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

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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.

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          An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer.

          David J Adelstein, Yi Li, George Adams … (2003)
          The Head and Neck Intergroup conducted a phase III randomized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer. Eligible patients were randomly assigned between arm A (the control), single daily fractionated radiation (70 Gy at 2 Gy/d); arm B, identical radiation therapy with concurrent bolus cisplatin, given on days 1, 22, and 43; and arm C, a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy, 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle. Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and, if necessary, as salvage therapy on all three treatment arms. Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test. Between 1992 and 1999, 295 patients were entered on this trial. This did not meet the accrual goal of 362 patients and resulted in premature study closure. Grade 3 or worse toxicity occurred in 52% of patients enrolled in arm A, compared with 89% enrolled in arm B (P <.0001) and 77% enrolled in arm C (P <.001). With a median follow-up of 41 months, the 3-year projected overall survival for patients enrolled in arm A is 23%, compared with 37% for arm B (P =.014) and 27% for arm C (P = not significant). The addition of concurrent high-dose, single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival, although it also increases toxicity. The loss of efficacy resulting from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery.
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            Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes.

            Jung Eun Park, Hon Sen Tan, Arnab Datta … (2010)
            Under hypoxia, tumor cells produce a secretion that modulates their microenvironment to facilitate tumor angiogenesis and metastasis. Here, we observed that hypoxic or reoxygenated A431 carcinoma cells exhibited enhanced angiogenic and metastatic potential such as reduced cell-cell and cell-extracellular matrix adhesion, increased invasiveness, and production of a secretion with increased chorioallantoic membrane angiogenic activity. Consistent with these observations, quantitative proteomics revealed that under hypoxia the tumor cells secreted proteins involved in angiogenesis, focal adhesion, extracellular matrix-receptor interaction, and immune cell recruitment. Unexpectedly, the secreted proteins were predominantly cytoplasmic and membrane proteins. Ultracentrifugation at 100,000 x g precipitated 54% of the secreted proteins and enriched for many exosome-associated proteins such as the tetraspanins and Alix and also proteins with the potential to facilitate angiogenesis and metastasis. Two tetraspanins, CD9 and CD81, co-immunoprecipitated. Together, these data suggested that tumor cells secrete proteins and exosomes with the potential to modulate their microenvironment and facilitate angiogenesis and metastasis.
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              Senescence-associated exosome release from human prostate cancer cells.

              Brian D Lehmann, Matthew S Paine, Adam M Brooks … (2008)
              Males of advanced age represent a rapidly growing population at risk for prostate cancer. In the contemporary setting of earlier detection, a majority of prostate carcinomas are still clinically localized and often treated using radiation therapy. Our recent studies have shown that premature cellular senescence, rather than apoptosis, accounts for most of the clonogenic death induced by clinically relevant doses of irradiation in prostate cancer cells. We show here that this treatment-induced senescence was associated with a significantly increased release of exosome-like microvesicles. In premature senescence, this novel secretory phenotype was dependent on the activation of p53. In addition, the release of exosome-like microvesicles also increased during proliferative senescence in normal human diploid fibroblasts. These data support the hypothesis that senescence, initiated either by telomere attrition (e.g., aging) or DNA damage (e.g., radiotherapy), may induce a p53-dependent increase in the biogenesis of exosome-like vesicles. Ultrastructural analysis and RNA interference-mediated knockdown of Tsg101 provided significant evidence that the additional exosomes released by prematurely senescent prostate cancer cells were principally derived from multivesicular endosomes. Moreover, these exosomes were enriched in B7-H3 protein, a recently identified diagnostic marker for prostate cancer, and an abundance of what has recently been termed "exosomal shuttle RNA." Our findings are consistent with the proposal that exosomes can transfer cargos, with both immunoregulatory potential and genetic information, between cells through a novel mechanism that may be recruited to increase exosome release during accelerated and replicative cellular senescence.
              Article 0 comments Cited 223 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Pierre Busson: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 23 March 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 3
                Electronic Location Identifier: e0152213
                Affiliations
                [1 ]Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Radiation Biology, Neuherberg, Germany
                [2 ]Department of Chemistry, Technical University of Munich, Munich, Germany
                [3 ]Radiation Biology, Technical University of Munich, Munich, Germany
                Gustave Roussy, FRANCE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: LM SM MA. Performed the experiments: LM CP KW RY TH. Analyzed the data: LM CP SM MA. Contributed reagents/materials/analysis tools: CP SM MA. Wrote the paper: LM CP RY TH MA SM.

                Article
                Publisher ID: PONE-D-15-49685
                DOI: 10.1371/journal.pone.0152213
                PMC ID: 4805173
                PubMed ID: 27006994
                SO-VID: f9b2bcce-264a-425b-bcd3-92a83ed8d276
                Copyright © © 2016 Mutschelknaus et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 16 November 2015
                Date accepted : 10 March 2016
                Page count
                Figures: 4, Tables: 0, Pages: 16
                Funding
                The authors have no support or funding to report.
                Categories
                Subject: Research Article
                Subject: Biology and life sciences
                Subject: Genetics
                Subject: DNA
                Subject: DNA repair
                Subject: Biology and life sciences
                Subject: Biochemistry
                Subject: Nucleic acids
                Subject: DNA
                Subject: DNA repair
                Subject: Medicine and Health Sciences
                Subject: Otorhinolaryngology
                Subject: Head and Neck Cancers
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Head and Neck Tumors
                Subject: Head and Neck Squamous Cell Carcinoma
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Carcinomas
                Subject: Squamous Cell Carcinomas
                Subject: Head and Neck Squamous Cell Carcinoma
                Subject: Research and Analysis Methods
                Subject: Microscopy
                Subject: Light Microscopy
                Subject: Fluorescence Microscopy
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancer Treatment
                Subject: Radiation Therapy
                Subject: Medicine and Health Sciences
                Subject: Clinical Medicine
                Subject: Clinical Oncology
                Subject: Radiation Therapy
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Clinical Oncology
                Subject: Radiation Therapy
                Subject: Physical Sciences
                Subject: Physics
                Subject: Nuclear Physics
                Subject: Radiation
                Subject: Ionizing Radiation
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cell Physiology
                Subject: Cell Communication
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancer Treatment
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files.

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