Abstract
Radiation is utilized in the therapy of more than 50% of cancer patients. Unfortunately, many malignancies become resistant to radiation over time. We investigated the hypothesis that one method of a cancer cell's ability to survive radiation occurs through cellular communication via exosomes. Exosomes are cell-derived vesicles containing DNA, RNA, and protein. Three properties were analyzed: 1) exosome function, 2) exosome profile and 3) exosome uptake/blockade. To analyze exosome function, we show radiation-derived exosomes increased proliferation and enabled recipient cancer cells to survive radiation in vitro. Furthermore, radiation-derived exosomes increased tumor burden and decreased survival in an in vivo model. To address the mechanism underlying the alterations by exosomes in recipient cells, we obtained a profile of radiation-derived exosomes that showed expression changes favoring a resistant/proliferative profile. Radiation-derived exosomes contain elevated oncogenic miR-889, oncogenic mRNAs, and proteins of the proteasome pathway, Notch, Jak-STAT, and cell cycle pathways. Radiation-derived exosomes contain decreased levels of tumor-suppressive miR-516, miR-365, and multiple tumor-suppressive mRNAs. Ingenuity pathway analysis revealed the most represented networks included cell cycle, growth/survival. Upregulation of DNM2 correlated with increased exosome uptake. To analyze the property of exosome blockade, heparin and simvastatin were used to inhibit uptake of exosomes in recipient cells resulting in inhibited induction of proliferation and cellular survival. Because these agents have shown some success as cancer therapies, our data suggest their mechanism of action could be limiting exosome communication between cells. The results of our study identify a novel exosome-based mechanism that may underlie a cancer cell's ability to survive radiation.
Highlights
More than fifty percent of cancer patients, including patients with the most devastating central nervous system malignancy, glioblastoma [1, 2, 3], receive radiation as a critical component of their standard treatment regimen [4]
These markers are expressed by exosomes from glioma cell lines with and without radiation treatment (Figure 1F, 1G)
We explored whether the stress of radiation alters the dynamics of exosomes released from multiple cancer cell types
Summary
More than fifty percent of cancer patients, including patients with the most devastating central nervous system malignancy, glioblastoma [1, 2, 3], receive radiation as a critical component of their standard treatment regimen [4]. We propose that cellular communication via exosomes is critical to the ability of cancer cells to survive radiation therapy. Recent studies have demonstrated that ionizing radiation increases the release of exosomes from glioblastoma cells and alters their contents rendering the exosomes more oncogenic [27]. Changes in exosome content due to radiation have been identified [27, 28, 29, 30], the potential role of exosomes in induction of radiation survival and proliferation in recipient cancer cells induced by these radiation-derived exosomes has not been explored
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