Potential of serum microRNAs as biomarkers of radiation injury and tools for individualization of radiotherapy

  • Author Footnotes
    1 These authors contributed equally to this work.
    Bartłomiej Tomasik
    1 These authors contributed equally to this work.
    Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland

    Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    Justyna Chałubińska-Fendler
    1 These authors contributed equally to this work.
    Radiology Therapeutic Centre, Zgorzelec, Poland
    Search for articles by this author
  • Dipanjan Chowdhury
    Reprint requests: Dipanjan Chowdhury, Department of Radiation Oncology, Harvard Medical School, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115; Wojciech Fendler, Department of Biostatistics and Translational Medicine, Medical University of Lodz, 15 Mazowiecka Street, 92-215 Lodz, Poland.
    Department of Radiation Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
    Search for articles by this author
  • Wojciech Fendler
    Reprint requests: Dipanjan Chowdhury, Department of Radiation Oncology, Harvard Medical School, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115; Wojciech Fendler, Department of Biostatistics and Translational Medicine, Medical University of Lodz, 15 Mazowiecka Street, 92-215 Lodz, Poland.
    Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland

    Department of Radiation Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.


      Due to tremendous technological advances, radiation oncologists are now capable of personalized treatment plans and deliver the dose in a highly precise manner. However, a crucial challenge is how to escalate radiation doses to cancer cells while reducing damage to surrounding healthy tissues. This determines the probability of achieving therapeutic success whilst safeguarding patients from complications. The current dose constraints rely on observational data. Therefore, incidental toxicity observed in a minority of patients limits the admissible dose thresholds for the whole population, theoretically narrowing down the curative potential of radiotherapy. Future tools for measurements of individual's radiosensitivity before and during treatment would allow proper treatment personalization. Variation in tissue tolerance is at least partially genetically-determined and recent progress in the field of molecular biology raises the possibility that novel assays will allow to predict the response to ionizing radiation. Recently, microRNAs have garnered interest as stable biomarkers of tumor radiation response and normal-tissue toxicity. Preclinical studies in mice and nonhuman primates have shown that serum circulating microRNAs can be used to accurately distinguish pre- and postirradiation states and predict the biological impact of high-dose irradiation. First reports from human studies are also encouraging, however biology-driven precision radiation oncology, which tailors treatment to individual patient's needs, still remains to be translated into clinical studies. In this review, we summarize current knowledge about the potential of serum microRNAs as biodosimeters and biomarkers for radiation injury to lung and hematopoietic cells.


      AGO proteins (Argonaute proteins), CTCAE (common toxicity criteria for adverse events), Dicer (Helicase with RNase motif), Drosha (ribonuclease III enzyme involved in miRNA maturation), DSB (double strand breaks), DVH (dose-volume histogram), EORTC (European Organization for Research and Treatment for Cancer), GWAS (Genome Wide Association Studies), HDL (high density lipoprotein), ICRP (International Commission on Radiological Protection), IL (interleukin), IR (ionizing radiation), LASSO (least absolute shrinkage and selection operator), LSF (late side effects), miRNA (microRNA (ribonucleic acid)), NPM1 (nucleophosmine 1), NTCP (normal tissue complication probability), pri-miRNA (primary miRNA), pre-miRNA (precursor-miRNA), QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic), RAPPER study (Radiogenomics: Assessment of Polymorphisms for Predicting the Effects of Radiotherapy study), RILT (radiation-induced lung toxicity), RISC (RNA-induced silencing complex), RNAse (ribonuclease), ROS (reactive oxygen species), RP (radiation pneumonitis), RT (radiotherapy), RTOG (Radiation Therapy Oncology Group), siRNA (small interfering RNA), SNP (single nucleotide polymorphism), SOMA (subjective, objective, management, analytic), TD 5/5 (the probability of 5% complication within 5 years after radiotherapy), TD 50/5 (the probability of 50% complication within 5 years after radiotherapy), TGF-β (transforming growth factor beta), Vx (percentage of volume receiving x dose), RNA (ribonucleic acid), MIP (macrophage inflammatory protein), MCP (monocyte chemoattractant protein 1), TRBP (TAR RNA binding protein)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Begg AC
        • Stewart FA
        • Vens C
        Strategies to improve radiotherapy with targeted drugs.
        Nat Rev Cancer. 2011; 11: 239-253
        • Barton MB
        • Jacob S
        • Shafiq J
        • et al.
        Estimating the demand for radiotherapy from the evidence: a review of changes from 2003 to 2012.
        Radiother Oncol. 2014; 112: 140-144
        • Scaife JE
        • Barnett GC
        • Noble DJ
        • et al.
        Exploiting biological and physical determinants of radiotherapy toxicity to individualize treatment.
        Br J Radiol. 2015; 8820150172
        • Thoms J
        • Bristow RG
        DNA repair targeting and radiotherapy: a focus on the therapeutic ratio.
        Semin Radiat Oncol. 2010; 20: 217-222
        • Burnet NG
        • Nyman J
        • Turesson I
        • Wurm R
        • Yarnold JR
        • Peacock JH
        Prediction of normal-tissue tolerance to radiotherapy from in-vitro cellular radiation sensitivity.
        Lancet. 1992; 339: 1570-1571
        • Johansen J
        • Bentzen SM
        • Overgaard J
        • Overgaard M
        Evidence for a positive correlation between in vitro radiosensitivity of normal human skin fibroblasts and the occurrence of subcutaneous fibrosis after radiotherapy.
        Int J Radiat Biol. 1994; 66: 407-412
        • Russell NS
        • Grummels A
        • Hart AA
        • et al.
        Low predictive value of intrinsic fibroblast radiosensitivity for fibrosis development following radiotherapy for breast cancer.
        Int J Radiat Biol. 1998; 73: 661-670
        • Budach W
        • Classen J
        • Belka C
        • Bamberg M
        Clinical impact of predictive assays for acute and late radiation morbidity.
        Strahlenther Onkol. 1998; 174: 20-24
        • Bentzen SM.
        Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology.
        Nat Rev Cancer. 2006; 6: 702-713
        • Andreassen CN
        • Schack LMH
        • Laursen LV
        • Alsner J
        Radiogenomics—current status, challenges and future directions.
        Cancer Lett. 2016; 382: 127-136
        • Kim JH
        • Jenrow KA
        • Brown SL
        Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials.
        Radiat Oncol J. 2014; 32: 103-115
        • Mitchell PS
        • Parkin RK
        • Kroh EM
        • et al.
        Circulating microRNAs as stable blood-based markers for cancer detection.
        Proc Natl Acad Sci USA. 2008; 105: 10513-10518
        • Valadi H
        • Ekström K
        • Bossios A
        • Sjöstrand M
        • Lee JJ
        • Lötvall JO
        Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.
        Nat Cell Biol. 2007; 9: 654-659
        • Gupta SK
        • Bang C
        • Thum T
        Circulating MicroRNAs as biomarkers and potential paracrine mediators of cardiovascular disease.
        Circ Cardiovasc Genet. 2010; 3: 484-488
        • Acharya SS
        • Fendler W
        • Watson J
        • et al.
        Serum microRNAs are early indicators of survival after radiation-induced hematopoietic injury.
        Sci Transl Med. 2015; 7 (287ra69)
        • Fendler W
        • Malachowska B
        • Meghani K
        • et al.
        Evolutionarily conserved serum microRNAs predict radiation-induced fatality in nonhuman primates.
        Sci Transl Med. 2017; 9 (eaal2408)
        • Li L
        • Story M
        • Legerski RJ
        Cellular responses to ionizing radiation damage.
        Int J Radiat Oncol Biol Phys. 2001; 49: 1157-1162
        • Metheetrairut C
        • Slack FJ
        MicroRNAs in the ionizing radiation response and in radiotherapy.
        Curr Opin Genet Dev. 2013; 23: 12-19
        • Maier P
        • Hartmann L
        • Wenz F
        • Herskind C
        Cellular pathways in response to ionizing radiation and their targetability for tumor radiosensitization.
        Int J Mol Sci. 2016; ( 17
        • Willers H
        • Held KD
        Introduction to clinical radiation biology.
        Hematol Oncol Clin North Am. 2006; 20: 1-24
        • Bastianutto C
        • Mian A
        • Symes J
        • et al.
        Local radiotherapy induces homing of hematopoietic stem cells to the irradiated bone marrow.
        Cancer Res. 2007; 67: 10112-10116
        • Shi X
        • Shiao SL
        The role of macrophage phenotype in regulating the response to radiation therapy.
        Transl Res. 2018; 191: 64-80
        • Takemura N
        • Kurashima Y
        • Mori Y
        • et al.
        Eosinophil depletion suppresses radiation-induced small intestinal fibrosis.
        Sci Transl Med. 2018; 10 (eaan0333)
        • Wynn T
        Cellular and molecular mechanisms of fibrosis.
        J Pathol. 2008; 214: 199-210
        • Yamada T
        • Nakanishi Y
        • Homma T
        • et al.
        Airspace enlargement with fibrosis shows characteristic histology and immunohistology different from usual interstitial pneumonia, nonspecific interstitial pneumonia and centrilobular emphysema.
        Pathol Int. 2013; 63: 206-213
        • Taylor AMR
        • Harnden DG
        • Arlett CF
        • et al.
        Ataxia telangiectasia: a human mutation with abnormal radiation sensitivity.
        Nature. 1975; 258: 427-429
        • Woods WG
        • Byrne TD
        • Kim TH
        Sensitivity of cultured cells to gamma radiation in a patient exhibiting marked in vivo radiation sensitivity.
        Cancer. 1988; 62: 2341-2345
        • Leong T
        • Borg M
        • McKay M
        Clinical and cellular radiosensitivity in inherited human syndromes.
        Clin Oncol (R Coll Radiol). 2004; 16: 206-209
        • Patel AB
        • Hallemeier CL
        • Petersen IA
        • Jensen AW
        • Osborn TG
        • Miller RC
        Acute and late toxicities of radiotherapy for patients with discoid lupus erythematosus: a retrospective case-control study.
        Radiat Oncol. 2012; 7: 22
        • Peacock J
        • Ashton A
        • Bliss J
        • et al.
        Cellular radiosensitivity and complication risk after curative radiotherapy.
        Radiother Oncol. 2000; 55: 173-178
        • Dikomey E
        • Borgmann K
        • Peacock J
        • Jung H
        Why recent studies relating normal tissue response to individual radiosensitivity might have failed and how new studies should be performed.
        Int J Radiat Oncol Biol Phys. 2003; 56: 1194-1200
        • Lin A
        • Abu-Isa E
        • Griffith KA
        • Ben-Josef E
        Toxicity of radiotherapy in patients with collagen vascular disease.
        Cancer. 2008; 113: 648-653
        • Rubin P
        • Casarett G
        A direction for clinical radiation pathology. 6. Karger Publishers, 1972: 1-16
        • Emami B
        • Lyman J
        • Brown A
        • et al.
        Tolerance of normal tissue to therapeutic irradiation.
        Int J Radiat Oncol Biol Phys. 1991; 21: 109-122
        • Lyman JT
        Complication probability as assessed from dose-volume histograms.
        Radiat Res Suppl. 1985; 8: S13-S19
        • Kutcher GJ
        • Burman C
        • Brewster L
        • Goitein M
        • Mohan R
        Histogram reduction method for calculating complication probabilities for three-dimensional treatment planning evaluations.
        Int J Radiat Oncol Biol Phys. 1991; 21: 137-146
        • Burman C
        • Kutcher GJ
        • Emami B
        • Goitein M
        Fitting of normal tissue tolerance data to an analytic function.
        Int J Radiat Oncol Biol Phys. 1991; 21: 123-135
      1. 1990 Recommendations of the International Commission on Radiological Protection.
        Ann ICRP. 1991; 21: 1-201
        • Bentzen SM
        • Constine LS
        • Deasy JO
        • et al.
        Quantitative analyses of normal tissue effects in the clinic (QUANTEC): an introduction to the scientific issues.
        Int J Radiat Oncol Biol Phys. 2010; 76: S3-S9
        • Davidson SE
        • Burns M
        • Routledge J
        • et al.
        Short report: a morbidity scoring system for Clinical Oncology practice: questionnaires produced from the LENT SOMA scoring system.
        Clin Oncol (R Coll Radiol). 2002; 14: 68-69
        • Trotti A
        • Colevas AD
        • Setser A
        • et al.
        CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment.
        Semin Radiat Oncol. 2003; 13: 176-181
        • Pavy JJ
        • Denekamp J
        • Letschert J
        • et al.
        EORTC late effects working group. Late effects toxicity scoring: the SOMA scale.
        Int J Radiat Oncol Biol Phys. 1995; 31: 1043-1047
        • Cox JD
        • Stetz J
        • Pajak TF
        Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC).
        Int J Radiat Oncol. 1995; 31: 1341-1346
        • Dawson LA
        • Biersack M
        • Lockwood G
        • Eisbruch A
        • Lawrence TS
        • Ten Haken RK
        Use of principal component analysis to evaluate the partial organ tolerance of normal tissues to radiation.
        Int J Radiat Oncol. 2005; 62: 829-837
        • El Naqa I
        • Bradley J
        • Blanco AI
        • et al.
        Multivariable modeling of radiotherapy outcomes, including dose–volume and clinical factors.
        Int J Radiat Oncol. 2006; 64: 1275-1286
        • Gulliford SL
        • Webb S
        • Rowbottom CG
        • Corne DW
        • Dearnaley DP
        Use of artificial neural networks to predict biological outcomes for patients receiving radical radiotherapy of the prostate.
        Radiother Oncol. 2004; 71: 3-12
        • Chen S
        • Zhou S
        • Yin F-F
        • Marks LB
        • Das SK
        Investigation of the support vector machine algorithm to predict lung radiation-induced pneumonitis.
        Med Phys. 2007; 34: 3808-3814
        • Ospina JD
        • Zhu J
        • Chira C
        • et al.
        Random forests to predict rectal toxicity following prostate cancer radiation therapy.
        Int J Radiat Oncol. 2014; 89: 1024-1031
        • Lee T-F
        • Chao P-J
        • Ting H-M
        • et al.
        Using multivariate regression model with least absolute shrinkage and selection operator (LASSO) to predict the incidence of Xerostomia after intensity-modulated radiotherapy for head and neck cancer.
        PLoS One. 2014; 9: e89700
        • Kong C
        • Zhu X-Z
        • Lee T-F
        • et al.
        LASSO-based NTCP model for radiation-induced temporal lobe injury developing after intensity-modulated radiotherapy of nasopharyngeal carcinoma.
        Sci Rep. 2016; 6: 26378
        • Barnett GC
        • West CML
        • Dunning AM
        • et al.
        Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype.
        Nat Rev Cancer. 2009; 9: 134-142
        • West C
        • Rosenstein BS
        • Alsner J
        • et al.
        Establishment of a Radiogenomics Consortium.
        Int J Radiat Oncol. 2010; 76: 1295-1296
        • Barnett GC
        • Coles CE
        • Elliott RM
        • et al.
        Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: a prospective analysis study.
        Lancet Oncol. 2012; 13: 65-77
        • Talbot CJ
        • Tanteles GA
        • Barnett GC
        • et al.
        A replicated association between polymorphisms near TNFα and risk for adverse reactions to radiotherapy.
        Br J Cancer. 2012; 107: 748-753
        • Seibold P
        • Behrens S
        • Schmezer P
        • et al.
        XRCC1 polymorphism associated with late toxicity after radiation therapy in breast cancer patients.
        Int J Radiat Oncol. 2015; 92: 1084-1092
        • Kerns SL
        • Stock RG
        • Stone NN
        • et al.
        Genome-wide association study identifies a region on chromosome 11q14.3 associated with late rectal bleeding following radiation therapy for prostate cancer.
        Radiother Oncol. 2013; 107: 372-376
        • Barnett GC
        • Thompson D
        • Fachal L
        • et al.
        A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity.
        Radiother Oncol. 2014; 111: 178-185
        • Fachal L
        • Gómez-Caamaño A
        • Barnett GC
        • et al.
        A three-stage genome-wide association study identifies a susceptibility locus for late radiotherapy toxicity at 2q24.1.
        Nat Genet. 2014; 46: 891-894
        • Barnett GC
        • Kerns SL
        • Noble DJ
        • Dunning AM
        • West CML
        • Burnet NG
        Incorporating genetic biomarkers into predictive models of normal tissue toxicity.
        Clin Oncol. 2015; 27: 579-587
        • Yin M
        • Liao Z
        • Liu Z
        • et al.
        Functional polymorphisms of base excision repair genes XRCC1 and APEX1 predict risk of radiation pneumonitis in patients with non–small cell lung cancer treated with definitive radiation therapy.
        Int J Radiat Oncol. 2011; 81: e67-e73
        • Wen J
        • Liu H
        • Wang Q
        • et al.
        Genetic variants of the LIN28B gene predict severe radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy.
        Eur J Cancer. 2014; 50: 1706-1716
        • Schaue D
        • Kachikwu EL
        • McBride WH
        Cytokines in radiobiological responses: a review.
        Radiat Res. 2012; 178: 505-523
        • Gratchev A
        TGF-β signalling in tumour associated macrophages.
        Immunobiology. 2017; 222: 75-81
        • Ehrhart EJ
        • Segarini P
        • Tsang ML
        • Carroll AG
        • Barcellos-Hoff MH
        Latent transforming growth factor beta1 activation in situ: quantitative and functional evidence after low-dose gamma-irradiation.
        FASEB J. 1997; 11: 991-1002
        • Anscher MS
        • Kong FM
        • Andrews K
        • et al.
        Plasma transforming growth factor beta1 as a predictor of radiation pneumonitis.
        Int J Radiat Oncol Biol Phys. 1998; 41: 1029-1035
        • Zhao L
        • Wang L
        • Ji W
        • et al.
        Elevation of plasma TGF-β1 during radiation therapy predicts radiation-induced lung toxicity in patients with non-small-cell lung cancer: a combined analysis from Beijing and Michigan.
        Int J Radiat Oncol. 2009; 74: 1385-1390
        • Anscher MS
        • Marks LB
        • Shafman TD
        • et al.
        Risk of long-term complications after TFG-beta1-guided very-high-dose thoracic radiotherapy.
        Int J Radiat Oncol Biol Phys. 2003; 56: 988-995
        • Zhang X-J
        • Sun J-G
        • Sun J
        • et al.
        Prediction of radiation pneumonitis in lung cancer patients: a systematic review.
        J Cancer Res Clin Oncol. 2012; 138: 2103-2116
        • Anscher MS
        • Marks LB
        • Shafman TD
        • et al.
        Using plasma transforming growth factor beta-1 during radiotherapy to select patients for dose escalation.
        J Clin Oncol. 2001; 19: 3758-3765
        • Hart JP
        • Broadwater G
        • Rabbani Z
        • et al.
        Cytokine profiling for prediction of symptomatic radiation-induced lung injury.
        Int J Radiat Oncol. 2005; 63: 1448-1454
        • Arpin D
        • Perol D
        • Blay J-Y
        • et al.
        Early variations of circulating interleukin-6 and interleukin-10 levels during thoracic radiotherapy are predictive for radiation pneumonitis.
        J Clin Oncol. 2005; 23: 8748-8756
        • Jiang Y
        • Chen X
        • Tian W
        • Yin X
        • Wang J
        • Yang H
        The role of TGF-β1-miR-21-ROS pathway in bystander responses induced by irradiated non-small-cell lung cancer cells.
        Br J Cancer. 2014; 111: 772-780
        • Xu C
        • Yu P
        • Han X
        • et al.
        TGF-β promotes immune responses in the presence of mesenchymal stem cells.
        J Immunol. 2014; 192: 103-109
        • Tian B
        • Li X
        • Kalita M
        • et al.
        Analysis of the TGFβ-induced program in primary airway epithelial cells shows essential role of NF-κB/RelA signaling network in type II epithelial mesenchymal transition.
        BMC Genomics. 2015; 16: 529
        • Pietras EM
        Inflammation: a key regulator of hematopoietic stem cell fate in health and disease.
        Blood. 2017; 130: 1693-1698
        • Neta R
        Modulation of radiation damage by cytokines.
        Stem Cells. 2009; 15: 87-94
        • Postow MA
        • Sidlow R
        • Hellmann MD
        Immune-related adverse events associated with immune checkpoint blockade.
        (Longo DL, ed)N Engl J Med. 378. 2018: 158-168
        • Du S
        • Zhou L
        • Alexander GS
        • et al.
        PD-1 modulates radiation-induced cardiac toxicity through cytotoxic T lymphocytes.
        J Thorac Oncol. 2018; 13: 510-520
        • Gong X
        • Li X
        • Jiang T
        • et al.
        Combined radiotherapy and anti–PD-L1 antibody synergistically enhances antitumor effect in non–small cell lung cancer.
        J Thorac Oncol. 2017; 12: 1085-1097
        • Lambin P
        • Rios-Velazquez E
        • Leijenaar R
        • et al.
        Radiomics: extracting more information from medical images using advanced feature analysis.
        Eur J Cancer. 2012; 48: 441-446
        • Lambin P
        • Leijenaar RTH
        • Deist TM
        • et al.
        Radiomics: the bridge between medical imaging and personalized medicine.
        Nat Rev Clin Oncol. 2017; 14: 749-762
        • Defraene G
        • van Elmpt W
        • Crijns W
        • Slagmolen P
        • De Ruysscher D
        CT characteristics allow identification of patient-specific susceptibility for radiation-induced lung damage.
        Radiother Oncol. 2015; 117: 29-35
        • Moran A
        • Daly ME
        • Yip SSF
        • Yamamoto T
        Radiomics-based assessment of radiation-induced lung injury after stereotactic body radiotherapy.
        Clin Lung Cancer. 2017; 18: e425-e431
        • Afonso-Grunz F
        • Müller S
        Principles of miRNA–mRNA interactions: beyond sequence complementarity.
        Cell Mol Life Sci. 2015; 72: 3127-3141
        • Krol J
        • Loedige I
        • Filipowicz W
        The widespread regulation of microRNA biogenesis, function and decay.
        Nat Rev Genet. 2010; 11: 597-610
        • Ha M
        • Kim VN
        Regulation of microRNA biogenesis.
        Nat Rev Mol Cell Biol. 2014; 15: 509-524
        • Mitchell PS
        • Parkin RK
        • Kroh EM
        • et al.
        Circulating microRNAs as stable blood-based markers for cancer detection.
        Proc Natl Acad Sci. 2008; 105: 10513-10518
        • Turchinovich A
        • Burwinkel B
        Distinct AGO1 and AGO2 associated miRNA profiles in human cells and blood plasma.
        RNA Biol. 2012; 9: 1066-1075
        • Turchinovich A
        • Weiz L
        • Burwinkel B
        Extracellular miRNAs: the mystery of their origin and function.
        Trends Biochem Sci. 2012; 37: 460-465
        • Guduric-Fuchs J
        • O'Connor A
        • Camp B
        • O'Neill CL
        • Medina RJ
        • Simpson DA
        Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types.
        BMC Genomics. 2012; 13: 357
        • Skog J
        • Würdinger T
        • van Rijn S
        • et al.
        Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers.
        Nat Cell Biol. 2008; 10: 1470-1476
      2. Lotvall J, Valadi H. Cell to cell signalling via exosomes through esRNA. Cell Adh Migr 1:156–8.

        • Yang Q
        • Diamond MP
        • Al-Hendy A
        The emerging role of extracellular vesicle-derived miRNAs: implication in cancer progression and stem cell related diseases.
        J Clin epigenetics. 2016; ( 2
        • Kraemer A
        • Anastasov N
        • Angermeier M
        • Winkler K
        • Atkinson MJ
        • Moertl S
        MicroRNA-mediated processes are essential for the cellular radiation response.
        Radiat Res. 2011; 176: 575-586
        • Surova O
        • Akbar NS
        • Zhivotovsky B
        Knock-down of core proteins regulating MicroRNA biogenesis has no effect on sensitivity of lung cancer cells to ionizing radiation.
        PLoS One. 2012; 7 (Bernhard EJ, ed.): e33134
        • Zhang X
        • Wan G
        • Berger FG
        • He X
        • Lu X
        The ATM kinase induces MicroRNA biogenesis in the DNA damage response.
        Mol Cell. 2011; 41: 371-383
        • He X
        • He L
        • Hannon GJ
        The Guardian's Little Helper: MicroRNAs in the p53 tumor suppressor network.
        Cancer Res. 2007; 67: 11099-11101
        • Graham MV
        • Purdy JA
        • Emami B
        • et al.
        Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC).
        Int J Radiat Oncol Biol Phys. 1999; 45: 323-329
        • Wang D
        • Sun J
        • Zhu J
        • Li X
        • Zhen Y
        • Sui S
        Functional dosimetric metrics for predicting radiation-induced lung injury in non-small cell lung cancer patients treated with chemoradiotherapy.
        Radiat Oncol. 2012; 7: 69
        • van Luijk P
        • Faber H
        • Meertens H
        • et al.
        The impact of heart irradiation on dose–volume effects in the rat lung.
        Int J Radiat Oncol. 2007; 69: 552-559
        • Tucker SL
        • Liao Z
        • Dinh J
        • et al.
        Is there an impact of heart exposure on the incidence of radiation pneumonitis? Analysis of data from a large clinical cohort.
        Acta Oncol (Madr). 2014; 53: 590-596
        • Burnet NG
        • Wurm R
        • Nyman J
        • Peacock JH
        Normal tissue radiosensitivity—how important is it?.
        Clin Oncol (R Coll Radiol). 1996; 8: 25-34
        • Dinh T-KT
        • Fendler W
        • Chałubińska-Fendler J
        • et al.
        Circulating miR-29a and miR-150 correlate with delivered dose during thoracic radiation therapy for non-small cell lung cancer.
        Radiat Oncol. 2016; 11: 61
        • Moskwa P
        • Buffa FM
        • Pan Y
        • et al.
        miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors.
        Mol Cell. 2011; 41: 210-220
        • Cui W
        • Ma J
        • Wang Y
        • Biswal S
        Plasma miRNA as biomarkers for assessment of total-body radiation exposure dosimetry.
        (Jagetia GC, ed.)PLoS One. 6. 2011: e22988
        • Wei W
        • He J
        • Wang J
        • et al.
        Serum microRNAs as early indicators for estimation of exposure degree in response to ionizing irradiation.
        Radiat Res. 2017; 188: 342-354
        • Kiang JG
        • Smith JT
        • Anderson MN
        • et al.
        Hemorrhage enhances cytokine, complement component 3, and caspase-3, and regulates microRNAs associated with intestinal damage after whole-body gamma-irradiation in combined injury..
        (Li JJ, ed.)PLoS One. 12. 2017e0184393
        • Jacob NK
        • Cooley JV
        • Yee TN
        • et al.
        Identification of sensitive serum microRNA biomarkers for radiation biodosimetry..
        PLoS One. 2013; 8 (Camphausen K, ed): e57603
        • Templin T
        • Young EF
        • Smilenov LB
        Proton radiation-induced miRNA signatures in mouse blood: characterization and comparison with 56Fe-ion and gamma radiation.
        Int J Radiat Biol. 2012; 88: 531-539
        • Menon N
        • Rogers CJ
        • Lukaszewicz AI
        • et al.
        Detection of acute radiation sickness: a feasibility study in non-human primates circulating mirnas for triage in radiological events.
        (Amendola R, ed.)PLoS One. 11. 2016e0167333
        • Port M
        • Herodin F
        • Valente M
        • et al.
        MicroRNA expression for early prediction of late occurring hematologic acute radiation syndrome in baboons.
        (Fornace AJ, ed.)PLoS One. 11. 2016e0165307