Abstract
Simple SummaryThe study of RNAs in the extracellular environment in physiological and pathological conditions has become a growing field of research with intriguing applications in diagnostics and prognostics. Such extracellular RNAs are passively or actively released by all cells into biological fluids to spread biological signals to other cells. The perturbation of such RNA-based cell-to-cell communications in cancer can be easily identified by molecular analysis of liquid biopsies, even if source cells secreting RNAs are often elusive. In uveal melanoma (UM), extracellular RNAs can be assayed in serum, plasma, and vitreous and aqueous humor. In this review, we explore the possibility that extracellular RNA alterations in UM could partially match with RNA dysregulations observed in tumor tissues and provide information to better understand UM biology.Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults, showing a high mortality due to metastasis. Although it is considered a rare disease, a growing number of papers have reported altered levels of RNAs (i.e., coding and non-coding RNAs) in cancerous tissues and biological fluids from UM patients. The presence of circulating RNAs, whose dysregulation is associated with UM, paved the way to the possibility of exploiting it for diagnostic and prognostic purposes. However, the biological meaning and the origin of such RNAs in blood and ocular fluids of UM patients remain unexplored. In this review, we report the state of the art of circulating RNAs in UM and debate whether the amount and types of RNAs measured in bodily fluids mirror the RNA alterations from source cancer cells. Based on literature data, extracellular RNAs in UM patients do not represent, with rare exceptions, a snapshot of RNA dysregulations occurring in cancerous tissues, but rather the complex and heterogeneous outcome of a systemic dysfunction, including immune system activity, that modifies the mechanisms of RNA delivery from several cell types.
Highlights
No data about these miRNAs in serum of Uveal melanoma (UM) patients are available to date, except for miR-211 [83], which showed an increased expression in serum of patients affected by localized UM compared to uveal nevi and in metastatic compared to localized UM
About 90% of exosomal miRNAs were detected in vitreous humor, suggesting that the majority of vitreal miRNAs are included in nanovesicles
Dysregulated miRNAs showed a significant positive expression correlation, suggesting that vitreal miRNA alteration in UM eyes is sustained by modifications of exosomal cargo and, is actively influenced by tumor cell activity
Summary
Cytoplasmatic fragments from dying cells are trapped inside the apoptotic bodies, which are swallowed by neighboring living cells via phosphatidylserine signaling By this passive mechanism, several miRNAs are transported into the apoptotic bodies, and potentially released into the circulation and captured by recipient cells [20]. The RNA content changes according to the donor cell type [33], and noticeable qualitative and quantitative differences have been reported between cancer cells and their physiological counterparts [34,35,36] This growing number of experimental observations, including eye cancer [12,37,38,39] and retinal degeneration [40,41,42,43,44], paved the way for extracellular RNA exploitation for diagnostic and prognostic purposes [45]. How much does the RNA from liquid biopsies replicate that from source tumor biopsies? In this review, we report the state of the art of extracellular RNA findings in uveal melanoma to shed light on the relationship between RNA dysregulations inside uveal melanoma cells and in the relative extracellular environments or patient bodily fluids
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