Open access peer-reviewed chapter

Exosomes in Cancer Diagnosis and Radiation Therapy

Written By

Ai Nakaoka, Kana Kobayashi, Mennaallah Hassan and Ryohei Sasaki

Submitted: 17 October 2021 Reviewed: 18 November 2021 Published: 19 December 2021

DOI: 10.5772/intechopen.101684

From the Edited Volume

Extracellular Vesicles - Role in Diseases, Pathogenesis and Therapy

Edited by Manash K. Paul

Chapter metrics overview

331 Chapter Downloads

View Full Metrics


Exosomes are a subgroup of extracellular vesicles that are released by all types of cells, including tumor cells, and mediate intercellular communication via the transport of various intracellular components, including microRNAs, messenger RNAs, and proteins. Radiation produces reactive oxygen species and induces DNA double-strand break in cancer cells and normal cells. Cancer cells have severe damage and die by irradiation, but normal cells can keep proliferation with their high DNA repair ability. Irradiated cells generate communication signals and cause biological changes in neighboring or distant non-irradiated cells. This review outlines the role of exosomes in radiation therapy. In the tumor microenvironment, exosomes are considered to regulate cell survival, migration, and resistance to therapy by interacting with vascular endothelial cells and various types of immune cells. Nowadays, radiation therapy is typically combined with immunotherapy. Regulation of the activity of exosomes may overcome the problem of resistance to immunotherapy. Furthermore, exosomes can attenuate resistance to chemotherapy by transporting certain types of microRNA. The current evidence suggests that exosomes may be useful in the diagnosis and treatment of cancer in the future.


  • exosomes
  • cancer
  • microRNAs
  • liquid biopsy
  • radiation therapy

1. Introduction

Approximately half of all patients with cancer receive radiation therapy as part of their treatment making it critical in the treatment of cancer [1]. Radiation therapy is used in curative and palliative regimens to achieve locoregional control [2]. Furthermore, radiation therapy is often combined with surgery, chemotherapy, and more recently, immunotherapy [3]. Despite the progress made in approaches to deliver radiation, precision medicine and combined therapies, resistance to treatment, and recurrence continue to occur in the clinical setting. According to recent studies, components of exosomes such as miRNAs and lncRNAs perpetuate drug resistance. In gastric cancer, it is reported that exosomes from M2-macrophage-induced miR-21 mediated upregulation of PI3K/Akt signaling and reduced apoptosis and cisplatin resistance [4]. In breast cancer, exosomal miR-221/222 modulated p27 and estrogen receptor (ER) for tamoxifen resistance, and exosomal cargo-lncRNA UCA1 mediated tamoxifen resistance [5, 6]. In prostate cancer, cancer-associated fibroblast-derived exosomes conferred gemcitabine resistance via Snail and miR-146a [7].

Biologically, radiation induces damage to DNA and other host cell structures by oxidative stress [8]. Following exposure to X-rays, free radical production caused by the interaction of ionizing radiation with water molecules and redox-mediated biological pathways are responsible for oxidative DNA damage and cell death. Interaction of free radicals with DNA causes the formation of different types of DNA oxidation in both nucleus and mitochondria. Oxidation of DNA and also cell death through necrosis or apoptosis can stimulate inflammatory responses and oxidative stress, leading to further DNA damage. Oxidized cell-free DNA is elevated in cancer patients and also patients undergoing radiation therapy for their malignancies [9, 10].

Irradiated cells generate communication signals and cause biological changes in neighboring or distant non-irradiated cells. This phenomenon is known as the radiation-induced bystander effect (RIBE) [11, 12]. Although, the exact mechanism of RIBE remains unclear, there is increasing evidence to suggest that exosomal microRNAs (miRNAs) support various cellular regulatory roles in the response to radiation [13, 14, 15].

Radiation therapy has recently been shown to have systemic immune-modulating effects in patients with cancer, including an abscopal effect whereby local radiation elicits a systemic immune response and alleviates the tumor burden in untreated areas [16]. Although, the mechanism of the abscopal effect remains to be fully elucidated, there is accumulating evidence indicating a strong association between this effect and tumor-derived exosomes.

Exosomes are membrane vesicles with a diameter of 30–150 nm that are released by the fusion of an organelle in the endocytic pathway, the multivesicular body, and the plasma membrane [17]. Exosomes are released in a four-stage process, namely, initiation, endocytosis, formation of multivesicular bodies, and release of exosomes. The exosome with its cargo, consisting of messenger RNA (mRNA), miRNA, mitochondrial DNA (mtDNA), single-stranded DNA, double-stranded DNA, retrotransposons, and various proteins (MHC class I and II molecules, cytokines, adhesion molecules, transmembrane molecules, integrins, and tetraspanin) are released by the host cells and transferred to the recipient cells [18, 19, 20]. Exosomes are a subgroup of extracellular vesicles that are released by all types of cells, including tumor cells. Exosomes mediate intercellular communication by transporting various intracellular components, including cargos [21] and induce a variety of phenomena, including the proliferation of cancer cells [22], metastasis [23], and resistance to treatment [24]. Tumor-derived exosomes affect not only cancer cells themselves but also vascular endothelial cells and various types of immune cells (Figure 1). Exosomes released from tumor cells may affect proximal tumor cells and stromal cells in the local microenvironment and can also have systemic effects via their functional components, such as microRNAs and proteins, via the circulation. Emerging evidence suggests that tumor-derived exosomes have both immunostimulatory and immunosuppressive activity that depends on the molecules inside these structures and the status of immune cells in the tumor microenvironment [24, 25].

Figure 1.

Cancer-derived exosomes mediate various intercellular communications and induce the proliferation of cancer cells. Through communication with endothelial cells, vascular endothelial barriers are destroyed and metastasis is induced by cancer-derived exosomes. NK and CD8-positive cells are suppressed by cancer-derived exosomes. Macrophages are activated into M2 macrophages by cancer-derived exosomes. NK, natural killer.


2. Diagnosis of exosome-mediated cancer using liquid biopsies

Liquid biopsy is a term generally used to describe the collection of body fluid and has been explored as a non-invasive complementary tool for the diagnosis of cancer. Non-invasive measurement of cancer biomarkers using liquid biopsy allows for patient stratification, screening, monitoring of response to treatment, and detecting minimal residual disease following recurrence. Extracellular vesicles are considered to be significant biomarkers in the liquid biopsy-based diagnosis of cancer, and profiling of these vesicles has the potential to improve the early detection of cancer.

Liquid biopsy can provide more comprehensive information on the genetic landscape and track genomic evolution during disease progression in patients. The main biological biomarkers used in liquid biopsy include circulating tumor cells, circulating tumor DNA, and exosomes originating from healthy tissue or tumor tissue [26]. Given that many tissues are difficult or impossible to biopsy or resect, conventional biopsies cannot provide information on the efficacy of treatment. Exosomes can be easily acquired from most types of body fluid; therefore, they are attracting attention as biomarkers in liquid biopsy for diagnosis (Figure 2).

Figure 2.

Schema showing the liquid biopsy technique. Exosomes are released from cancer cells and enter blood vessels. Early diagnosis can be assisted by minimally invasive analysis of exosomes in blood vessels.


3. Roles of exosomes in common malignant diseases

3.1 Breast cancer

Early diagnosis of breast cancer increases the chances of cure and survival. Although, mammography is widely used, it is difficult to detect cancers in women with dense mammary gland tissue when using this method [27], and unnecessary radiated exposure should be avoided. Blood, nipple suction fluid, sweat, urine, and tears are being investigated as alternative diagnostic methods; among these, urine and tear tests have relatively high sensitivity and specificity. For example, the urinary miRNA profile in patients with primary breast cancer is different from that in healthy controls [28, 29, 30]. Cala et al. identified cancer-specific patterns and constructed models for the early diagnosis of breast cancer. They found that a combination of succinic acid and dimethylheptanoyl carnitine was able to separate patients with breast cancer (n = 31) from healthy controls (n = 29) with a sensitivity of 93.5% and a specificity of 86.2% [29].

Currently, reported urinary biomarkers of breast cancer are still in the discovery stage, and their specificity and sensitivity need to be verified in cohort studies. There are also multiple reports of biomarkers in tears [31, 32, 33, 34, 35], which are relatively easy to obtain using non-invasive methods. Inubushi et al. compared the exosomes in tears from five women with metastatic breast cancer with those from eight healthy volunteers and found higher amounts of exosome markers in tears than in serum and higher expression of breast cancer-specific miR-21 and miR-200c in tears from the patients with metastatic breast cancer [35]. Therefore, exosomes in tears could also be a useful diagnostic and prognostic biomarker.

Drug resistance is also a factor that affects prognosis. The role of exosomes in drug resistance has received a great deal of attention. There are numerous reports on the association between exosomes and drug resistance in breast cancer [36, 37, 38, 39, 40, 41, 42, 43]. Biomarkers can be used to predict the response of a tumor to a particular treatment and may reflect tumor susceptibility and drug resistance. Although, few methods are currently recommended for routine clinical application, blood-based monitoring of the therapeutic response is a minimally invasive and promising technique. Based on those methods, liquid biopsy analysis may bring novel information as biomarkers of breast cancer [44, 45].

3.2 Prostate cancer

Prostate cancer is a tumor with a high mortality rate, and early diagnosis has a significant effect on the prognosis. Serum and urinary exosomes are promising non-invasive biomarkers that could aid in early diagnosis [46, 47, 48]. Prostate cancer has a good prognosis when hormone therapy is effective, but castrate-resistant prostate cancer has a markedly worse prognosis. Hessvik et al. identified 36 exosomal miRNAs as candidate biomarkers for prostate cancer in clinical studies [49]. Moreover, plasma miR-1290 and miR-375 levels correlate with reduced overall survival and have been identified as potential prognostic biomarkers of castrate-resistant prostate cancer [50, 51]. Expression of AR-V7 RNA in circulating tumor cells was identified as a predictor of the response to enzalutamide (an anti-androgen) and abiraterone (an anti-androgen and CYP17 inhibitor) in prostate cancer [52]. Del Re et al. detected the AR-V7 transcript preferentially in patients resistant to treatment with enzalutamide or abiraterone and proposed that the level of the AR-V7 transcript measured in extracellular vesicles in plasma could serve as a biomarker [53].

3.3 Lung cancer

Screening with low-dose CT is currently used for early diagnosis of lung cancer but is associated with radiation exposure. miRNAs derived from exosomes in body fluids are stable and relatively easy to obtain. Therefore, they are expected to be useful biomarkers for the early diagnosis of lung cancer [54, 55, 56, 57, 58, 59, 60, 61]. Asakura et al. reported that serum miR-1268b and miR-6075 expression levels showed 99% sensitivity and 99% specificity for the diagnosis of lung cancer regardless of histological type or TNM stage [61]. This finding may lead to significant improvements in the results of screening for lung cancer and selection of more effective treatment for non-small cell lung cancer (NSCLC). Lebanony et al. reported that expression of exosomal miR-205 can distinguish between squamous and non-flat epithelial lung cancer even in poorly differentiated tumors [60]. Biomarkers that can predict the progression of lung cancer are also being investigated. Downregulation of miR-503 relative to non-malignant lung tissue has been observed in NSCLC tissue. For example, Liu et al. reported a link between the miR-503 level and advanced tumor stage and a poor prognosis [62]. These findings indicate that miR-503 may be a useful biomarker of survival in patients with NSCLC.


4. Exosome in radio-resistance

Radio-resistance is induced by certain conditions or pathways, and eventually limits the efficacies of radiation therapy. Molecular oxygen status is recognized as one of the most influential factors regulating radio-resistance. In general, cancer cells may be radio-resistant under hypoxic conditions in solid tumors [63, 64, 65]. Adapting to the hypoxic conditions, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. It is widely known that tumor cells in the hypoxia microenvironment induced radio-resistance by hypoxia-inducible factor 1 (HIF-1) and several pathways such as phosphatidylinositol 3-kinase Akt/mammalian target of rapamycin (mTOR), nuclear factor-κB (NF-κB) [66, 67, 68]. Tumor-derived exosomes promote angiogenesis by suppressing the expression of factor-inhibiting hypoxia-inducible factor 1 (HIF-1) and by transporting numerous pro-angiogenic biomolecules like vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and microRNAs. The hypoxic condition induces angiogenesis. Uptake of the tumor-derived exosomes by normal endothelial cells activates angiogenic signaling pathways in endothelial cells and stimulates new vessel formation [69]. Exosomes can affect T cells through direct receptor-ligand interactions, but in ECs, exosomes usually use the internalization pathway [70].

The NF-κB is known as the most important transcription factors regulating the expression of a large number of genes involved in cellular processes, such as inflammatory responses, cellular growth, developmental processes and apoptosis. The inducers of NF-κB activity are highly variable, including ROS, TNFα, IL-1β, LPS, isoproterenol, ionizing radiation, viruses, and chemotherapeutic reagents [71]. Active NF-κB enters the nucleus and up-regulates the transcription of Bcl-2, Bcl-xL, XIAP, survivin and Akt leading to chemo- and radio-resistance. Yoshida and coworkers demonstrated that NF-κB is the strongest indicator of radio-resistance in laryngeal squamous cell carcinoma cases treated with radiation therapy alone without surgery nor combined chemotherapy [72]. As for the relationship between exosomes and NF-κB, Zeng et al. elaborated that exosomal miR-183-5p shuttled by M2-TAM mediated Akt/NF-κB pathway to accelerate colon cancer progression through targeting thioesterase superfamily member 4 (THEM4) [73]. Li J et al. demonstrated that hypoxic colorectal cancer-derived extracellular vesicles deliver microRNA-361-3p to facilitate cell proliferation by targeting TRAF3 via the noncanonical NF-κB pathways [74].

Farias et al. reported that exosomes derived from irradiated MSCs (mesenchymal stem cells) delay tumor growth and reduce metastasis after treatment with MSC plus radiation therapy [75]. In this report, the authors indicate that the effect of MSCs on the tumor is associated with ANXA1; recognized as an anti-inflammatory mediator which regulates migration and cellular responses. They also showed MSCs plus radiation therapy administered on an experimental murine model had a positive effect on the tumor-volume reduction of the contralateral, untreated tumor [75]. According to these reports, exosomes derived from MSC are expected to be able to improve the efficacy of irradiation for radiation-resistant cancers.


5. Perspectives on the future use of exosomes in radiation therapy

Radiation induces oxidative stress in host cells [8], and the RIBE induced by exosomes has been investigated in several studies. It has been reported that irradiated cells release more exosomes than non-irradiated cells [12, 76, 77]. Arscott et al. identified a relationship between increased secretion of exosomes and overexpression or mutation of p53 in glioblastoma cells [78]. Furthermore, it has been found that exosomes derived from irradiated cells are taken up by neighboring cells in greater numbers than those derived from non-irradiated cells [79]. Hazawa et al. suggested that one reason for this difference could be the enhancement of cellular attachment to exosomes via augmented formation of the CD29/CD81 complex induced by radiation [80]. Thus, the influence of irradiation is transferred to neighboring cells via interaction with exosomal cargo. Although, the mechanism via which cargo is included in exosomes is not clearly understood, exosomal expression of miRNA influences the effect of irradiation on cells [79, 81]. Nakaoka et al. also investigated this effect and found that exosomes derived from irradiated MIAPaCa-2 human pancreatic cancer cells induced a radiosensitive effect on neighboring cells through an increase in levels of reactive oxygen species in cells [79], which they attributed to a reduction in expression of antioxidant enzymes via changes in the miRNA profile in exosomes. A summary of the molecules involved in RIBE is presented in Table 1.

CargoMoleculeCell lineInteractionsRef.
miRNAsmiR-7-5pBEP2DInduction of autophagy13
miR-208aNon-small cell lung cancer cellsPromotion of cell proliferation
Induction of radioresistance
miR-301aGlioblastoma cellsPromotion of radiation resistance15
miR-6823-5pMIAPaCa-2Enhancement of radiosensitive effect79
ProteinsConnective tissue growth factor
Insulin-like growth factor-binding protein 2
LN18, U87MG and U251Enhancement of tumorigenesis and migration78

Table 1.

Radiation-induced bystander effect induced by exosomes.

Radiation therapy can have profound immune-stimulatory effects and is increasingly viewed as a promising partner in combination therapy for patients receiving immunotherapy. Intrinsic events in cancer cells induced by DNA damage are central to the immune-modifying effects of radiation therapy [82]. These events have been investigated in studies of the DNA damage response, which focuses on the tumor microenvironment. In addition to its ability to destroy cancer cells by damaging DNA, radiation therapy can modulate both the immunotherapy and adjuvant therapy of tumors by triggering the release of pro-inflammatory mediators, increasing tumor-infiltrating immune-stimulatory cells. and enhancing the expression of neoantigens [82, 83, 84] and immune-stimulatory signaling by cyclic dinucleotide cyclic GMP-AMP. Understanding the mechanistic basis of radiation therapy as an anticancer treatment has been transformed by the recent discovery that DNA damage in cycling cancer cells can activate cytoplasmic nucleic acid sensors [82, 83]. The cGAS (cytoplasmic DNA-sensing cyclic GMP–AMP synthase)-STING (stimulator of interferon genes) pathway is involved in this process [85, 86]. Using this pathway, tumor-derived exosomes can shuttle TREX1-sensitive type I interferon-stimulatory double-stranded DNA from irradiated cancer cells to dendritic cells (Figure 3) [87].

Figure 3.

Radiation and immune response via cancer-derived exosomes in the tumor microenvironment. The pathway related to activation of cytoplasmic nucleic acid sensors. Tumor-derived exosomes can transport type I IFN-stimulatory dsDNA from irradiated cancer cells to dendritic cells via the STING pathway. T-cells produce IFN-𝛾. Inhibition of activation of CD8-positive T-cells by PD-1/L1 binding. cGAS cytoplasmic DNA-sensing cyclic GMP-AMP synthase; dsDNA, double-stranded DNA; IFN, interferon; STING, stimulator of interferon genes.


6. Exosomes in chemotherapy and other therapy

Chemo-resistance should be solved for effective cancer therapy. Several studies indicated that signal transducer and activator of transcription 3 (STAT3), focal adhesion kinase (FAK) and epithelial-mesenchymal transition (EMT) contribute to the development of chemotherapeutic resistance [88, 89, 90, 91]. The anti-apoptotic signal which is activated by the STAT3 pathway is an important factor in causing initial drug resistance [88]. FAK is reported to promote invasive tumor growth with β-catenin [89]. EMT is popular with the induction of cancer metastasis [90], but it is also deeply related to drug resistance. Mani et al. reported that EMT may cause cancer cells to acquire epithelial stem cell properties [91]. EMT formation induces chemo-resistance [92] and it is induced by various signaling pathways, such as TGFβ, Wnt signal, etc. [93, 94].

Several studies have demonstrated that exosomal activity might be involved in chemo-resistance. In EMT, Shan et al. indicated that downregulation of exosomal miR-148b-3p may offer opportunities in the treatment of bladder cancer by increasing chemosensitivity via inhibition of the Wnt/β-catenin pathway and promoting expression of PTEN [95]. In addition to it, Liu et al. reported that exosome-transmitted miR-128-3p increased chemosensitivity of oxaliplatin-resistant colorectal cancer by suppressing epithelial-mesenchymal transition and inducing drug accumulation in cancer cells [96]. Furthermore, exosomes derived from cancer-associated fibroblasts and cancer cells are often reported to contribute to chemo-resistance [97, 98]. According to these reports, exosomes are also important to the regulation of chemotherapy.


7. Conclusions

Exosomes play a critical role in cancer progression, including cell–cell communication, tumor-stromal interactions, activation of signaling pathways, and immunomodulation. Emerging data indicate that radiation-derived exosomes increase tumor burden, decrease survival, cause radiation-induced bystander effects and promote radio-resistance. Exosomes show abilities as diagnostic and predictive biomarkers in various malignancies. Exosomes play a role in radio- and chemo-resistance through multiple pathways. The mechanism of the intercellular communication by exosomes, the transport of exosomal cargo, the secretion mechanism, cell dependence, immune response and radiation response have been intensively explored. Specifically, research on exosomes about radiation therapy has been expanding. Radiation-exposed cells release altered exosomes, and those exosomes play a role as cargo to bring multiple messages to their recipient cells leading to various radiation responses. Further understanding of the mechanisms of exosome-mediated radio-resistance might ultimately lead to the development of novel treatment strategies.



This research was supported by Grants-in-Aid for Exploratory Research (21 J21801 to AN, and 21 K07642 to KK) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.


Conflict of interest

The authors declare no conflict of interest.


  1. 1. Delaney G, Jacob S, Featherstone C, Barton M. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer. 2005;104:1129-1137. DOI: 10.1002/cncr.21324
  2. 2. Grass GD, Krishna N, Kim S. The immune mechanisms of abscopal effect in radiation therapy. Current Problems in Cancer. 2016;40:10-24. DOI: 10.1016/j.currproblcancer.2015.10.003
  3. 3. Yaromina A, Krause M, Baumann M. Individualization of cancer treatment from radiotherapy perspective. Molecular Oncology. 2012;6:211-221. DOI: 10.1016/j.molonc.2012.01.007
  4. 4. Liao J, Liu R, Shi YJ, Yin LH, Pu YP. Exosome-shuttling microRNA-21 promotes cell migration and invasion-targeting PDCD4 in esophageal cancer. International Journal of Oncology. 2016;48:2567-2579. DOI: 10.3892/ijo.2016.3453
  5. 5. Wei Y, Lai X, Yu S, Chen S, Ma Y, Zhang Y, et al. Exosomal miR-221/222 enhances tamoxifen resistance in recipient ER-positive breast cancer cells. Breast Cancer Research and Treatment. 2014;147:423-431. DOI: 10.1007/s10549-014-3037-0
  6. 6. Xu CG, Yang MF, Ren YQ, Wu CH, Wang LQ. Exosomes mediated transfer of lncRNA UCA1 results in increased tamoxifen resistance in breast cancer cells. European Review for Medical and Pharmacological Sciences. 2016;20:4362-4368
  7. 7. Richards KE, Zeleniak AE, Fishel ML, Wu J, Littlepage LE, Hill R. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene. 2017;36:1770-1778. DOI: 10.1038/onc.2016.353
  8. 8. Ward JF, Evans JW, Limoli CL, Calabro-Jones PM. Radiation and hydrogen peroxide induced free radical damage to DNA. British Journal of Cancer. 1987;55:105-112
  9. 9. Cheng C, Omura-Minamisawa M, Kang Y, Hara T, Koike I, Inoue T. Quantification of circulating cell-free DNA in the plasma of cancer patients during radiation therapy. Cancer Science. 2009;100:303-309. DOI: 10.1111/j.1349-7006.2008.01021.x
  10. 10. Deligezer U, Eralp Y, Akisik EZ, Akisik EE, Saip P, Topuz E, et al. Effect of adjuvant chemotherapy on integrity of free serum DNA in patients with breast cancer. Annals of the New York Academy of Sciences. 2008;113:175-179. DOI: 10.1196/annals.1448.010
  11. 11. Al-Mayah AHJ, Irons SL, Pink RC, Carter DRF, Kadhim MA. Possible role of exosomes containing RNA in mediating nontargeted effect of ionizing radiation. Radiation Research. 2012;177:539-545. DOI: 10.1667/rr2868.1
  12. 12. Al-Mayah A, Bright S, Chapman K, Irons S, Luo P, Carter D, et al. The non-targeted effects of radiation are perpetuated by exosomes. Mutation Research. 2015;772:38-45. DOI: 10.1016/j.mrfmmm.2014.12.007
  13. 13. Song M, Wang Y, Shang ZF, Liu XD, Xie DF, Wang Q, et al. Bystander autophagy mediated by radiation-induced exosomal miR-7-5p in non-targeted human bronchial epithelial cells. Scientific Reports. 2016;6:30165. DOI: 10.1038/srep30165
  14. 14. Tang Y, Cui Y, Li Z, Jiao Z, Zhang Y, He Y, et al. Radiation-induced miR-208a increases the proliferation and radioresistance by targeting p21 in human lung cancer cells. Journal of Experimental & Clinical Cancer Research. 2016;35:7. DOI: 10.1186/s13046-016-0285-3
  15. 15. Yue X, Lan F, Xia T. Hypoxic glioma cell-secreted exosomal miR-301a activates Wnt/β-catenin signaling and promotes radiation resistance by targeting TCEAL7. Molecular Therapy. 2019;27:1939-1949. DOI: 10.1016/j.ymthe.2019.07.011
  16. 16. Hu ZI, McArthur HL, Ho AY. The abscopal effect of radiation therapy: what is it and how can we use it in breast cancer? Current Breast Cancer Reports. 2017;9:45-51. DOI: 10.1007/s12609-017-0234-y
  17. 17. Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cellular and Molecular Life Sciences. 2018;75:193-208. DOI: 10.1007/s00018-017-2595-9
  18. 18. Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nature Reviews. Immunology. 2002;2:569-579. DOI: 10.1038/nri855
  19. 19. Zhang C, Ji Q, Yang Y, Li Q, Wang Z. Exosome: Function and role in cancer metastasis and drug resistance. Technology in Cancer Research & Treatment. 2018;17:1-12. DOI: 10.1177/1533033818763450
  20. 20. McAndrews KM, Kalluri R. Mechanisms associated with biogenesis of exosomes in cancer. Molecular Cancer. 2019;18:52. DOI: 10.1186/s12943-019-0963-9
  21. 21. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology. 2007;9:654-659. DOI: 10.1038/ncb1596
  22. 22. Wu H, Zhou J, Mei S, Wu D, Mu Z, Chen B, et al. Circulating exosomal microRNA-96 promotes cell proliferation, migration and drug resistance by targeting LMO7. Journal of Cellular and Molecular Medicine. 2017;21:1228-1236. DOI: 10.1111/jcmm
  23. 23. Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, et al. Cancer secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell. 2014;25:501-515. DOI: 10.1016/j.ccr.2014.03.007
  24. 24. Li I, Nabet BY. Exosomes in the tumor microenvironment as mediators of cancer therapy resistance. Molecular Cancer. 2019;18:32. DOI: 10.1186/s12943-019-0975-5
  25. 25. Whiteside TL. Exosomes and tumor-mediated immune suppression. Journal of Clinical Investigation. 2016;126:1216-1223. DOI: 10.1172/JCI81136
  26. 26. De Rubis G, Krishnan SR, Bebawy M. Circulating tumor DNA – Current state of play and future perspectives. Pharmacological Research. 2018;136:35-44. DOI: 10.1016/j.phrs.2018.08.017
  27. 27. Bakker MF, de Lange SV, Pijnappel RM, Mann RM, PHM P, Monninkhof EM, et al. Supplemental MRI screening for women with extremely dense breast tissue. The New England Journal of Medicine. 2019;381:2091-2102. DOI: 10.1056/NEJMoa1903986
  28. 28. Ando W, Kikuchi K, Uematsu T, Yokomori H, Takaki T, Sogabe M, et al. Novel breast cancer screening: Combined expression of miR-21 and MMP-1 in urinary exosomes detects 95% of breast cancer without metastasis. Scientific Reports. 2019;9:13595. DOI: 10.1038/s41598-019-50084-5
  29. 29. Cala M, Aldana J, Sanchez J, Guio J, Meesters RJW. Urinary metabolite and lipid alterations in Colombian Hispanic women with breast cancer: A pilot study. Journal of Pharmaceutical and Biomedical Analysis. 2018;152:234-241. DOI: 10.1016/j.jpba.2018.02.009
  30. 30. Dinges SS, Hohm A, Vandergrift LA, Nowak J, Habbel P, Kaltashov IA, et al. Cancer metabolomic markers in urine: Evidence, techniques and recommendations. Nature Reviews. Urology. 2019;16:339-362. DOI: 10.1038/s41585-019-0185-3
  31. 31. Lebrecht A, Boehm D, Schmidt M, Koelbl H, Grus FH. Surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry to detect breast cancer markers in tears and serum. Cancer Genomics and Proteomics. 2009;6:75-83
  32. 32. Lebrecht A, Boehm D, Schmidt M, Koelbl H, Schwirz RL, Grus FH. Diagnosis of breast cancer by tear proteomic pattern. Cancer Genomics and Proteomics. 2009;6:177-182
  33. 33. Böhm D, Keller K, Pieter J, Boehm N, Wolters D, Siggelkow W, et al. Comparison of tear protein levels in breast cancer patients and healthy controls using a de novo proteomic approach. Oncology Reports. 2012;28:429-438. DOI: 10.3892/or.2012.1849
  34. 34. Kim S, Kim TG, Lee SH, Kim W, Bang A, Moon SW, Song J, Shin JH, Yu JS. Choi S. Label-free surface-enhanced Raman spectroscopy biosensor for on-site breast cancer detection using human tears. ACS Applied Materials & Interfaces 2020;12:7897-7904. DOI: 10.1021/acsami.9b19421
  35. 35. Inubushi S, Kawaguchi H, Mizumoto S, Kunihisa T, Baba M, Kitayama Y, et al. Oncogenic miRNAs identified in tear exosomes from metastatic breast cancer patients. Anticancer Research. 2020;40:3091-3096. DOI: 10.21873/anticanres.14290
  36. 36. Wang X, Pei X, Guo G, Qian X, Dou D, Zhang Z, et al. Exosome-mediated transfer of long noncoding RNA H19 induces doxorubicin resistance in breast cancer. Journal of Cellular Physiology. 2020;235:6896-6904. DOI: 10.1002/jcp.29585
  37. 37. Wang B, Zhang Y, Ye M, Wu J, Ma L, Chen H. Cisplatin-resistant MDA-MB-231 cell-derived exosomes increase the resistance of recipient cells in an exosomal miR-423-5p-dependent manner. Current Drug Metabolism. 2019;20:804-814. DOI: 10.2174/1389200220666190819151946
  38. 38. Yang SJ, Wang DD, Li J, Xu HZ, Shen HY, Chen X, et al. Predictive role of GSTP1-containing exosomes in chemotherapy-resistant breast cancer. Gene. 2017;623:5-14. DOI: 10.1016/j.gene.2017.04.031
  39. 39. Ning K, Wang T, Sun X, Zhang P, Chen Y, Jin J, et al. UCH-L1-containing exosomes mediate chemotherapeutic resistance transfer in breast cancer. Journal of Surgical Oncology. 2017;115:932-940. DOI: 10.1002/jso.24614
  40. 40. Li XJ, Ren ZJ, Tang JH, Yu Q. Exosomal microRNA MiR-1246 promotes cell proliferation, invasion and drug resistance by targeting CCNG2 in breast cancer. Cellular Physiology and Biochemistry. 2017;44:1741-1748. DOI: 10.1159/000485780
  41. 41. Muluhngwi P, Klinge CM. Identification of miRNAs as biomarkers for acquired endocrine resistance in breast cancer. Molecular and Cellular Endocrinology. 2017;456:76-86. DOI: 10.1016/j.mce.2017.02.004
  42. 42. Semina SE, Scherbakov AM, Vnukova AA, Bagrov DV, Evtushenko EG, Safronova VM, et al. Exosome-mediated transfer of cancer cell resistance to antiestrogen drugs. Molecules. 2018;23:829. DOI: 10.3390/molecules23040829
  43. 43. Martinez VG, O’Neill S, Salimu J, Breslin S, Clayton A, Crown J, et al. Resistance to HER2-targeted anti-cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesicles. Oncoimmunology. 2017;6:e1362530. DOI: 10.1080/2162402X.2017.1362530
  44. 44. Braden AM, Stankowski RV, Engel JM, Onitilo AA. Breast cancer biomarkers: risk assessment, diagnosis, prognosis, prediction of treatment efficacy and toxicity, and recurrence. Current Pharmaceutical Design. 2014;20:4879-4898. DOI: 10.2174/1381612819666131125145517
  45. 45. Bardelli A, Pantel K. Liquid biopsies, what we do not know (yet). Cancer Cell. 2017;31:172-179. DOI: 10.1016/j.ccell.2017.01.002
  46. 46. Campos-Carrillo A, Weitzel JN, Sahoo P, Rockne R, Mokhnatkin JV, Murtaza M, et al. Circulating tumor DNA as an early cancer detection tool. Pharmacology & Therapeutics. 2020;207:107458. DOI: 10.1016/j.pharmthera.2019.107458
  47. 47. Vlaeminck-Guillem V. Extracellular vesicles in prostate cancer carcinogenesis, diagnosis, and management. Frontiers in Oncology. 2018;8:222. DOI: 10.3389/fonc.2018.00222
  48. 48. Øverbye A, Skotland T, Koehler CJ, Thiede B, Seierstad T, Berge V, et al. Identification of prostate cancer biomarkers in urinary exosomes. Oncotarget. 2015;6:30357-30376. DOI: 10.18632/oncotarget.4851
  49. 49. Hessvik NP, Sandvig K, Llorente A. Exosomal miRNAs as biomarkers for prostate cancer. Frontiers in Genetics. 2013;4:36. DOI: 10.3389/fgene.2013.00036
  50. 50. Huang X, Yuan T, Tschannen M, Sun Z, Jacob H, Du M, et al. Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genomics. 2013;14:319. DOI: 10.1186/1471-2164-14-319
  51. 51. Huang X, Yuan T, Liang M, Du M, Xia S, Dittmar R, et al. Exosomal miR-1290 and miR-375 as prognostic markers in castration-resistant prostate cancer. European Urology. 2015;67:33-41. DOI: 10.1016/j.eururo.2014.07.035
  52. 52. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. The New England Journal of Medicine. 2014;371:1028-1038. DOI: 10.1056/NEJMoa1315815
  53. 53. Re MD, Biasco E, Crucitta S, Derosa L, Rofi E, Orlandini C, et al. The detection of androgen receptor splice variant 7 in plasma-derived exosomal RNA strongly predicts resistance to hormonal therapy in metastatic prostate cancer patients. European Urology. 2017;71:680-687. DOI: 10.1016/j.eururo.2016.08.012
  54. 54. Kanaoka R, Iinuma H, Dejima H, Sakai T, Uehara H, Matsutani N, et al. Usefulness of plasma exosomal microRNA-451a as a noninvasive biomarker for early prediction of recurrence and prognosis of non-small cell lung cancer. Oncology. 2018;94:311-323. DOI: 10.1159/000487006
  55. 55. Zhou X, Wen W, Shan X, Zhu W, Xu J, Guo R, et al. A six-microRNA panel in plasma was identified as a potential biomarker for lung adenocarcinoma diagnosis. Oncotarget. 2017;8:6513-6525. DOI: 10.18632/oncotarget.14311
  56. 56. Liu Q, Yu Z, Yuan S, Xie W, Li C, Hu Z, et al. Circulating exosomal microRNAs as prognostic biomarkers for non-small-cell lung cancer. Oncotarget. 2017;8:13048-13058. DOI: 10.18632/oncotarget.14369
  57. 57. Grimolizzi F, Monaco F, Leoni F, Bracci M, Staffolani S, Bersaglieri C, et al. Exosomal miR-126 as a circulating biomarker in non-small-cell lung cancer regulating cancer progression. Scientific Reports. 2017;7:15277. DOI: 10.1186/s12935-020-01653-6
  58. 58. Jin X, Chen Y, Chen H, Fei S, Chen D, Cai X, et al. Evaluation of tumor-derived exosomal miRNA as potential diagnostic biomarkers for early-stage non-small cell lung cancer using next-generation sequencing. Clinical Cancer Research. 2017;23:5311-5319. DOI: 10.1158/1078-0432.CCR-17-0577
  59. 59. Lai X, Friedman A. Exosomal miRs in lung cancer: a mathematical model. PLoS One. 2016;11:e0167706. DOI: 10.1371/journal.pone.0167706
  60. 60. Lebanony D, Benjamin H, Gilad S, Ezagouri M, Dov A, Ashkenazi K, et al. Diagnostic assay based on hsa-miR-205 expression distinguishes squamous from nonsquamous non-small-cell lung carcinoma. Journal of Clinical Oncology. 2009;27:2030-2037. DOI: 10.1200/JCO.2008.19.4134
  61. 61. Asakura K, Kadota T, Matsuzaki J, Yoshida Y, Yamamoto Y, Nakagawa K, et al. A miRNA-based diagnostic model predicts resectable lung cancer in humans with high accuracy. Communications Biology. 2020;3:134. DOI: 10.1038/s42003-020-0863-y
  62. 62. Liu L, Qu W, Zhong Z. Down-regulation of miR-503 expression predicate advanced mythological features and poor prognosis in patients with NSCLC. International Journal of Clinical and Experimental Pathology. 2015;8:5609-5613
  63. 63. Brown JM, Giaccia AJ. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Research. 1998;58:1408-1416
  64. 64. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nature Reviews. Cancer. 2004;4:437-447. DOI: 10.1038/nrc1367
  65. 65. Kizaka-Kondoh S, Inoue M, Harada H, Hiraoka M. Tumor hypoxia: A target for selective cancer therapy. Cancer Science. 2003;94:1021-1028. DOI: 10.1111/j.1349-7006.2003.tb01395.x
  66. 66. Deep G, Panigrahi GK. Hypoxia-induced signaling promotes prostate cancer progression: Exosomes role as messenger of hypoxic response in tumor microenvironment. Critical Reviews in Oncogenesis. 2015;20:419-434. DOI: 10.1615/CritRevOncog.v20.i5-6.130
  67. 67. Raja R, Kale S, Thorat D, Soundararajan G, Lohite K, Mane A, et al. Hypoxia-driven osteopontin contributes to breast tumor growth through modulation of HIF1α-mediated VEGF-dependent angiogenesis. Oncogene. 2014;33:2053-2064. DOI: 10.1038/onc.2013.171
  68. 68. Toulany M, Rodemann HP. Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation. Seminars in Cancer Biology. 2015;35:180-190. DOI: 10.1016/j.semcancer.2015.07.003
  69. 69. Olejarz W, Kubiak-Tomaszewska G, Chrzanowska A, Lorenc T. Exosomes in angiogenesis and anti-angiogenic therapy in cancers. International Journal of Molecular Sciences. 2020;21:5840. DOI: 10.3390/ijms21165840
  70. 70. Huang A, Dong J, Li S, Wang C, Ding H, Li H, et al. Exosomal transfer of vasorin expressed in hepatocellular carcinoma cells promotes migration of human umbilical vein endothelial cells. International Journal of Biological Sciences. 2015;11:961-969. DOI: 10.7150/ijbs.11943
  71. 71. Aggarwal BB, Vijayalekshmi RV, Sung B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clinical Cancer Research. 2009;15:425-430. DOI: 10.1158/1078-0432.CCR-08-0149
  72. 72. Yoshida K, Sasaki R, Nishimura H, Okamoto Y, Suzuki Y, Kawabe T, et al. Nuclear factor-kappaB expression as a novel marker of radioresistance in early-stage laryngeal cancer. Head & Neck. 2010;32:646-655. DOI: 10.1002/hed.21239
  73. 73. Zhang S, Li D, Zhao M, Yang F, Sang C, Yan C, et al. Exosomal miR-183-5p shuttled by M2 polarized tumor-associated macrophage promotes the development of colon cancer via targeting THEM4 mediated PI3K/AKT and NF-κB Pathways. Front Oncol. 2021;25(11):672684. DOI: 10.3389/fonc.2021.672684
  74. 74. Li J, Yang P, Chen F, Tan Y, Huang C, Shen H, et al. Hypoxiccolorectal cancer-derived extracellular vesicles deliver microRNA-361-3p to facilitate cell proliferation by targeting TRAF3 via the noncanonical NF-κB pathways. Clinical and Translational Medicine. 2021;11:e349. DOI: 10.1002/ctm2.349
  75. 75. Farias VA, O'Valle F, Serrano-Saenz S, Anderson P, Andrés E, López-Peñalver J, et al. Exosomes derived from mesenchymal stem cells enhance radiotherapy-induced cell death in tumor and metastatic tumor foci. Molecular Cancer. 2018;17:122. DOI: 10.1186/s12943-018-0867-0
  76. 76. Jella KK, Rani S, O'Driscoll L, McClean B, Byrne HJ, Lyng FM. Exosomes are involved in mediating radiation induced bystander signaling in human keratinocyte cells. Radiation Research. 2014;181:138-145. DOI: 10.1667/RR13337.1
  77. 77. Lehmann BD, Paine MS, Brooks AM, McCubrey JA, Renegar RH, Wang R, et al. Senescence-associated exosome release from human prostate cancer cells. Cancer Research. 2008;68:7864-7871. DOI: 10.1158/0008-5472.CAN-07-6538
  78. 78. Arscott WT, Tandle AT, Zhao S, Shabason JE, Gordon IK, Schlaff CD, et al. Ionizing radiation and glioblastoma exosomes: implications in tumor biology and cell migration. Translational Oncology. 2013;6:638-648. DOI: 10.1593/tlo.13640
  79. 79. Nakaoka A, Nakahana M, Inubushi S, Akasaka H, Salah M, Fujita Y, et al. Exosome-mediated radiosensitizing effect on neighboring cancer cells via increase in intracellular levels of reactive oxygen species. Oncology Reports. 2021;45:13. DOI: 10.3892/or.2021.7964
  80. 80. Hazawa M, Tomiyama K, Saotome-Nakamura A, Obara C, Yasuda T, Gotoh T, et al. Radiation increases the cellular uptake of exosomes through CD29/CD81 complex formation. Biochemical and Biophysical Research Communications. 2014;446:1165-1171. DOI: 10.1016/j.bbrc.2014.03.067
  81. 81. Niemoeller OM, Niyazi M, Corradini S, Zehentmayr F, Li M, Lauber K, et al. MicroRNA expression profiles in human cancer cells after ionizing radiation. Radiation Oncology. 2011;6:29. DOI: 10.1186/1748-717X-6-29
  82. 82. Harding SM, Benci JL, Irianto J, Discher DE, Minn AJ, Greenberg RA. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature. 2017;548:466-470. DOI: 10.1038/nature23470
  83. 83. Mackenzie KJ, Carroll P, Martin CA, Murina O, Fluteau A, Simpson DJ, et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature. 2017;548:461-465. DOI: 10.1038/nature23449
  84. 84. Dillon MT, Bergerhoff KF, Pedersen M, Whittock H, Crespo-Rodriguez E, Patin EC, et al. ATR inhibition potentiates the radiation-induced inflammatory tumor microenvironment. Clinical Cancer Research. 2019;25:3392-3403. DOI: 10.1158/1078-0432.CCR-18-1821
  85. 85. Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41:843-852. DOI: 10.1016/j.immuni.2014.10.019
  86. 86. Vance RE. Cytosolic DNA sensing: the field narrows. Immunity. 2016;45:227-228. DOI: 10.1016/j.immuni.2016.08.006
  87. 87. Diamond JM, Vanpouille-Box C, Spada S, Rudqvist NP, Chapman JR, Ueberheide BM, et al. Exosomes shuttle TREX1-sensitive IFN-stimulatory dsDNA from irradiated cancer cells to DCs. Cancer Immunology Research. 2018;6:910-920. DOI: 10.1158/2326-6066.CIR-17-0581
  88. 88. Lee H, Herrmann A, Deng JH, Kujawski M, Niu G, Li Z, et al. Persistently activated STAT3 maintains constitutive NF-κB activity in tumors. Cancer Cell. 2009;15:283-293. DOI: 10.1016/j.ccr.2009.02.015
  89. 89. Diaz Osterman CJ, Ozmadenci D, Kleinschmidt EG, Taylor KN, Barrie AM, Jiang S, et al. FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy. eLife. 2019;8:e47327. DOI: 10.7554/eLife.47327
  90. 90. Micalizzi D, Farabaugh S, Ford H. Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. Journal of Mammary Gland Biology and Neoplasia. 2010;15:117-134. DOI: 10.1007/s10911-010-9178-9
  91. 91. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704-715. DOI: 10.1016/j.cell.2008.03.027
  92. 92. Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong STC, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015;527:472-476. DOI: 10.1038/nature15748
  93. 93. Papageorgis P. TGFβ signaling in tumor initiation, epithelial-to-mesenchymal transition, and metastasis. Journal of Oncology. 2015;2015:587193. DOI: 10.1155/2015/587193
  94. 94. Dissanayake SK, Wade M, Johnson CE, O’Connell MP, Leotlela PD, French AD, et al. The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. The Journal of Biological Chemistry. 2007;282:17259-17271. DOI: 10.1074/jbc.M700075200
  95. 95. Shan G, Zhou X, Gu J, Zhou D, Cheng W, Wu H, et al. Downregulated exosomal microRNA-148b-3p in cancer associated fibroblasts enhance chemosensitivity of bladder cancer cells by downregulating the Wnt/β-catenin pathway and upregulating PTEN. Cellular Oncology (Dordr). 2021;44:45-59. DOI: 10.1007/s13402-020-00500-0
  96. 96. Liu T, Zhang X, Du L, Wang Y, Liu X, Tian H, et al. Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancer. Molecular Cancer. 2019;18:43. DOI: 10.1186/s12943-019-0981-7
  97. 97. Shan G, Gu J, Zhou D, Li L, Cheng W, Wang Y, et al. Cancer-associated fibroblast-secreted exosomal miR-423-5p promotes chemotherapy resistance in prostate cancer by targeting GREM2 through the TGF-β signaling pathway. Experimental & Molecular Medicine. 2020;52:1809-1822. DOI: 10.1038/s12276-020-0431-z
  98. 98. Wang X, Zhang H, Yang H, Bai M, Ning T, Deng T, et al. Exosome-delivered circRNA promotes glycolysis to induce chemoresistance through the miR-122-PKM2 axis in colorectal cancer. Molecular Oncology. 2020;14:539-555. DOI: 10.1002/1878-0261.12629

Written By

Ai Nakaoka, Kana Kobayashi, Mennaallah Hassan and Ryohei Sasaki

Submitted: 17 October 2021 Reviewed: 18 November 2021 Published: 19 December 2021