Abstract
Rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue tumor, which exists in oncoprotein PAX-FOXO1 fusion positive and fusion negative subtypes, with the fusion-positive RMS being characterized by a more aggressive clinical behavior. Exosomes are small membranous vesicles secreted into body fluids by multiple cell types, including tumor cells, and have been implicated in metastatic progression through paracrine signaling. We characterized exosomes secreted by a panel of 5 RMS cell lines. Expression array analysis showed that, for both fusion-positive and fusion-negative cells, exosome miRNA clustered well together and to a higher extent than cellular miRNA. While enriched miRNA in exosomes of fusion-negative RMS cells were distinct from those of fusion-positive RMS cells, the most significant predicted disease and functions in both groups were related to processes relevant to cancer and tissue remodelling. Functionally, we found that RMS-derived exosomes exerted a positive effect on cellular proliferation of recipient RMS cells and fibroblasts, induced cellular migration and invasion of fibroblasts, and promoted angiogenesis. These findings show that RMS-derived exosomes enhance invasive properties of recipient cells, and that exosome content of fusion-positive RMS is different than that of fusion-negative RMS, possibly contributing to the different metastatic propensity of the two subtypes.
Highlights
Respectively) may be more useful in prognostication and clinical allocation of therapy[3]
The fusion oncoprotein PAX3-FOXO1 was not present in exosomes derived from the fusion-positive RMS cell lines Rh30 and Rh41, despite being clearly present in the corresponding cell lysates (Fig. 1b)
To evaluate whether RMS-derived exosomes are taken up by recipient cells, we used fibroblasts transduced with retrovirus expressing green fluorescent protein (GFP), and treated them with RMS-derived exosomes stained red with the PKH26 membrane dye
Summary
Respectively) may be more useful in prognostication and clinical allocation of therapy[3]. Exosomes are small secreted membrane-bound particles measuring 30 to 120 nm in diameter, that have been shown to play important roles in cell-cell signaling and cellular communication, promoting secretion of growth factors, cytokines, and angiogenic factors by stromal cells, proliferation of endothelial cells, and metastasis. Exosomes derived from cancer cells have been demonstrated to promote angiogenesis, invasion, migration and proliferation in recipient cells to support tumor growth[9]. RMS is a interesting tumor where paracrine signaling is likely important, the fusion-positive subtype, which is known to be highly metastatic. We hypothesized that RMS-derived exosomes enhance invasiveness of RMS cells and associated fibroblasts via paracrine signaling, contributing to the known metastatic behavior of this aggressive tumor
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