biological processes includes migration, differentiation, proliferation, apoptosis, stress adaptation and gene expression [164]. In this context, growth factors also play a role, as activation of their receptors (e.g., PDGF receptor) causes ROS to modulate transduction signals. In melanoma tumour cells, a set of factors strongly influencing the over-production of ROS have been described. These factors are the deregulation of antioxidant enzymes, mitochondrial dysfunction, alteration of the expression of transcription factors, disrupted signalling pathways, aberrant metabolism, alteration in proliferation and acquisition of the metastatic phenotype [165; 166; 167]. The relationship between overproduction of ROS before and during tumour development has been reported by several authors over the last two decades [168; 169; 170]. In addition, the increased ROS levels, specifically in melanoma cells, have been documented by several authors [165; 171].