# Diabetic Retinopathy and Ocular Melanoma: How Far We Are?
## 4 Uveal Melanoma, Angiogenesis and Anti-Angiogenic Therapy
Thus, the radiosensitizing action of bevacizumab is thought to be related to the cytokine-uveal melanoma-endothelial cell interaction. Interleukin 8 (IL8 or CXCL) is a pro-inflammatory CXC chemokine expressed in positively regulated tumours together with VEGF, and both induce the formation of new blood vessels. IL8 expression is regulated by inflammatory signs and chemical and environmental stress, among other factors [200]. The biological effects are regulated by binding of IL8 to cell surface protein G-coupled receptors (CXCR1 and CXCR2). While CXCR1 is activated by IL8, CXCR2 can bind to different CXC chemokines, for example melanoma growth stimulating activity (MGSA), macrophage inflammatory protein 1 (MIP1) and neutrophil activating protein 2 (NAP2) [200; 201]. IL8 is highly expressed in many types of cancer, as it plays a crucial role in tumour development [202; 203]. IL8 further induces the expression of VEGFR2 and VEGF-A. Thus, there is a synergistic relationship between IL8 and VEGF in the formation and development of new blood vessels. However, some studies report that IL8 produced by tumour cells is related to VEGF-directed therapeutic resistance. Thus, it is thought that the IL8 signalling pathway can act independently of VEGF, compensating for it [204]. It is known that in uveal melanoma patients, the IL8 levels in eye fluids are quite high, highlighting the possibility that this signalling pathway may be an alternative mechanism of resistance to radiation therapy in this tumour [205; 206]. Thus, the effect of radiotherapy, bevacizumab and their relationship with cytokine expression and the CXCR2 receptor was studied. The interaction between inflammation and angiogenesis, i.e., interaction between inflammatory and endothelial cells, is crucial for the activation of the pathways that lead to tumour development [207]. The interaction between malignant and inflammatory cells has been shown to enable endothelial cell growth, leading to neoangiogenesis, tumour development and therapeutic resistance. Radiotherapy associated with anti-VEGF therapy activates the IL8 pathway through endothelial cells and may be an alternative approach against tumour angiogenesis. These experimental results show that endothelial cells can activate different pathways, leading to therapeutic resistance. Thus, the IL8 pathway can be used together with anti-VEGF therapy, preventing the tumour from activating the cell escape mechanism, avoiding therapeutic resistance and dominating tumour neoangiogenesis [206]. Figure 3 illustrates the signalling pathways and interactions between cells in uveal melanoma proliferation. In oncology, the MAPK signal cascade (RAS, RAF, MEK and ERK enzymes) is a fundamental pathway. The role of RAS and BRAF in cell development and survival and also induction of oncogenesis is dependent on MEK protein kinase function [208; 209]. Studies have shown that BRAF inhibitors verumafenib and dabrafenib (the first MAPK pathway inhibitors) have relevant clinical activity in melanomas with activating mutations at position 600 [210; 211; 212]. Following this discovery, more allosteric MEK inhibitors have been clinically developed. Trametinib has a distinct pharmacodynamic from all MEK allosteric inhibitors and has a more sustained inhibition [213; 214]. The clinical efficacy of trametinib as a MEK inhibitor has been reported by several studies. [PERSON] et al. showed a positive response in melanoma patients with BRAFV600E or BRAFV600K mutations [215]. [PERSON] et al. showed greater survival in BRAF mutant melanoma patients in comparison to chemotherapy [216]. However, when comparing trametinib with the BRAF inhibitors verumafenib and dabrafenib, the latter show a higher response rate in melanoma patients and a progression-free survival [211; 216; 217]. The effectiveness of MEK inhibition is clinically proven, and therefore, new combined forms of treatment are under research and development.