Abstract
Increased angiogenesis is associated with a higher metastasis- and mortality rate in uveal melanoma (UM). Recently, it was demonstrated that genetic events, such as 8q-gain and BAP1-loss, influence the level of immune infiltrate. We aimed to determine whether genetic events, and specific cytokines, relate to angiogenesis in UM. Data from UM patients who underwent enucleation between 1999 and 2008 were analysed. Microvascular density (MVD) and the presence of infiltrating immune cells were determined with immunohistochemistry (IHC) and immunofluorescence in 43 cases. Chromosome status, BAP1 IHC and mRNA expression of angiogenesis-related genes were known in 54 cases. Tumours with monosomy 3/BAP1-loss showed a higher MVD compared to tumours with disomy 3/normal BAP1 expression (p = 0.008 and p = 0.004, respectively). Within BAP1-positive lesions (n = 20), 8q-gain did not relate to MVD (p = 0.51). A high MVD was associated with an increased expression of angiopoietin 2 (ANGPT2) (p = 0.041), Von Willebrand Factor (VWF) (p = 0.010), a decreased expression of vascular endothelial growth factor B (VEGF-B) (p = 0.024), and increased numbers of tumour-infiltrating macrophages (CD68+, p = 0.017; CD68+CD163+, p = 0.031) and lymphocytes (CD4+, p = 0.027). Concluding, vascular density of UM relates to its genetic profile: Monosomy 3 and BAP1-loss are associated with an increased MVD, while an early event (gain of 8q) is not independently related to MVD, but may initiate a preparation phase towards development of vessels. Interestingly, VEGF-B expression is decreased in UM with a high MVD.
Highlights
Uveal melanoma (UM) is the most common ocular malignancy in Caucasian adults
As a high Microvascular density (MVD) is known to be associated with a bad prognosis in UM, we first determined whether our population confirmed the existing assumptions
As we already know that genetic events are closely associated with the immunological microenvironment in UM, including the presence of macrophages and lymphocytes, we analysed whether genetic events play a role in the MVD and the expression of angiogenic factors in UM
Summary
Uveal melanoma (UM) is the most common ocular malignancy in Caucasian adults. The disease is often lethal with up to 50% of patients developing metastases [1]. Research has focussed on targeted and immunotherapeutic therapies, as promising results were obtained in the treatment of, for example, cutaneous melanoma. Results in UM are disappointing; and questions remain regarding the mechanisms leading to metastases and the tumour’s resistance to treatment. We sought to learn more about the relation between the tumour’s immunological microenvironment and the development of angiogenesis, which is an important parameter in growth and behaviour of UM, and a potential target for therapy. Restricted by the limits of diffusion (1–2 mm), an expanding UM requires new vessels to grow
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