Abstract
Simple SummaryWe hypothesize that proangiogenic factors such as angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), two targetable cytokines, may play a role in tumor development in uveal melanoma. We determined the expression of these cytokines in both uveal melanoma tissue as well as in aqueous humor, which provides a unique combination of data. We observed that ANG-2, in contrast to ANG-1, showed more expression in high-risk tumors and was associated with the development of metastases. Its presence in aqueous humor correlated with expression in tumor tissue. Knowledge about the expression of these cytokines may help to identify targets for personalized treatment.Uveal melanoma (UM) metastasize haematogeneously, and tumor blood vessel density is an important prognostic factor. We hypothesized that proangiogenic factors such as angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), two targetable cytokines, might play a role in tumor development and metastatic behavior. mRNA levels of ANG-1 and ANG-2 were determined in 64 tumors using an Illumina HT-12 v4 mRNA chip and compared to clinical, pathologic, and genetic tumor parameters. Tissue expression was also determined by immunohistochemistry (IHC). Samples of aqueous humor were collected from 83 UM-containing enucleated eyes and protein levels that were determined in a multiplex proximity extension assay. High tissue gene expression of ANG-2, but not of ANG-1, was associated with high tumor thickness, high largest basal diameter, involvement of the ciliary body, and with UM-related death (ANG-2 mRNA p < 0.001; ANG-2 aqueous protein p < 0.001). The presence of the ANG-2 protein in aqueous humor correlated with its mRNA expression in the tumor (r = 0.309, p = 0.03). IHC showed that ANG-2 was expressed in macrophages as well as tumor cells. The presence of ANG-2 in the tumor and in aqueous humor, especially in high-risk tumors, make ANG-2 a potential targetable cytokine in uveal melanoma.
Highlights
Uveal melanoma (UM) is a rare type of cancer, but it is the most common primary tumor of the eye, with an estimated incidence rate of 5–9 per 1.000.000 person–years [1].Despite successful treatment of the primary tumor, about 50% of all patients develop metastases [2,3]
All medical records were analyzed for clinical information and pathology reports were used to obtain histopathological characteristics, including tumor size, ciliary body involvement, cell type, tumor node metastasis (TNM)/American Joint Committee of Cancer (AJCC) Edition 8 stage and chromosome status [39]
Such a correlation suggests that angiopoietins may be treatment targets in primary and metastatic UM
Summary
Uveal melanoma (UM) is a rare type of cancer, but it is the most common primary tumor of the eye, with an estimated incidence rate of 5–9 per 1.000.000 person–years [1].Despite successful treatment of the primary tumor, about 50% of all patients develop metastases [2,3]. Once metastatic disease has developed, survival is short, with a median survival rate of only 6 months [2,5] Because of this poor prognosis and lack of improvement over time, it is of great importance to identify novel targets for the effective treatment of metastatic UM or for the prevention of metastatic outgrowth. Tumorinfiltrating leukocytes may be a source of proangiogenic cytokines, and, in UM, the presence of an inflammatory phenotype is associated with a bad prognosis. This inflammatory phenotype is characterized by an increased expression of human leukocyte antigens (HLA)
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