Tumour Angiogenesis in Uveal Melanoma Is Related to Genetic Evolution

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.

BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar-like features and activated PKA

“…In a therapeutic perspective, the 2 groups of tumors could benefit from anti-angiogenic drugs such as sorafenib 58 due to their common enrichment in markers of angiogenesis and endothelial cells ( Figure 4A and Supplementary Figure 2). Of note, a link between BAP1 alterations and angiogenesis was also recently described in uveal melanoma 59 . Finally, as BAP1 HCC are highly infiltrated by lymphocytes ( Figure 2J), a feature also described in BAP1 mutated peritoneal mesothelioma 60 , they can be considered as good candidates for immunotherapy.…”

The targeted LHRH analog AEZS-108 alters expression of genes related to angiogenesis and development of metastasis in uveal melanoma

“…Since lymphatic vessels are absent in the eye, angiogenesis plays a pivotal role in the development of UM and subsequently, in the development of metastasis [35,36,44,45]. Based on the special characteristics of uveal melanoma, our further aim was to investigate the effect of AEZS-108 on the expression of the genes related to angiogenesis and migration in OCM3 cells by qRT- For comparison, the corresponding mRNA expression levels of MASPIN are shown below the qPCR graphs for each treatments.…”

“…Our results shows that AEZS-108, as well as doxorubicin significantly inhibited the proliferation of OCM3 human uveal melanoma cells. Angiogenesis has a pivotal role in the development of UM because lymphatic vessels are not present in the eye to promote distant metastasis [35,36]. This special characteristics of UM also led us to investigate the effect of AEZS-108 on the expression of the genes involved in angiogenesis and metastasis in an in vitro model of UM.…”

Uveal Melanoma

“…Consistent with this observation, Voropaev et al show that knockdown of the hypoxia mediators cAMP response element-binding protein (CREB) or HIF1α in UM cells by means of replication-competent retroviral vectors dramatically decreases UM tumor progression [32]. Brouwer et al also address tumor angiogenesis and show that the monosomy 3 and the loss of BAP1 is associated with an increased microvascular density [37]. Van Beek et al report on rare cases of regional lymphatic spread showing the recruitment of intratumoral lymphatics by uveal melanomas with extraocular extension from subconjunctival lymphatics [45].…”