Researchers in this study demonstrate that oxygen deprived Ewing’s sarcoma cells release exosomes, which transmit signals to enhance tumor survival.
A recent study was published in Oncotarget about Ewing’s sarcoma (EWS) and performed by researchers from the University of Nebraska Medical Center and Creighton University – both located in Omaha, Nebraska, USA.
Ewing’s sarcoma is a bone tumor that develops in children and adolescents. Treatment for this aggressive and highly malignant pediatric disease can be very successful in the early stages. However, patients that reach the later stages of EWS may only have a five-year survival rate of 25% or less. These poor outcomes are partly related to drug-resistant, stem-like cancer cells.
The researchers demonstrate that hypoxic (oxygen deprived) EWS cells release exosomes, which are the mechanisms that enhance tumor survival by promoting stem-like characteristics within the EWS cells.
Hypoxia Regulated Exosomes
“Recently, small extracellular vesicles called exosomes have been described as important mediators of cell-to-cell communication that transduce signals to neighboring cells and cells outside the local [tumor microenvironment] TME.”
The role of exosomes in Ewing’s sarcoma has been only mildly explored. Researchers that have investigated, believe it may be a mechanism that allows for hypoxic cells (hypoxia is essential for tumor growth) to communicate outside of the TME and promote aggressive tumors. Exosomes also carry with them cargo, including lipids, proteins, mRNAs, miRNAs, and gDNA.
“The role of hypoxia regulated exosomes and miRNA in EWS is currently unknown and highlights a major gap in scientific knowledge.”
Stemness Enhanced by miR-210
Researchers have found evidence to suggest that hypoxia may be able to “exert its effects” beyond the local microenvironment by signaling to nearby normoxic (normal oxygen) tumor cells. The miRNA that hypoxic Ewing’s sarcoma exosomes carry are uniquely hypoxia regulated. The exosome miRNA cargo delivery to the cancer cells has been shown to reprogram cancer cells and lead to tumor growth, cancer progression, and drug resistance.
Stemness is described by researchers as cells having the combined ability to perpetuate their lineage, give rise to differentiated cells, and interact with their environment. Stemness of cancer cells is a key feature for cancer progression and, in many cases, the source of its survival. MiR-210 is an miRNA directly overexpressed and up-regulated by hypoxia, and one that also regulates cell responses to decreased oxygen levels. Researchers sought to evaluate MiR-210 in hypoxic EWS exosomes and its role in the formation of stem-like cells in EWS.
The researchers found that the transfer of hypoxic exosomal miR-210 to normoxic cells silences caspase-8-associated protein 2 (CASP8AP2), which resulted in increased sphere formation (stemness) and cancer cell survival.
“We identified a hypoxia regulated miRNA significantly expressed in hypoxic cells and hypoxic exosomes and characterized a potential target that facilitates an apoptotic pathway critical to sphere formation.”
The researchers showed that miR-210 can enhance stemness by downregulating CASP8AP2. More importantly, the suppression of CASP8AP2 led to a reduction of cell death cells and increased sphere formation. This is the first study to describe a mechanism where the miRNA cargo in a hypoxic exosome is involved in regulating the survival of stem-like cells.
The authors of the paper state that future studies will further investigate the effects of EWS derived exosomal miRNAs on target genes and the role these interactions play in driving aggressiveness in hypoxic EWS tumors.
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Click here to read the full scientific paper, published in Oncotarget.