Correlation between the Expression of Angiogenic Factors and Stem Cell Markers in Human Uveal Melanoma.

Klára Fodor,Gábor Halmos,Éva Sipos,Lóránt Székvölgyi,Nikoletta Dobos,Kata Dull,Gábor Méhes,Andrew V. Schally,János Nagy,Zita Steiber

doi:10.3390/life10120310

Abstract

Uveal melanoma (UM) is the most common malignant tumor of the eye with extremely high metastatic potential. UM tumor cells can disseminate only hematogenously, thus, angiogenic signals have a particular role in the prognosis of the disease. Although the presence of cancer stem cells (CSCs) in densely vascularized UMs has been reported previously, their role in the process of hematogenous spread of UM has not been studied. In this study, we investigated the regulation of angiogenesis in UM in correlation with the presence of CSCs. Seventy UM samples were collected to analyze the expression of CSC markers and angiogenic factors. The expression of CSC markers was studied by RT-PCR, Western blotting techniques and IHC-TMA technique. RT-PCR showed high expression of CSC markers, particularly nestin, FZD6 and SOX10 and somewhat lower expression of NGFR. The protein expression of FZD6, HIF-1α and VEGFA was further evaluated in 52 UM samples by the IHC-TMA technique. We report here for the first time a significant correlation between FZD6 and VEGFA expression in UM samples. The observed correlation between FZD6 and VEGFA suggests the presence of CSCs in UM that are associated with the vascularization process.

Highlights

Uveal melanoma (UM) is a very rare disease, it is the most common primary intraocular malignancy in adults
In order to assess the presence of cancer stem cells (CSCs) in UM samples, we investigated the expression of five melanocyte stem cell markers by RT-PCR, Western blotting and immunohistochemistry (IHC) using the tissue microarray technique (IHC-TMA)
We further analyzed the results of five patients previously treated with ruthenium applicator and we found that all of them expressed the five stem cell markers investigated to the UM specimens not treated with ruthenium

Summary

Introduction

Uveal melanoma (UM) is a very rare disease, it is the most common primary intraocular malignancy in adults. Targeting transcriptional regulators may represent a promising therapeutic option in UM or these factors might contribute to the development of resistance against anti-VEGF targeted therapies. This can be the explanation for the studies demonstrating controversial or variable results in cell lines and animal models. Yang et al reported a successful reduction of the tumor volume of UM and the number of distant metastases in mouse models treated by intraperitoneally administered bevacizumab [17] In another clinical study, all patients received intraocular treatment with ranibizumab, a molecule that was developed from bevacizumab for the treatment of age-related macular degeneration. All patients showed tumor progression, this study had to be terminated and ranibizumab was suggested only as an adjunct treatment [18]

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