Exosomes Derived from Squamous Head and Neck Cancer Promote Cell Survival after Ionizing Radiation.

Ramesh Yentrapalli,Michael John Atkinson,Carsten Peters,Lisa Mutschelknaus,Theresa Heider,Klaudia Winkler,Pierre Busson,Simone Moertl

doi:10.1371/journal.pone.0152213

Ramesh Yentrapalli, Michael John Atkinson + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0152213

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Abstract

Exosomes are nanometer-sized extracellular vesicles that are believed to function as intercellular communicators. Here, we report that exosomes are able to modify the radiation response of the head and neck cancer cell lines BHY and FaDu. Exosomes were isolated from the conditioned medium of irradiated as well as non-irradiated head and neck cancer cells by serial centrifugation. Quantification using NanoSight technology indicated an increased exosome release from irradiated compared to non-irradiated cells 24 hours after treatment. To test whether the released exosomes influence the radiation response of other cells the exosomes were transferred to non-irradiated and irradiated recipient cells. We found an enhanced uptake of exosomes isolated from both irradiated and non-irradiated cells by irradiated recipient cells compared to non-irradiated recipient cells. Functional analyses by exosome transfer indicated that all exosomes (from non-irradiated and irradiated donor cells) increase the proliferation of non-irradiated recipient cells and the survival of irradiated recipient cells. The survival-promoting effects are more pronounced when exosomes isolated from irradiated compared to non-irradiated donor cells are transferred. A possible mechanism for the increased survival after irradiation could be the increase in DNA double-strand break repair monitored at 6, 8 and 10 h after the transfer of exosomes isolated from irradiated cells. This is abrogated by the destabilization of the exosomes. Our results demonstrate that radiation influences both the abundance and action of exosomes on recipient cells. Exosomes transmit prosurvival effects by promoting the proliferation and radioresistance of head and neck cancer cells. Taken together, this study indicates a functional role of exosomes in the response of tumor cells to radiation exposure within a therapeutic dose range and encourages that exosomes are useful objects of study for a better understanding of tumor radiation response.

Highlights

Exosomes are a subclass of extracellular microvesicles that are secreted by most cell types, including tumor cells
Exosomes released by the head and neck tumor cell line BHY were isolated by differential ultra-centrifugation
We have evaluated the role of exosomes in the response of head and neck cancer cells to radiation

Summary

Introduction

Exosomes are a subclass of extracellular microvesicles that are secreted by most cell types, including tumor cells. They are endocytic in origin and released into the extracellular environment through fusion of cytosolic multivesicular bodies with the plasma membrane. Exosome cargo includes a wide range of proteins, mRNAs, microRNAs and long non-coding RNAs [1,2,3,4]. Functional studies reveal that exosomes act as extracellular communicators by delivering their content to a target cell via membrane fusion, or alternatively by endocytosis [5]. The transfer of murine mast cell exosomes to human mast cells results in the translation of murine mRNA, proving that the delivered RNA molecules are functional in the recipient cells [3]

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