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Tumour Angiogenesis in Uveal Melanoma Is Related to Genetic Evolution

1
Department of Ophthalmology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
2
Department of Ophthalmology, Jeroen Bosch Hospital, 5223 GZ ‘s-Hertogenbosch, The Netherlands
3
Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
4
Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
5
Department of Pathology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(7), 979; https://doi.org/10.3390/cancers11070979
Received: 29 May 2019 / Revised: 27 June 2019 / Accepted: 11 July 2019 / Published: 13 July 2019
(This article belongs to the Special Issue Uveal Melanoma)
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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. View Full-Text
Keywords: uveal melanoma; angiogenesis; oncology; BAP1; VEGF-B; chromosomes; macrophages uveal melanoma; angiogenesis; oncology; BAP1; VEGF-B; chromosomes; macrophages
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Brouwer, N.J.; Gezgin, G.; Wierenga, A.P.; Bronkhorst, I.H.; Marinkovic, M.; Luyten, G.P.; Versluis, M.; Kroes, W.G.; van der Velden, P.A.; Verdijk, R.M.; Jager, M.J. Tumour Angiogenesis in Uveal Melanoma Is Related to Genetic Evolution. Cancers 2019, 11, 979.

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