Open access peer-reviewed chapter

Regulation of Exosomes in the Pathogenesis of Breast Cancer

Written By

Congjian Shi, Hongqin Yang, Zhengchao Wang and Zhenghong Zhang

Submitted: 25 December 2020 Reviewed: 06 January 2021 Published: 22 April 2021

DOI: 10.5772/intechopen.95858

From the Edited Volume

Global Women's Health

Edited by Zhengchao Wang

Chapter metrics overview

388 Chapter Downloads

View Full Metrics

Abstract

Extracellular vesicles (EVs) are a heterogeneous group of endogenous nanoscale vesicles that are secreted by various cell types. Based on their biogenesis and size distribution, EVs can be broadly classified as exosomes and microvesicles. Exosomes are enveloped by lipid bilayers with a size of 30–150 nm in diameter, which contain diverse biomolecules, including lipids, proteins and nucleic acids. Exosomes transport their bioactive cargoes from original cells to recipient cells, thus play crucial roles in mediating intercellular communication. Breast cancer is the most common malignancy among women and remains a major health problem worldwide, diagnostic strategies and therapies aimed at breast cancer are still limited. Growing evidence shows that exosomes are involved in the pathogenesis of breast cancer, including tumorigenesis, invasion and metastasis. Here, we provide a straightforward overview of exosomes and highlight the role of exosomes in the pathogenesis of breast cancer, moreover, we discuss the potential application of exosomes as biomarkers and therapeutic tools in breast cancer diagnostics and therapeutics.

Keywords

  • extracellular vesicles
  • exosomes
  • breast cancer
  • miRNAs

1. Introduction

Extracellular vesicles (EVs) are heterogeneous membrane-bound vesicles which originate from endosomal or plasma membrane called exosomes or microvesicles, respectively [1]. The release of EVs was initially identified as a mode for cells to eliminate unwanted substances, however, the initial view with regard to EVs has changed dramatically with the deepening of research, and their crucial roles in diverse physiological and pathological processes have attracted extensive attention. According to their original cells, EVs are loaded with a specific set of preassembled bioactive cargoes, and give rise to phenotypic and genotypic changes in recipient cells [2, 3]. These cargoes enclosed within EVs are biologically significant, for example, three EV subtypes including one microvesicle and two exosome populations released by LIM1863 CRC (colorectal cancer) cells have distinct miRNA expression profiles [4]. EVs contribute to numerous aspects of normal physiological processes, including blood coagulation, immune surveillance, tissue repair and stem cell maintenance [5]. They are also closely related with diverse human diseases, including cancer, infectious diseases, neurologic diseases and cardiometabolic diseases [6]. Exosomes are a subtype of EVs and the application of exosomes as biomarkers and therapeutic tools has appeared as a promising area of research due to some preponderant properties of exosomes. Exosomes can be released according to the command received from adjacent and distant cells, or in response to the stimulation induced by local conditions [7]. Both normal and pathological cells are capable of secreting exosomes and they are stable in biological fluids [8]. Breast cancer is the most common malignancy affecting women, and its morbidity and mortality are estimated to increase in the coming years [9]. One in eight to ten women will be diagnosed with breast cancer during their lifetime [10], and breast cancer has seriously affected women’s health. Accumulating evidence indicates that exosomes are involved in the pathogenesis of breast cancer, including tumorigenesis, invasion and metastasis. Studies focused on exosomes might provide novel perspectives for revealing breast cancer pathogenesis and improving the current poor diagnostic and therapeutic status of breast cancer.

Advertisement

2. Extracellular vesicles

Cells naturally release EVs into the extracellular space, these nanoscale vesicles encompassing bioactive cargoes play crucial roles in diverse physiological and pathological processes. The term EVs represent several subtypes of vesicles, standardized criteria for distinguishing EVs subtypes are still under discussion, but it is universally acknowledged that they can be classified as two main categories: exosomes and microvesicles. Other EVs subtypes such as apoptotic bodies [11], spheresomes [12] and large oncosomes [13], are not mentioned in this review. Exosomes have endosomal origin, they are 30–150 nm in diameter and float at a density of 1.13–1.19 g/ml in sucrose gradient [14, 15]. Exosomes are essentially intraluminal vesicles (ILVs) generated by inward budding of endosomal membrane during the maturation of endosomes, then released to the extracellular space when multivesicular bodies (MVBs) (also referred to late endosomes) fuse with plasma membranes [16, 17]. Microvesicles, typically larger than exosomes (100–1000 nm in diameter), arise through direct outward budding and fission of plasma membrane [18], hence, the membrane composition of microvesicles can better reflect the membrane composition of original cells in contrast to exosomes. Although the origin of exosomes and microvesicles occurs at distinct intracellular locations, some common mechanisms participate in both processes. The modes by which recipient cells take up EVs including endocytosis, direct membrane fusion and receptor ligand binding [19], but the specific molecular mechanisms deserve further investigation.

At present, the biogenesis of EVs, the substances they contain and the biological effects they promote have been extensively studied, which make people find out the potential of EVs in clinical application. EVs subtypes like exosomes and microvesicles may perform different functions, and it is absolutely necessary to isolate high-purity EVs subtypes, which will be crucial for EV-related functionality and therapeutic value studies. But even in EV preparations with high-purity, electron microscopy (EM) results imply that they still contain co-purifying elements [20]. The isolation of EVs is challenging because EVs subtypes have some similarities, including their size, density, composition, and surface marker proteins [21]. Meanwhile, EVs derived from biological fluids contain a mixture of multiple EVs secreted by various cell types [22]. Therefore, it is imperative to formulate universal standard protocols for the preparation of EVs.

Due to some peculiar characteristics of EVs, they have prominent biotechnological potential. EVs are biocompatible and safe, coupled with nanoscale diameter, resulting in their long blood circulation half-life and high drug loading capacity, which makes them possible to be ideal drug delivery vehicles [23]. EVs represent an attractive group of therapeutic biomarkers and has tremendous potential in immune response regulation and tissue regeneration [5, 24]. EVs are extensively found in diverse bodily fluids, and it is a promising area to serve EVs as biomarkers for early diagnosis and accurate prognosis. Since EVs are derived from bodily fluids, the diagnostic methods are probably non-invasive and considerably less painful than some existing diagnostic methods (for example, liver biopsy). Meanwhile, the clinical application of EVs can also monitor the response of therapy, which will contribute to convalescent process.

Advertisement

3. Exosomes

Exosomes are enveloped by lipid bilayers and act as mediators of intercellular communication through transmitting diverse functional biomolecules from original cells to recipient cells, and they are secreted by virtually all cell types, such as stem cells, immune cells and tumor cells [25]. The cargoes transported by exosomes including lipids, proteins, RNA (coding and non-coding) and even DNA (genomic and mitochondrial) [26]. Exosomes can be detected and isolated from diverse bodily fluids, exemplified by blood, urine, saliva, cerebrospinal fluid and breast milk [27], they can also be obtained from cell culture-conditioned media [28]. Some specific surface proteins are considered as the makers of exosome, such as tetraspanin family (CD9, CD63 and CD81), heat shock protein 70 (HSP70) and major histocompatibility complex (MHC) molecules [29]. Exosomes also contain abundant ceramide, cholesterol and sphingomyelin, which may relate to their lipid raft microdomains [30]. Multiple genetic materials are detected in exosomes, and exosome-encapsulated miRNAs have obtained extra attention because of their vital roles in regulating gene expression and can be used as biomarkers for a variety of diseases [31].

Exosomes exhibit unique biogenesis mechanism. Plasma membrane buds inward through endocytosis, resulting the generation of early endosomes [32]. The process from early endosomes to late endosomes (also referred to MVBs) requires the involvement of Golgi complex, during which ILVs also accumulate by the invagination of endosomal membrane in their lumen [15]. Then, MVBs either fuse with lysosomes, which ILVs are degraded, or fuse with plasma membranes, which ILVs are released to the extracellular space as exosomes [33]. Fusion of MVBs with plasma membrane requires the assistance of soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) complexes [34]. The endosomal sorting complex required for transport (ESCRT) machinery, a vital participant in exosome biogenesis, is responsible for ILVs formation and protein sorting [35]. ESCRT machinery contains four complexes, ESCRT-0, ESCRT-I, ESCRT-II and ESCRT-III, as well as associated proteins, including ALIX, VPS4 and VTA1 [36]. ESCRT-0 recognizes the ubiquitinated cargoes, ESCRT-I and ESCRT-II initiate the budding process of ILVs, whereas ESCRT-III terminates this process [3, 37]. ESCRT-independent mechanisms also exist by the evidence that MVBs still form in the absence of ESCRTs [38], further studies report that the mechanisms are related with the sphingolipid ceramide [39] or some members of the tetraspanin family [40]. In single MVBs, a competitive relationship between ESCRT-dependent and ESCRT-independent mechanisms exists, which affects the size of ILVs formed inside [41], this makes it possible to identify different subpopulations of MVBs based on their ILVs size. A group of Rab GTPases including Rab11, Rab27a, and Rab27b, are also involved in the release of exosomes [42]. Once exosomes are released to the extracellular space, they may exist in the circulation or be taken up by adjacent and distant cells [43, 44].

Exosomal preparations with high-purity are significant for further exploration of exosomal biogenesis and functions, and techniques for exosomal isolation have made great advances. At present, the commonly used isolation techniques including ultracentrifugation-based techniques, size-based techniques, precipitation, immunocapture and microfluidic-based techniques [35, 45] (Table 1). Among them, ultracentrifugation is the most extensively used exosomal isolation technique for bodily fluids and cell culture supernatant [46]. Each technique has its own merits and demerits, and the combination of aforementioned techniques may lead to a more desirable isolation. Recent study showed that the acidic condition was more suitable for the isolation of exosomes [47], indicating that local pH of exosomes should be taken into account for future researches.

Isolation techniquesAdvantagesDisadvantagesReferences
Ultracentrifugation-based techniquesLow cost, most commonly usedTime-consuming, high equipment cost, low recovery[15, 45]
Size-based techniquesFast, convenient, high yieldLack specificity, requires dedicated equipment[17, 46]
PrecipitationEasy, does not require specialized equipmentLack specificity, time-consuming[15, 45, 46]
ImmunocaptureHigh purityExpensive, low capacity[28, 35]
Microfluidic-based techniquesFast, low cost, convenientLack standardization and large-scale tests on clinical samples, lack method validation[45, 52]

Table 1.

The advantages and disadvantages of different techniques used for exosome isolation.

Specific roles of the tumor microenvironment during cancer progression and metastasis have been widely studied [48], and cancer cell–derived exosomes can establish a favorable microenvironment to induce cell proliferation, angiogenesis, resistance to apoptosis and initiation of pre-metastatic niches through their bioactive content [22, 49]. The secretion of exosome appears to have an impact on drug resistance, for example, exosomes enriched in TAG72 imply that CRC patients might be resistant to 5-FU [50]. And cells under pathological status release even more exosomes, it is estimated that there are approximately 2,000 trillion exosomes presented in normal human blood and 4,000 trillion exosomes presented in the blood of cancer patients [51]. According to these results, it is feasible to serve exosomes as biomarkers for diagnosis and prognosis. Exosomes are capable of inducing anti-tumor responses through delivering tumor antigens to immune cells, and exosomes derived from T cells can suppress tumor development [52], demonstrating their great potential in modulating immune responses. Enlightened by the capability of exosomes that transmits biomolecules from original cells to recipient cells, accompanied with their biocompatibility, low immunogenicity and toxicity, high stability in the circulation, biological barrier permeability and potential targeting to specific sites [53], diverse strategies have been developed for loading therapeutic cargoes into exosomes, which have a broad application prospect.

Exosome plays important roles in tumor diagnostics and therapeutics. Tissue biopsy is usually acquired from the site of primary tumor and reflects its molecular traits over a period of time, therapies will be determined according to the results of tissue biopsy. However, the limitations of tissue biopsy are obvious, it is not comprehensive enough to reflect heterogeneity and dynamic evolution of tumor [54]. Exosome related liquid biopsy techniques including surface-enhanced Raman spectroscopy (SERS), next generation sequencing (NGS), digital droplet PCR (ddPCR) and molecular barcoding, have drawn extra attention due to its unique advantages of minimally invasive and serial biochemical tests [55]. Among diversified methods developed for liquid biopsy, SERS-based technique for detection of circulating tumor markers including exosomes is one of the most powerful methods, it owns the advantages of high sensitivity, specificity, tremendous spectral multiplexing capacity for simultaneous target detection, and its unique capability for obtaining intrinsic fingerprint spectra of biomolecules [56]. The application of exosome related liquid biopsy enables the improvement of various aspects of tumor management including early diagnosis and screening, prediction of prognosis, early detection of relapse, serial sampling and efficient longitudinal monitoring of disease progress and response to treatment [57]. Although exosome related liquid biopsy is a promising area, there are still some loopholes including difficult extraction and did not analyze the phenotypic studies of cells from tumor, that require further refinement and validation [58].

Advertisement

4. Breast cancer

Breast cancer is a disease with high heterogeneity, containing multiple tumor entities that have diverse clinical behavior and biological features [59], which complicate its diagnosis and treatment. Among women, breast cancer is the most common malignancy and the second leading causes of cancer-related death [60]. The 5-year overall survival rate for non-metastatic breast cancer patients is greater than 80%, whereas distant metastasis can reduce this rate to approximately 25%, and the main metastatic sites including bone, brain, liver and lung [61]. The diagnosis and treatment of patients are evaluated by clinical assessment, breast imaging, tumor size, histologic grade, lymph node involvement or acknowledged biomarkers, including estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2) and progesterone receptor (PR) [62]. The clinical classification of breast cancer should be reasonable, so as to select the most appropriate diagnostic strategy and therapy for each patient, and the molecular subtypes of breast cancer are represented by basal-like, HER2-enriched, normal breast-like, luminal A, luminal B and claudin-low [63]. The occurrence of breast cancer is influenced by age, race, obesity, smoke, drinking, oral contraceptives and other exogenous estrogens, age at menarche, age at menopause, age at first live birth and environmental toxins [64, 65], also, inherited genetic mutations are responsible for 5–10% of all breast cancer cases, and mutations in BRCA1 and BRCA2 are believed to increase the lifetime risk of being diagnosed with breast cancer by more than four times [66].

Breast cancer is generally diagnosed by mammography, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, core needle biopsy, excisional biopsy and histopathologic evaluation [65, 67]. Diagnosed patients with parallel clinical and biological characteristics may exhibit distinct responses to treatment and bring about different outcomes [68], therefore, the research on breast cancer treatment needs to be further deepened. At present, surgery and radiation are mentioned frequently in treatment, and three approaches are primarily adopted in medical oncology: ER + -related breast cancer aimed at anti-endocrine strategies, HER2 + -related breast cancer treated with HER2-targeted drugs and triple-negative breast cancer (TNBC) managed with traditional cytotoxic therapy [69]. More importantly, it is not just about choosing the appropriate treatment for each patient, the sequencing of therapies should also be considered.

Advertisement

5. Exosomal functionality and therapeutic value in breast cancer

It has been widely acknowledged that exosomes are important players in the pathogenesis of breast cancer (Figure 1). The release of exosomes induced by heparanase, hypoxia and other stimulation is involved in breast cancer angiogenesis, which facilitate tumorigenesis process of breast cancer [70]. Also, exosomes promote breast cancer tumorigenesis by modifying tumor microenvironment to permissive niches. Typically, alteration in miRNAs expression have been found to influence initiation and development of breast cancer [71], for example, compared with non-malignant breast cells or non-metastatic breast cancer cells, exosomal miR-10b is significantly upregulated in metastatic breast cancer cells [72]. Further research shows that RNA induced silencing complex-loading complex (RLC) proteins Dicer, AGO2 and TRBP, which have been proved to participate in miRNA biogenesis, can be detected in exosomes derived from the serum of breast cancer patients and breast cancer cells, moreover, Dicer inhibition in cancer exosomes obviously decelerates tumor growth in recipient cells [73]. Invasion plays an important role in cancer development, invasion ability of non-malignant breast cells can be induced by exosomes derived from metastatic breast cancer cells [72]. Metastatic breast cancer cells specifically express and release miR-105, during which exosomal miR-105 can transfer to endothelial cells and acts as an effective regulator of their migration [74]. Recent study also suggested that miR-7641 was identified as an important component of exosomes that could promote breast tumor metastasis [75]. Drug resistance are also closely related with exosomes as they are capable of transporting anti-cancer drugs outside breast cancer cells. Chen et al. reported that drug-resistant breast cancer cells might spread their drug-resistant capacity to sensitive cells through secreting exosomes, they further confirmed that this process was mediated by exosomal miRNAs [76]. Trastuzumab is a commonly used drugs to treat breast cancer, while exosome-transmitted cicHIPK3 could promote trastuzumab chemoresistance of drug-sensitive BC cells, decreasing the therapeutic effect [77]. Recent study showed that exosomal miR-155 regulated drug resistance of breast cancer [78] and chemotherapy with miR-155-targeting therapies may lead to satisfactory outcomes.

Figure 1.

Exosome in the pathogenesis of breast cancer. Exosome contribute to oncogenic transformation, angiogenesis, permissive niche formation and drug resistance in breast cancer.

Breast cancer is a disease which tends to metastasis, patients with early diagnosis, reasonable prognosis and accurate treatment usually have more favorable outcomes, yet approaches against breast cancer are still limited, and exosomes could be employed as novel biomarkers and therapeutic tools for patients with breast cancer. Hannafon and colleagues found that exosomes derived from breast cancer cells were enriched with specific miRNAs (miR-1246 and miR-21), what’s more, these miRNAs in plasma exosomes of breast cancer patients were significantly higher than those of healthy control subjects [79], and exosomes may play crucial roles as biomarkers for breast cancer. Distant metastasis or local recurrence of breast cancer are strongly related with exosomal miRNAs, including miR-17-5p, miR-93-5p, miR-130a-3p, miR-340-5p [80], which can serve as indicators for prognosis. Now that exosomes remain stable in biological fluids, they are also promising for early diagnosis or monitoring the treatment process of breast cancer. In contrast to delivering anticancer drugs outside breast cancer cells, exosomes can also target anticancer drugs to breast cancer cells after appropriate modifications, for example, exosomes modified by targeting ligands deliver doxorubicin to tumors [81], which improve the therapeutic efficacy. Exosomes derived from mesenchymal stem cells (MSCs) can be used as drug delivery vehicles to transport locked nucleic acid (LNA)-anti-miR-142-3p, therefore reducing tumorigenicity in breast cancer [82].

Advertisement

6. Summary

Over the past few decades, on account of great advances in our understanding of breast cancer biology, diverse diagnostic and prognostic strategies, as well as targeted therapies are continuously evolving, while the situation of breast cancer patients remains unsatisfactory. For prevention and treatment of breast cancer, we need not only to develop new biomarkers and therapeutic tools, but also to further investigate the potential molecular mechanisms. Fortunately, accompany by our comprehension of exosomes is becoming more refined, the role of exosomes in initiation and development of breast cancer has been widely explored, and it is meaningful to translate exosomal research achievements to develop safe and effective therapies, diagnostic methods, along with drug delivery vehicles, which may conduce to improve the unsatisfactory situation of breast cancer patients.

Advertisement

Acknowledgments

This study was supported by the Special Funds of the Central Government Guiding Local Science and Technology Development (2020L3008), Provincial Natural Science Foundation (2018J01721, 2018J01721, 2019J01674 and 2020J01176), the Educational Reform Project (Y201809 and I202003009) and Training Program of Innovation and Entrepreneurship for Undergraduates (CXXL2020291 and CXXL2020293) of the Fujian Normal University.

References

  1. 1. G. van Niel, G. D’Angelo, G. Raposo, Shedding light on the cell biology of extracellular vesicles, Nat Rev Mol Cell Biol 19(4) (2018) 213-228.
  2. 2. K.C. French, M.A. Antonyak, R.A. Cerione, Extracellular vesicle docking at the cellular port: Extracellular vesicle binding and uptake, Semin Cell Dev Biol 67 (2017) 48-55.
  3. 3. C. D'Souza-Schorey, J.S. Schorey, Regulation and mechanisms of extracellular vesicle biogenesis and secretion, Essays Biochem 62(2) (2018) 125-133.
  4. 4. H. Ji, M. Chen, D.W. Greening, W. He, A. Rai, W. Zhang, R.J. Simpson, Deep sequencing of RNA from three different extracellular vesicle (EV) subtypes released from the human LIM1863 colon cancer cell line uncovers distinct miRNA-enrichment signatures, PLoS One 9(10) (2014) e110314.
  5. 5. E.L.A. S, I. Mager, X.O. Breakefield, M.J. Wood, Extracellular vesicles: biology and emerging therapeutic opportunities, Nat Rev Drug Discov 12(5) (2013) 347-357.
  6. 6. R. Shah, T. Patel, J.E. Freedman, Circulating Extracellular Vesicles in Human Disease, N Engl J Med 379(10) (2018) 958-966.
  7. 7. M.D. Mitchell, H.N. Peiris, M. Kobayashi, Y.Q . Koh, G. Duncombe, S.E. Illanes, G.E. Rice, C. Salomon, Placental exosomes in normal and complicated pregnancy, Am J Obstet Gynecol 213(4 Suppl) (2015) S173-S181.
  8. 8. H. Im, K. Lee, R. Weissleder, H. Lee, C.M. Castro, Novel nanosensing technologies for exosome detection and profiling, Lab Chip 17(17) (2017) 2892-2898.
  9. 9. Z. Anastasiadi, G.D. Lianos, E. Ignatiadou, H.V. Harissis, M. Mitsis, Breast cancer in young women: an overview, Updates Surg 69(3) (2017) 313-317.
  10. 10. N. Harbeck, M. Gnant, Breast cancer, Lancet 389(10074) (2017) 1134-1150.
  11. 11. X. Xu, Y. Lai, Z.C. Hua, Apoptosis and apoptotic body: disease message and therapeutic target potentials, Biosci Rep 39(1) (2019) BSR20180992.
  12. 12. C. Junquera, T. Castiella, G. Munoz, R. Fernandez-Pacheco, M.J. Luesma, M. Monzon, Biogenesis of a new type of extracellular vesicles in gastrointestinal stromal tumors: ultrastructural profiles of spheresomes, Histochem Cell Biol 146(5) (2016) 557-567.
  13. 13. V.R. Minciacchi, M.R. Freeman, D. Di Vizio, Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes, Semin Cell Dev Biol 40 (2015) 41-51.
  14. 14. M.L. Merchant, I.M. Rood, J.K.J. Deegens, J.B. Klein, Isolation and characterization of urinary extracellular vesicles: implications for biomarker discovery, Nat Rev Nephrol 13(12) (2017) 731-749.
  15. 15. C. He, S. Zheng, Y. Luo, B. Wang, Exosome Theranostics: Biology and Translational Medicine, Theranostics 8(1) (2018) 237-255.
  16. 16. D.W. Greening, R. Xu, S.K. Gopal, A. Rai, R.J. Simpson, Proteomic insights into extracellular vesicle biology - defining exosomes and shed microvesicles, Expert Rev Proteomics 14(1) (2017) 69-95.
  17. 17. H. Bu, D. He, X. He, K. Wang, Exosomes: Isolation, Analysis, and Applications in Cancer Detection and Therapy, Chembiochem 20(4) (2019) 451-461.
  18. 18. L. Han, J. Xu, Q . Xu, B. Zhang, E.W. Lam, Y. Sun, Extracellular vesicles in the tumor microenvironment: Therapeutic resistance, clinical biomarkers, and targeting strategies, Med Res Rev 37(6) (2017) 1318-1349.
  19. 19. H.K. Karnati, J.H. Garcia, D. Tweedie, R.E. Becker, D. Kapogiannis, N.H. Greig, Neuronal Enriched Extracellular Vesicle Proteins as Biomarkers for Traumatic Brain Injury, J Neurotrauma 36(7) (2019) 975-987.
  20. 20. M. Gimona, K. Pachler, S. Laner-Plamberger, K. Schallmoser, E. Rohde, Manufacturing of Human Extracellular Vesicle-Based Therapeutics for Clinical Use, Int J Mol Sci 18(6) (2017) 1190.
  21. 21. D.W. Greening, R.J. Simpson, Understanding extracellular vesicle diversity - current status, Expert Rev Proteomics 15(11) (2018) 887-910.
  22. 22. C. Villarroya-Beltri, F. Baixauli, C. Gutierrez-Vazquez, F. Sanchez-Madrid, M. Mittelbrunn, Sorting it out: regulation of exosome loading, Semin Cancer Biol 28 (2014) 3-13.
  23. 23. O.Y. Kim, J. Lee, Y.S. Gho, Extracellular vesicle mimetics: Novel alternatives to extracellular vesicle-based theranostics, drug delivery, and vaccines, Semin Cell Dev Biol 67 (2017) 74-82.
  24. 24. S. Keshtkar, N. Azarpira, M.H. Ghahremani, Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine, Stem Cell Res Ther 9(1) (2018) 63.
  25. 25. S. Cui, Z. Cheng, W. Qin, L. Jiang, Exosomes as a liquid biopsy for lung cancer, Lung Cancer 116 (2018) 46-54.
  26. 26. S. Lakshmi, T.A. Hughes, S. Priya, Exosomes and exosomal RNAs in breast cancer: A status update, Eur J Cancer 144 (2020) 252-268.
  27. 27. Y.F. Zhang, J.B. Shi, C. Li, Small extracellular vesicle loading systems in cancer therapy: Current status and the way forward, Cytotherapy 21(11) (2019) 1122-1136.
  28. 28. K.W. Witwer, E.I. Buzas, L.T. Bemis, A. Bora, C. Lasser, J. Lotvall, E.N. Nolte-'t Hoen, M.G. Piper, S. Sivaraman, J. Skog, C. Thery, M.H. Wauben, F. Hochberg, Standardization of sample collection, isolation and analysis methods in extracellular vesicle research, J Extracell Vesicles 2 (2013) 20360.
  29. 29. S. Lee, S. Mankhong, J.H. Kang, Extracellular Vesicle as a Source of Alzheimer's Biomarkers: Opportunities and Challenges, Int J Mol Sci 20(7) (2019) 1728.
  30. 30. A.J. O'Loughlin, C.A. Woffindale, M.J. Wood, Exosomes and the emerging field of exosome-based gene therapy, Curr Gene Ther 12(4) (2012) 262-274.
  31. 31. A. Thind, C. Wilson, Exosomal miRNAs as cancer biomarkers and therapeutic targets, J Extracell Vesicles 5 (2016) 31292.
  32. 32. X. Xia, Y. Wang, Y. Huang, H. Zhang, H. Lu, J.C. Zheng, Exosomal miRNAs in central nervous system diseases: biomarkers, pathological mediators, protective factors and therapeutic agents, Prog Neurobiol 183 (2019) 101694.
  33. 33. M. Klingeborn, W.M. Dismuke, C. Bowes Rickman, W.D. Stamer, Roles of exosomes in the normal and diseased eye, Prog Retin Eye Res 59 (2017) 158-177.
  34. 34. M. Mathieu, L. Martin-Jaular, G. Lavieu, C. Thery, Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication, Nat Cell Biol 21(1) (2019) 9-17.
  35. 35. E. Willms, C. Cabanas, I. Mager, M.J.A. Wood, P. Vader, Extracellular Vesicle Heterogeneity: Subpopulations, Isolation Techniques, and Diverse Functions in Cancer Progression, Front Immunol 9 (2018) 738.
  36. 36. W.M. Henne, N.J. Buchkovich, S.D. Emr, The ESCRT pathway, Dev Cell 21(1) (2011) 77-91.
  37. 37. D.S. Choi, D.K. Kim, Y.K. Kim, Y.S. Gho, Proteomics of extracellular vesicles: Exosomes and ectosomes, Mass Spectrom Rev 34(4) (2015) 474-490.
  38. 38. S. Stuffers, C. Sem Wegner, H. Stenmark, A. Brech, Multivesicular endosome biogenesis in the absence of ESCRTs, Traffic 10(7) (2009) 925-937.
  39. 39. K. Trajkovic, C. Hsu, S. Chiantia, L. Rajendran, D. Wenzel, F. Wieland, P. Schwille, B. Brugger, M. Simons, Ceramide triggers budding of exosome vesicles into multivesicular endosomes, Science 319(5867) (2008) 1244-1247.
  40. 40. Z. Andreu, M. Yanez-Mo, Tetraspanins in extracellular vesicle formation and function, Front Immunol 5 (2014) 442.
  41. 41. J.R. Edgar, E.R. Eden, C.E. Futter, Hrs- and CD63-dependent competing mechanisms make different sized endosomal intraluminal vesicles, Traffic 15(2) (2014) 197-211.
  42. 42. E. de la Torre-Escudero, A.P.S. Bennett, A. Clarke, G.P. Brennan, M.W. Robinson, Extracellular Vesicle Biogenesis in Helminths: More than One Route to the Surface?, Trends Parasitol 32(12) (2016) 921-929.
  43. 43. T. Vagner, A. Chin, J. Mariscal, S. Bannykh, D.M. Engman, D. Di Vizio, Protein Composition Reflects Extracellular Vesicle Heterogeneity, Proteomics 19(8) (2019) e1800167.
  44. 44. A.M. Deleo, T. Ikezu, Extracellular Vesicle Biology in Alzheimer's Disease and Related Tauopathy, J Neuroimmune Pharm 13(3) (2018) 292-308.
  45. 45. P. Li, M. Kaslan, S.H. Lee, J. Yao, Z. Gao, Progress in Exosome Isolation Techniques, Theranostics 7(3) (2017) 789-804.
  46. 46. B.Y. Chen, C.W. Sung, C. Chen, C.M. Cheng, D.P. Lin, C.T. Huang, M.Y. Hsu, Advances in exosomes technology, Clin Chim Acta 493 (2019) 14-19.
  47. 47. J.J. Ban, M. Lee, W. Im, M. Kim, Low pH increases the yield of exosome isolation, Biochem Biophys Res Commun 461(1) (2015) 76-79.
  48. 48. D.F. Quail, J.A. Joyce, Microenvironmental regulation of tumor progression and metastasis, Nat Med 19(11) (2013) 1423-1437.
  49. 49. S.W. Ferguson, J. Nguyen, Exosomes as therapeutics: The implications of molecular composition and exosomal heterogeneity, J Control Release 228 (2016) 179-190.
  50. 50. Y. Xiao, Y. Li, Y. Yuan, B. Liu, S. Pan, Q . Liu, X. Qi, H. Zhou, W. Dong, L. Jia, The potential of exosomes derived from colorectal cancer as a biomarker, Clin Chim Acta 490 (2019) 186-193.
  51. 51. R. Kalluri, The biology and function of exosomes in cancer, J Clin Invest 126(4) (2016) 1208-1215.
  52. 52. E.V. Batrakova, M.S. Kim, Using exosomes, naturally-equipped nanocarriers, for drug delivery, J Control Release 219 (2015) 396-405.
  53. 53. J. Meldolesi, Exosomes and Ectosomes in Intercellular Communication, Curr Biol 28(8) (2018) R435-R444.
  54. 54. S. Mader, K. Pantel, Liquid Biopsy: Current Status and Future Perspectives, Oncol Res Treat 40(7-8) (2017) 404-408.
  55. 55. S. Alimirzaie, M. Bagherzadeh, M.R. Akbari, Liquid biopsy in breast cancer: A comprehensive review, Clin Genet 95(6) (2019) 643-660.
  56. 56. Y. Zhang, X. Mi, X. Tan, R. Xiang, Recent Progress on Liquid Biopsy Analysis using Surface-Enhanced Raman Spectroscopy, Theranostics 9(2) (2019) 491-525.
  57. 57. L. Giannopoulou, M. Zavridou, S. Kasimir-Bauer, E.S. Lianidou, Liquid biopsy in ovarian cancer: the potential of circulating miRNAs and exosomes, Transl Res 205 (2019) 77-91.
  58. 58. J. Wang, S. Chang, G. Li, Y. Sun, Application of liquid biopsy in precision medicine: opportunities and challenges, Front Med 11(4) (2017) 522-527.
  59. 59. B. Weigelt, J.S. Reis-Filho, Histological and molecular types of breast cancer: is there a unifying taxonomy?, Nat Rev Clin Oncol 6(12) (2009) 718-730.
  60. 60. I. Januskeviciene, V. Petrikaite, Heterogeneity of breast cancer: The importance of interaction between different tumor cell populations, Life Sci 239 (2019) 117009.
  61. 61. Y. Liang, H. Zhang, X. Song, Q . Yang, Metastatic heterogeneity of breast cancer: Molecular mechanism and potential therapeutic targets, Semin Cancer Biol 60 (2020) 14-27.
  62. 62. M. Keshtgar, T. Davidson, K. Pigott, M. Falzon, A. Jones, Current status and advances in management of early breast cancer, Int J Surg 8(3) (2010) 199-202.
  63. 63. P. Eroles, A. Bosch, J.A. Perez-Fidalgo, A. Lluch, Molecular biology in breast cancer: intrinsic subtypes and signaling pathways, Cancer Treat Rev 38(6) (2012) 698-707.
  64. 64. G. Wong, E. Au, S.V. Badve, W.H. Lim, Breast Cancer and Transplantation, Am J Transplant 17(9) (2017) 2243-2253.
  65. 65. C.B. Matsen, L.A. Neumayer, Breast cancer: a review for the general surgeon, JAMA Surg 148(10) (2013) 971-979.
  66. 66. J.A. de la Mare, L. Contu, M.C. Hunter, B. Moyo, J.N. Sterrenberg, K.C. Dhanani, L.Z. Mutsvunguma, A.L. Edkins, Breast cancer: current developments in molecular approaches to diagnosis and treatment, Recent Pat Anticancer Drug Discov 9(2) (2014) 153-175.
  67. 67. E.S. McDonald, A.S. Clark, J. Tchou, P. Zhang, G.M. Freedman, Clinical Diagnosis and Management of Breast Cancer, J Nucl Med 57 Suppl 1 (2016) 9S–16S.
  68. 68. E.A. Rakha, M.E. El-Sayed, J.S. Reis-Filho, I.O. Ellis, Expression profiling technology: its contribution to our understanding of breast cancer, Histopathology 52(1) (2008) 67-81.
  69. 69. K.A. Cadoo, T.A. Traina, T.A. King, Advances in molecular and clinical subtyping of breast cancer and their implications for therapy, Surg Oncol Clin N Am 22(4) (2013) 823-840.
  70. 70. D.D. Yu, Y. Wu, H.Y. Shen, M.M. Lv, W.X. Chen, X.H. Zhang, S.L. Zhong, J.H. Tang, J.H. Zhao, Exosomes in development, metastasis and drug resistance of breast cancer, Cancer Sci 106(8) (2015) 959-964.
  71. 71. S.H. Jafari, Z. Saadatpour, A. Salmaninejad, F. Momeni, M. Mokhtari, J.S. Nahand, M. Rahmati, H. Mirzaei, M. Kianmehr, Breast cancer diagnosis: Imaging techniques and biochemical markers, J Cell Physiol 233(7) (2018) 5200-5213.
  72. 72. R. Singh, R. Pochampally, K. Watabe, Z. Lu, Y.Y. Mo, Exosome-mediated transfer of miR-10b promotes cell invasion in breast cancer, Mol Cancer 13 (2014) 256.
  73. 73. S.A. Melo, H. Sugimoto, J.T. O'Connell, N. Kato, A. Villanueva, A. Vidal, L. Qiu, E. Vitkin, L.T. Perelman, C.A. Melo, A. Lucci, C. Ivan, G.A. Calin, R. Kalluri, Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis, Cancer Cell 26(5) (2014) 707-721.
  74. 74. W. Zhou, M.Y. Fong, Y. Min, G. Somlo, L. Liu, M.R. Palomares, Y. Yu, A. Chow, S.T. O'Connor, A.R. Chin, Y. Yen, Y. Wang, E.G. Marcusson, P. Chu, J. Wu, X. Wu, A.X. Li, Z. Li, H. Gao, X. Ren, M.P. Boldin, P.C. Lin, S.E. Wang, Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis, Cancer Cell 25(4) (2014) 501-515.
  75. 75. S. Shen, Y. Song, B. Zhao, Y. Xu, X. Ren, Y. Zhou, Q . Sun, Cancer-derived exosomal miR-7641 promotes breast cancer progression and metastasis, Cell Commun Signal 19(1) (2021) 20.
  76. 76. C.Y. Wu, S.L. Du, J. Zhang, A.L. Liang, Y.J. Liu, Exosomes and breast cancer: a comprehensive review of novel therapeutic strategies from diagnosis to treatment, Cancer Gene Ther 24(1) (2017) 6-12.
  77. 77. H. Zhang, C. Yan, Y. Wang, Exosome-mediated transfer of circHIPK3 promotes trastuzumab chemoresistance in breast cancer, J Drug Target (2021) 1-39.
  78. 78. J.C. Santos, N.D.S. Lima, L.O. Sarian, A. Matheu, M.L. Ribeiro, S.F.M. Derchain, Exosome-mediated breast cancer chemoresistance via miR-155 transfer, Sci Rep 8(1) (2018) 829.
  79. 79. B.N. Hannafon, Y.D. Trigoso, C.L. Calloway, Y.D. Zhao, D.H. Lum, A.L. Welm, Z.J. Zhao, K.E. Blick, W.C. Dooley, W.Q . Ding, Plasma exosome microRNAs are indicative of breast cancer, Breast Cancer Res 18(1) (2016) 90.
  80. 80. M. Wang, S. Ji, G. Shao, J. Zhang, K. Zhao, Z. Wang, A. Wu, Effect of exosome biomarkers for diagnosis and prognosis of breast cancer patients, Clin Transl Oncol 20(7) (2018) 906-911.
  81. 81. Y. Tian, S. Li, J. Song, T. Ji, M. Zhu, G.J. Anderson, J. Wei, G. Nie, A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy, Biomaterials 35(7) (2014) 2383-2390.
  82. 82. Z. Naseri, R.K. Oskuee, M.R. Jaafari, M. Forouzandeh Moghadam, Exosome-mediated delivery of functionally active miRNA-142-3p inhibitor reduces tumorigenicity of breast cancer in vitro and in vivo, Int J Nanomedicine 13 (2018) 7727-7747.

Written By

Congjian Shi, Hongqin Yang, Zhengchao Wang and Zhenghong Zhang

Submitted: 25 December 2020 Reviewed: 06 January 2021 Published: 22 April 2021