Abstract
Muscle-invasive bladder cancer (MIBC) represents a highly aggressive tumor type compared to non-muscle-invasive tumors. MIBC is characterized by specific molecular alterations, which may also modulate extracellular tumorigenic effects. Tumor-associated exosomes, especially exosomal miRNAs, are important regulators in the interaction between tumor cells and tumor microenvironment by affecting tumor-promoting processes in target cells. It is important to analyze whether their exosomal patterns also reflect the specific molecular characteristics of MIBC. The aim of this study was to compare the miRNA expression in secreted exosomes from urinary bladder cancer cells (UBC) with different degrees of invasiveness. By electron microscopy, nanotracking analysis and western blot we proofed a high quality of isolated exosomes. Microarray analysis identified an invasion-associated signature of 15 miRNAs, which is significantly altered in exosomes of invasive UBC compared to non-invasive counterparts. Therefrom, 9 miRNAs are consistent differently expressed in both, invasive cells and their secreted exosomes. The remaining 6 exosome-specific miRNAs are only deregulated in exosomes but not in their parental cells. MiRNA alterations were verified by qPCR in cell culture and urinary exosomes. In conclusion, we showed that exosomes from invasive UBC cells are characterized by a specific miRNA signature. Further analyses have to clarify the functional relevance of exosomal miRNAs secreted by invasive bladder cancer cells for modification of the tumor microenvironment and their putative role as molecular markers in liquid biopsies.
Highlights
Urothelial bladder cancer (UBC) is the 5th most common cancer in Europe
To the best of our knowledge, we present the first data indicating that exosomes secreted by invasive urinary bladder cancer cells (UBC) cells are characterized by a specific miRNA expression pattern
Invasive UBC cells are characterized by a specific miRNA expression pattern The miRNA microarray analysis revealed 37 miRNAs which were significantly differentially expressed (P < 0.05; Fold Change (FC) > 1.5) in invasive UBC cells (T24; J82; 253J-BV) compared to non-invasive cells (RT112; 5637). 29 miRNAs revealed a lower expression and 8 miRNAs a higher expression in these cell lines (Figure 1A)
Summary
Urothelial bladder cancer (UBC) is the 5th most common cancer in Europe. Around 70% of patients are diagnosed with a non-muscle-invasive tumor (NMIBC) and 30% with a muscle-invasive tumor (MIBC) [1]. 50% of patients with MIBC develop distant metastases in bones, lungs and liver associated with poor prognosis [2,3,4]. Recipient cells can internalize exosomes receptor-mediated, either by direct membrane fusion or by phagocytosis They are important players in the intercellular transfer regulating cell-cell communication [12, 13]. It is known that invasive UBC are characterized by specific molecular alterations including altered miRNA expression, so it would be important to analyze whether their exosomes are reflecting this aggressive tumor type [20, 21]. The aim of the study was the comparison of the miRNA expression pattern of secreted exosomes in correlation with the invasiveness of UBC cells in vitro and in vivo. To the best of our knowledge, we present the first data indicating that exosomes secreted by invasive UBC cells are characterized by a specific miRNA expression pattern
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