# Diabetic Retinopathy and Ocular Melanoma: How Far We Are?
## 4 Uveal Melanoma, Angiogenesis and Anti-Angiogenic Therapy  
Malignant melanoma is a type of tumour that develops from melanocytes and is amongst those with the highest death rate [127, 128]. The production and storage of high levels of melanin makes this tumour resistant to various therapies [129, 130]. Choroidal melanoma is treated either with radiotherapy (which can lead to vision loss) or by the removal of the eye by surgical resection. Therefore, the treatment approach of choroidal melanoma is quite debatable [131]. VEGFs influence invasion, migration, proliferation and tumour cell metastasis. The various growth factors and cytokines have an active effect on tissues and organs, promoting tumour development [132, 133, 134]. Several studies have shown high levels of VEGFs in patients with uveal melanoma, especially those with metastases [135]. Angiogenesis influences the development of metastases, being related to hypoxia and genetic mutations [136]. The relationship between microcirculatory problems and uveal melanomas, as well as the correlation with other eye diseases, has been described in the literature since the 1990s [137]. [PERSON] et al. have shown that VEGFs are expressed in uveal melanomas, promoting the formation and growth of new blood vessels, regulating vasopermeability and endothelial cell proliferation and migration [138]. In this study, the isoform VEGF-A is most expressed in patients with uveal melanoma, followed by VEGF-B, VEGF-C and VEGF-D isoforms. The expression of these VEGFs has a crucial role in angiogenesis, interfering with the progression and metastasis of uveal melanoma. High intraocular VEGF levels have also been shown to be associated with other diseases, such as DR, branch retinal vein occlusion, central retinal vein occlusion and uveitis [141, 139, 92, 140]. Among the different isoforms, VEGF-A isoform is the one mostly occurring in aqueous and vitreous humour of uveal melanoma patients and is also overexpressed in retinopathies caused by angiogenic proliferation [142, 143]. A study performed in enucleated eyes of uveal melanoma patients detected an overexpression of VEGF-A associated with the largest and more metastatic tumours [144]. The sharing of molecular pathways between ocular neovascularization diseases and tumor angiogenesis has indeed been highlighted [145]. As happens with other ocular diseases, VEGF-A is the major factor stimulating angiogenesis, being associated with the activation-migration-proliferation of endothelial cells, leading to the breakdown of the extracellular matrix [146]. The association of VEGF-A and pericytes is rarely described in the literature, however that surely exists. Indeed, pericytes have an important role in angiogenesis. The function of pericytes in angiogenesis is associated to maturation of newly formed vessels [147]. Pericytes have also been observed to follow endothelial cells in newly formed capillaries [148]. Pericytes contribute to the initiation and development of angiogenesis, and consequently, they are somehow involved in uveal melanoma, while the targeting of these cells for potential therapy is being studied [149]. [PERSON] reports the possibility of neovascular pericytes in uveal melanoma deriving from the host tissue and not from the tumour, given the presence of NG-2 negative and PDGF-\(\beta\)-receptor positive in NG2 knockout mice [149]. However, other important molecules, such as VEGF-A and platelet-derived growth factor-BB (PDGF), are instrumental in the early stages of angiogenesis, namely in the cellular activation process, and somehow, its receptor, PDGF-\(\beta\), is present in pericytes. The role of PDGF-\(\beta\) is mainly associated with the proliferation and migration of pericytes along the capillaries [150]. However, in the maturation stage of angiogenesis, the permeability of pericytes is decreased, inducing new blood vessels activated by PDGF-\(\beta\) signalling [151].