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 Table of Contents  
Year : 2017  |  Volume : 3  |  Issue : 2  |  Page : 58-63

Exosomes biology: Function and clinical implications in lung cancer

1 Department of Thoracic Oncology, Memorial Cancer Institute, Florida International University, Pembroke Pines, FL, USA
2 Department of Oncology, Phase I-Early Clinical Trials Unit, Antwerp University Hospital, Center for Oncological Research, Antwerp University, Antwerp, Belgium

Date of Submission01-Aug-2016
Date of Acceptance10-Jan-2017
Date of Web Publication27-Apr-2017

Correspondence Address:
Luis E Raez
Department of Thoracic Oncology, Memorial Cancer Institute, Florida International University, 801 N. Flamingo Road, Suite 11, Pembroke Pines, FL 33028
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ctm.ctm_32_16

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Lung cancer is the most common malignancy in the United States, totaling 225,000 cases per year. In recent years, several new treatment options have become available based on the molecular and cellular characterization of the disease. More recently, "liquid biopsies" have received attention to complement traditional tissue biopsies and to enhance the spectrum of analysis for tumor-derived factors. As one of these tumor characteristics, extracellular vesicles (EVs) are lipid bilayered EVs that can cargo a variety of factors, including growth factors and their receptors, RNA transcripts, microRNAs, and DNA, among others. Initial acceptance as mere physiological products has been attributed to the presence of exosomes in healthy individuals, and the large diversity of exosomes that have made the assignment of distinct pathophysiological roles difficult. While their role in clinical application has not yet been established, they have emerged from their once thought innocent role as a bystander to a critical mediator of intratumoral signaling, tumor progression, chemotherapy resistance, and metastasis. In this review, we have summarized the structure and biology of EVs, their role in lung cancer, and the potential diagnostic and therapeutic implications for the treatment of this complex disease.

Keywords: Exosomes, liquid biopsy, lung cancer, molecular targeting

How to cite this article:
Dietrich MF, Rolfo C, Reclusa P, Giallombardo M, Valentino A, Raez LE. Exosomes biology: Function and clinical implications in lung cancer. Cancer Transl Med 2017;3:58-63

How to cite this URL:
Dietrich MF, Rolfo C, Reclusa P, Giallombardo M, Valentino A, Raez LE. Exosomes biology: Function and clinical implications in lung cancer. Cancer Transl Med [serial online] 2017 [cited 2018 Jun 20];3:58-63. Available from: http://www.cancertm.com/text.asp?2017/3/2/58/202227

  Introduction Top

Extracellular vesicles (EVs) encompass a broad family of bilayered lipid vesicles that have specific function in cell–cell communication. EVs are lipid-based, bilayered structures with a size range of 40–1000 nm that occur in a multitude, if not all, cell types.[1] These exocytically formed EVs were originally described in reticulocytes in the early 1980s by several groups who followed the transferrin receptor as a marker of maturation from reticulocyte to erythrocyte and recognized initial endocytic uptake with subsequent extracellular secretion through the fusion of multivesicular bodies (MVBs) with the plasma membrane.[2],[3] Excretion of the transferrin receptor was thought to be a simple mechanism of discarding unnecessary cellular components following maturation into erythrocytes. Recognition of their importance as key mediators of intercellular communication in cancer was originally hindered by several factors, including a presence in healthy individuals, their large variety in size and cargo content, the unappreciated role of "liposomes" as vectors in physiological functions, and in part, through consideration as technical artifacts from membrane isolation procedures.[4] In addition, the broad nomenclature and diversity of its usage in the literature contributed to this confusion. An overlap also seems to exist between endocellular and membrane-derived vesicles due to indiscriminate isolation techniques by centrifugation.[5] Therefore, a clear distinction from the literature appears difficult, and clear differentiation by origin may remain technically challenging.

Based on the cellular origin within the cell, EVs are differentiated into ectosomes, also known as microparticles, that occur through fusion and budding with the plasma cell membrane,[6],[7] whereas exosomes originate from MVBs inside the cell that is only later fused with the plasma cell membrane before their extracellular secretion.[8] Common laboratory techniques using centrifugation and size exclusion filters are not able to reliably distinguish between these two based on cellular origin, and thus a large overlap between these two types of vesicles remains present in the literature. For purposes of this review, we will focus on the role of exosomes as part of the EV family and their implications in lung cancer. In particular, we will focus on disease initiation, conferred resistance through microenvironmental influences, and promotion of metastatic potential.

From the time that we used to treat with a "one size fits all" approach to "personalized medicine" in lung cancer, about 30% of lung cancer patients are now therapeutically benefitting from molecular analysis.[9],[10],[11] Detection and serial monitoring of biomarkers have become increasingly more important to detect molecular vulnerabilities and follow their evolution.[12],[13] "Liquid biopsy" describes a more novel concept of tumor characterization through analysis of circulating components of tissue-resident cancer in various body fluids, predominantly obtained from blood or serum. Circulating tumor cells were first utilized in clinical application with some prognostic information in breast and other cancer types but with low utility in lung cancer.[14] More recently, cell-free DNA (cfDNA) has been utilized to provide genomic information,[15],[16] and epidermal growth factor receptor (EGFR) testing based on this methodology has become approved by the Food and Drug Administration for clinical companion testing in nonsmall cell lung cancer.[17] There is always cfDNA shed from apoptotic or necrotic cells that can be isolated and utilized for genetic analysis through next-generation sequencing, with an increase in concentration from cancer cell populations. Another clinical application of "liquid biopsy" is the analysis of circulating protein composition from serum/plasma and is further utilized in the VeriStrat test, predicting a response to inhibitor erlotinib independent of mutation status in the EGFR tyrosine kinase domain.[18] Other circulating factors, for example, circulating vascular endothelial growth factor (VEGF), have been investigated to predict therapy responses but have not yet reached a level of clinical applicability to guide therapy.[19]

Although cancer-related exosomes, sometimes referred to as "oncosomes" in the literature, have been described over 30 years ago,[20],[21] they have only more recently become a focus of clinical investigation in lung cancer. While the extent of involvement, physiological processes and clinical utility in disease of these particles remain to be fully understood, basic and translational science has made remarkable progress to elicit functions with a potential of clinical exploitation.[22] The idea is to discover clinical utility,[23] but most likely the benefit will be in assessing early detection, recurrence, prognosis or disease monitoring.[24],[25],[26]

  Structural Properties of Exosomes Top

Exosomes are a heterogeneous group of bilayered lipid vesicles that originate from cytosolic compartments of the cell [Figure 1]. All cell types are capable of secreting exosomes in both physiological and pathological conditions. Exosomes range in size from 40 to 150 nm.[27],[28] Technical preparation, cell of origin, and cargo may be some of the influences to contribute to this diversity. The inhibition of exosomes secretion could be an interesting treatment due to the many roles that exosomes play in tumor development; however, mechanisms of exosome secretion are still unclear. It has been demonstrated that exosomes can be released directly from the plasmatic membrane;[29] however, the majority are released from the endosomal compartment. Several proteins have been described to be implied in the exosome secretion machinery with contradictory results.[30],[31] The endosomal sorting complex required for transport has been described as one of the most important members of the exosome formation since it seems to be the complex that organizes the cargo of the exosomes during its formation and may contribute to targeting the receptor to the intraluminal vesicles.[32],[33] In addition, some lipids seem to be required for exosome secretion as ceramide.[34] In any case, the exosomes when released get coated by the plasmatic membrane, such that membrane composition mimics the content of any intracellular membrane, including cholesterol, sphingomyelin, etc.[35] The content cargo of exosome includes DNA, virtually all types of RNA including mRNA, tRNA, microRNAs (miRNAs), mature proteins such as growth factors and growth factor receptors as well as lipids and metabolites. The exact composition of exosomes seems to be dependent on currently unknown factors; however, the presence of certain cancer-specific oncogenic drivers suggests a more directed role rather than a random process of formation.[36],[37]
Figure 1: Exosomes biogenesis

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  Exosomes In Lung Cancer Top

Exosomes are detected in healthy individuals as well as those affected by cancer.[38] This omnipresence likely contributed to a delay in identifying the importance of exosomes in various processes that are important to cancer.[39] The estimated number of exosomes in circulation is estimated around 2000 trillion in healthy individuals, with up to 4000 trillion reported in cancer patients.[40],[41] It is unclear whether this increase is related to increase exosome secretion through tumor cells or a more general phenomenon.[8]

Exosomes have been described to play pleiotropic roles, such as tumor progression, metastasis, angiogenesis, immunomodulation, and horizontal transfer. Below, different experiments are described, which support these roles.

Al-Nedawi et al.[42] demonstrated transfer of a truncated, oncogenic version of the EGFR, known as EGFRvIII, can be "shared" between glioma cells through exosomal transport. In these experiments, incubating wild-type EGFR carrying U373 with exosomes extracted from the supernatant of EGFRvIII carrying U373 demonstrated anchoring of the mutant receptor in the plasma membrane. Further, activation of downstream MEK/Erk1/2 signaling further suggested functional activation of the pathway by the mutant receptor, rather than inconsequential colocalization of the receptor with the plasma membrane. These findings support the idea that exosomes can promote the tumor growth through different mechanisms. The findings were complemented by a study that described EGFRvIII-containing exosomes in blood in 7 out of 25 glioblastoma patients.[43],[44] In the same study, mRNAs and miRNAs were detected in exosomes that are involved in a variety of cellular and metabolic processes relevant to glioblastoma. These were found in concentrations largely exceeding their normal cellular counterparts, thus suggesting a relevant physiological role. These findings supported the role of exosomes in tumor cell growth in a paracrine/intratumoral manner with an infection-like process of horizontal transfer of a malignant phenotype within the tumor microenvironment. The underlying signals that target specific cells remain unclear; however, the presence of mutant protein expression in only a subset of cells provides an intriguing contribution to tumor heterogeneity. Valadi et al.[45] were the first to demonstrate exosomes carrying mRNA and miRNAs and their influence to modulate gene expression in recipient cells. In a translational study, Rolfo et al.[36] were able to demonstrate a tumor histology-specific miRNA signature affecting the EGFR signaling pathway in nonsmall cell lung cancer (NSCLC), further supporting a clinical role for exosomal messenger function.

The tumor microenvironment consists not only of cancer cells but also of a variety of cell types necessary for tumor growth including nontransformed counterparts to cancer cells, fibroblasts, vascular endothelial cells, tissue-resident macrophages, and dendritic cells, among others. Exosomes have the ability to guide cell–cell communication between all of these types. For example, exosomes can transfer transformative molecules from a cancer cell to a nonaffected cell.[46],[47] Delivered cargo functional changes delivered by exosomal influence seem to evolve on induction of cellular transformation.[48] In fact, this communication is bidirectional, and activation of cells in the microenvironment by exosomes can, in turn, deliver exosomes that can contribute to chemoresistance and immunomodulation of the primary breast cancer cells through activation of both STAT1/NOTCH3 and JAG1 cellular pathways.[49] Further, exosomes carrying EGFR from A431, A549, and DLD-1 lung cancer cell lines were shown to enhance angiogenesis through upregulation of VEGF expression, an important pathway in local tumor growth.[50] Fibroblast growth factor and platelet-derived growth factor were equally found in exosomes, both on the transcriptional and protein level.[51] Exosomes containing matrix metalloproteinases can contribute to local tumor cell expansion and allow for malignant growth including tumor support structures of blood vessels and tumor-associated stroma.[52]

Hoshino et al.[53] were able to demonstrate the contribution of exosomes to the development of metastasis in an organ-specific manner through cellular alterations through upregulation of integrins to form the premetastatic niche in several xenograft models of NSCLC. The composition of exosomes may be underlying the preferential organotropism of certain cancer types. In an immunocompromised murine model, isolated exosomes from liver and/or lung metastatic tumor cell lines have demonstrated preferential localization of exosomes within their respective metastatic target environment, suggesting a role in the promotion of organ-specific metastasis before arrival of malignant cells from the primary tumor. The analysis demonstrated a correlation between the expression of integrins and the metastatic potential of the tumor cell. The uptake of malignant cells was then confirmed to be cell-type specific in their respective target organs. Lung-tropic exosomes from melanoma cells predominantly co-localized with S100A4-positive fibroblasts in the lung while exosomes derived from pancreatic cancer colocalized to Kupffer cells in the liver, the primary site of metastasis in this model. This study not only provided powerful evidence of exosome-directed organotropism through integrin-mediated signaling but also a proof-of-principle that blocking integrins through decoy peptides can successfully ablate exosome adhesion in an organic-specific manner. Similar results were obtained in a murine model of pancreatic cancer with predilection to hepatic metastasis through exosome-mediated initiation of a premetastatic niche.[54] Increased exosome formation has been found in hypoxic tumor environments of breast cancer,[55] glioma,[56] leukemia and prostate cancer [57] models, suggesting that hypoxic environments within enlarging tumors could accelerate the development of distant metastasis through a forced secretion of exosomes.

One of the major developments in the treatment of lung cancer and melanomas was the recent advent of immunotherapy. These rely on blocking negative regulators, for example, PD-1 and PD-L1, of T-cell activation in the microenvironment as well as inflammatory signals.[57],[58] Modulation of immune signals into an immunosuppressive microenvironment has been described to be mediated by exosomes [59],[60],[61] through humoral and cellular mechanisms, therefore, allowing tumors to escape immune surveillance in the microenvironment and indicating a possible role in treatment resistance to the newly introduced checkpoint inhibitor therapies. In contrast, exosomes have demonstrated their versatility in (pre-) metastatic sites by upregulation of inflammatory processes and recruitment of bone marrow-derived immune cells, a critical step in preparing the "soil" for the premetastatic niche.[53]

  Potential Clinical Applications Of Exosomes Top

Most of the information implicating a contribution of exosomes to cancer development and progression is derived from in vitro or murine in vivo models. Human-derived data are still in its infancy. While the exact contribution of exosomes to cancer development and progression is still largely unclear, it is conceivable that targeting exosomes could attain a role in cancer diagnosis, prediction, and therapy. Given the versatile functions of exosomes, multiple diagnostic and therapeutic angles could prove beneficial.

Exosomes have been described as powerful tools for different cancer diagnoses. In lung cancer, this field is still under development due to the lack of information regarding NSCLC biomarkers. However, Jakobsen et al.[62] have described a protein profile from exosomes derived from patients with advance NSCLC showing an improvement compared to the expression of CD91 described by Ueda et al.[63] Our group is actively trying to use exosomes for the identification of actionable mutations and trying to find a role in the serial follow-up of specific mutations, such as T790M.

Many miRNAs and proteins have been described as prognostic factors for patients with NSCLC. For example, let-7f and miR-30-3p are related to poor outcome and miR-373 and miR-512 silenced miRNAs that suppress tumor growth, and when reactivation is produced, decrease the tumor growth and the invasiveness.[64] However, prognostic factors inside the exosomes have yet to be implemented into clinical practice.

For conventional chemotherapy, exosomes have been described to shuttle agents such as cisplatin and doxorubicin out of the cell and thus could contribute to chemoresistance.[62] Inhibition of this clearance mechanism would increase sensitivity to therapy and augment an anti-tumor effect. Further, targeted agents such as trastuzumab could lose their specificity, as Her2/ErbB2 receptors are negatively regulated through exosomal export, suggesting a lack of clinical efficacy of this agent.[63] In addition, inhibition of the cellular cross-talk in the tumor environment could increase sensitivity to treatment by blocking microenvironmental-derived supportive signals, including growth factors, RNA transcripts, and miRNAs. In a study focusing on lung cancer-derived exosomes, epithelial-to-mesenchymal transition was demonstrated in human bronchial epithelial cells, suggesting a role of exosomes in malignant microenvironmental transformation.[64] For most tumor types, early detection before development is crucial for curative intent approaches. Several studies now suggest that exosomes play a key role in the development of metastasis through activation of the target tissue environment through growth factors enhancing vascular permeability, increased tissue inflammation resulting in extracellular matrix remodeling, and enhanced angiogenesis as well as recruitment of bone marrow-derived immune cells.[65] These immune cells have been previously implicated in the formation of the premetastatic niche, however, without a clear understanding of the activating signals.[66] Blocking exosomal release from the cell may suppress the development of a favorable tumor microenvironment in the premetastatic niche, and thus prevent disease progression. Peptide-mediated blockades of integrins critical to this process have shown some preclinical promise although similar studies in humans, to the best our knowledge, have not yet been initiated. On the contrary, exosome-mediated suppression of anti-inflammatory signals within the tumor microenvironment could enhance the efficacy of recently introduced immunotherapy in lung cancer.

Liposomal formulation of chemotherapeutic agents, for example, doxorubicin or irinotecan, has been utilized clinically to enhance delivery to cancer cells.[67] Another mechanism of cancer cell-specific delivery includes drug-antibody conjugate, for example, T-DM1 in breast cancer, utilizing a growth factor receptor as a homing beacon to a drug coupled antibody. It is plausible to assume that exosomes have the capability of combining properties of both, including a liposomal envelope with a yet-to-be-identified targeting structure for recipient cells. Given the results of several preclinical studies, it is less likely that exosomal delivery is merely a random process. The success of utilizing exosomes in clinical efforts will largely depend on an improved understanding of exosomal regulation, including the biogenic triggers of information, their specific cargo selection, and identification of "zip codes" for target cells.

  Conclusion Top

Exosomes have emerged from innocent bystanders of physiological cellular exports to central regulators of signaling in cancer growth and development. The ability to freely access exosomes by simple phlebotomy further makes them an attractive object of investigation in cancer. Recognition of their reflection of intratumoral properties indeed widens the spectrum of diagnostic possibility. For example, the presence of EGFR-activating mutations through sequencing of exosomes enables clinicians to perform prognostic and predictive assessments as well as the possibility to guide therapeutic applications. The most important step in taking exosomes from a basic science phenomenon into clinical practice is gaining an improved understanding of exosome biology, in particular, the signals responsible for formation, cargo selection, and labeling for the respective target cell population. Modifying the signaling of exosomes into tumor suppressing properties could be a "trojan horse" approach to undermine tumor signaling although at this point in time this seems rather hypothetical. In clinical practice, delivery of messenger transcripts (siRNA, shRNA, etc.) for therapeutic purposes has largely failed due to low target concentration and lack of target cell specificity. The plethoric nature of exosome involvement in virtually all aspects of cellular function indicates that diagnostic and therapeutic approaches will have to focus on highly context-dependent applications. It remains intriguing that exosomes are freely accessible, and analysis of their content could be utilized to diagnose cancer early, guide therapy, and monitor disease recurrence in a noninvasive manner.

Financial support and sponsorship


Conflicts of interest

LR receives research support from Exosomes DX.

  References Top

Trams EG, Lauter CJ, Salem N Jr., Heine U. Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim Biophys Acta 1981; 645 (1): 63–70.  Back to cited text no. 1
Harding C, Heuser J, Stahl P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 1983; 97 (2): 329–39.  Back to cited text no. 2
Pan BT, Teng K, Wu C, Adam M, Johnstone RM. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol 1985; 101 (3): 942–8.  Back to cited text no. 3
Cocucci E, Racchetti G, Meldolesi J. Shedding microvesicles: artefacts no more. Trends Cell Biol 2009; 19 (2): 43–51.  Back to cited text no. 4
Théry C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol 2006. doi:10.1002/0471143030.cb0322s30.  Back to cited text no. 5
Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, Ratajczak MZ. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 2006; 20 (5): 847–56.  Back to cited text no. 6
Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 2006; 20 (9): 1487–95.  Back to cited text no. 7
Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 2014; 30: 255–89.  Back to cited text no. 8
Awad MM, Engelman JA, Shaw AT. Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med 2013; 369 (12): 1173.  Back to cited text no. 9
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353 (2): 123–32.  Back to cited text no. 10
Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan W, Stephenson P, Shreeve SM, Tye LM, Christensen JG, Wilner KD, Clark JW, Iafrate AJ. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 2014; 371 (21): 1963–71.  Back to cited text no. 11
Dietrich MF, Yan SX, Schiller JH. Response to crizotinib/erlotinib combination in a patient with a primary EGFR-mutant adenocarcinoma and a primary c-met-amplified adenocarcinoma of the lung. J Thorac Oncol 2015; 10 (5): e23–5.  Back to cited text no. 12
Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015; 372 (18): 1689–99.  Back to cited text no. 13
Matikas A, Syrigos KN, Agelaki S. Circulating biomarkers in non-small-cell lung cancer: current status and future challenges. Clin Lung Cancer 2016; 17 (6): 507–16.  Back to cited text no. 14
Oxnard GR, Thress KS, Alden RS, Lawrance R, Paweletz CP, Cantarini M, Yang JC, Barrett JC, Jänne PA. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol 2016; 34 (28): 3375–82.  Back to cited text no. 15
Ai B, Liu H, Huang Y, Peng P. Circulating cell-free DNA as a prognostic and predictive biomarker in non-small cell lung cancer. Oncotarget 2016; 7 (28): 44583–95.  Back to cited text no. 16
Wu YL, Zhou C, Liam CK, Wu G, Liu X, Zhong Z, Lu S, Cheng Y, Han B, Chen L, Huang C, Qin S, Zhu Y, Pan H, Liang H, Li E, Jiang G, How SH, Fernando MC, Zhang Y, Xia F, Zuo Y. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 2015; 26 (9): 1883–9.  Back to cited text no. 17
Molina-Pinelo S, Pastor MD, Paz-Ares L. VeriStrat: a prognostic and/or predictive biomarker for advanced lung cancer patients? Expert Rev Respir Med 2014; 8 (1): 1–4.  Back to cited text no. 18
Hu P, Liu W, Wang L, Yang M, Du J. High circulating VEGF level predicts poor overall survival in lung cancer. J Cancer Res Clin Oncol 2013; 139 (7): 1157–67.  Back to cited text no. 19
Taylor DD, Doellgast GJ. Quantitation of peroxidase-antibody binding to membrane fragments using column chromatography. Anal Biochem 1979; 98 (1): 53–9.  Back to cited text no. 20
Taylor DD, Homesley HD, Doellgast GJ. Binding of specific peroxidase-labeled antibody to placental-type phosphatase on tumor-derived membrane fragments. Cancer Res 1980; 40 (11): 4064–9.  Back to cited text no. 21
Tkach M, Théry C. Communication by extracellular vesicles: where we are and where we need to go. Cell 2016; 164 (6): 1226–32.  Back to cited text no. 22
Besse B, Charrier M, Lapierre V, Dansin E, Lantz O, Planchard D, Le Chevalier T, Livartoski A, Barlesi F, Laplanche A, Ploix S, Vimond N, Peguillet I, Théry C, Lacroix L, Zoernig I, Dhodapkar K, Dhodapkar M, Viaud S, Soria JC, Reiners KS, Pogge von Strandmann E, Vély F, Rusakiewicz S, Eggermont A, Pitt JM, Zitvogel L, Chaput N. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. Oncoimmunology 2015; 5 (4): e1071008.  Back to cited text no. 23
Sandfeld-Paulsen B, Jakobsen KR, Bæk R, Folkersen BH, Rasmussen TR, Meldgaard P, Varming K, Jørgensen MM, Sorensen BS. Exosomal proteins as diagnostic biomarkers in lung cancer. J Thorac Oncol 2016; 11 (10): 1701–10.  Back to cited text no. 24
Ruiz-Martinez M, Navarro A, Marrades RM, Viñolas N, Santasusagna S, Muñoz C, Ramírez J, Molins L, Monzo M. YKT6 expression, exosome release, and survival in non-small cell lung cancer. Oncotarget 2016; 7 (32): 51515–24.  Back to cited text no. 25
Rosell R, Wei J, Taron M. Circulating MicroRNA signatures of tumor-derived exosomes for early diagnosis of non-small-cell lung cancer. Clin Lung Cancer 2009; 10 (1): 8–9.  Back to cited text no. 26
Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 2013; 200 (4): 373–83.  Back to cited text no. 27
Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 2009; 9 (8): 581–93.  Back to cited text no. 28
Booth AM, Fang Y, Fallon JK, Yang JM, Hildreth JE, Gould SJ. Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J Cell Biol 2006; 172 (6): 923–35.  Back to cited text no. 29
Fang Y, Wu N, Gan X, Yan W, Morrell JC, Gould SJ. Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes. PLoS Biol 2007; 5 (6): e158.  Back to cited text no. 30
Bobrie A, Colombo M, Raposo G, Théry C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic 2011; 12 (12): 1659–68.  Back to cited text no. 31
Tamai K, Tanaka N, Nakano T, Kakazu E, Kondo Y, Inoue J, Shiina M, Fukushima K, Hoshino T, Sano K, Ueno Y, Shimosegawa T, Sugamura K. Exosome secretion of dendritic cells is regulated by Hrs, an ESCRT-0 protein. Biochem Biophys Res Commun 2010; 399 (3): 384–90.  Back to cited text no. 32
Colombo M, Moita C, van Niel G, Kowal J, Vigneron J, Benaroch P, Manel N, Moita LF, Théry C, Raposo G. Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J Cell Sci 2013; 126(Pt 24): 5553–65.  Back to cited text no. 33
Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brügger B, Simons M. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 2008; 319 (5867): 1244–7.  Back to cited text no. 34
Stahl PD, Barbieri MA. Multivesicular bodies and multivesicular endosomes: the "ins and outs" of endosomal traffic. Sci STKE 2002; 2002 (141): pe32.  Back to cited text no. 35
Rolfo C, Chacartegui J, Giallombardo M, Alessandro R, Peeters M. 71P Exosomes isolated in plasma of non-small cell lung cancer patients contain microRNA related to the EGFR pathway: proof of concept. J Thorac Oncol 2016; 11 4 Suppl: S85.  Back to cited text no. 36
Demory Beckler M, Higginbotham JN, Franklin JL, Ham AJ, Halvey PJ, Imasuen IE, Whitwell C, Li M, Liebler DC, Coffey RJ. Proteomic analysis of exosomes from mutant KRAS colon cancer cells identifies intercellular transfer of mutant KRAS. Mol Cell Proteomics 2013; 12 (2): 343–55.  Back to cited text no. 37
Dvorak HF, Quay SC, Orenstein NS, Dvorak AM, Hahn P, Bitzer AM, Carvalho AC. Tumor shedding and coagulation. Science 1981; 212 (4497): 923–4.  Back to cited text no. 38
Caradec J, Kharmate G, Hosseini-Beheshti E, Adomat H, Gleave M, Guns E. Reproducibility and efficiency of serum-derived exosome extraction methods. Clin Biochem 2014; 47 (13–14): 1286–92.  Back to cited text no. 39
Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, LeBleu VS, Mittendorf EA, Weitz J, Rahbari N, Reissfelder C, Pilarsky C, Fraga MF, Piwnica-Worms D, Kalluri R. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015; 523 (7559): 177–82.  Back to cited text no. 40
Melo SA, Sugimoto H, O'Connell JT, Kato N, Villanueva A, Vidal A, Qiu L, Vitkin E, Perelman LT, Melo CA, Lucci A, Ivan C, Calin GA, Kalluri R. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 2014; 26 (5): 707–21.  Back to cited text no. 41
Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, Rak J. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 2008; 10 (5): 619–24.  Back to cited text no. 42
Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr., Carter BS, Krichevsky AM, Breakefield XO. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008; 10 (12): 1470–6.  Back to cited text no. 43
Glioblastoma produces tumor-promoting microvesicles. Nat Clin Pract Neurol 2009; 5 (3): 120–1.  Back to cited text no. 44
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 (6): 654–9.  Back to cited text no. 45
Antonyak MA, Cerione RA. Emerging picture of the distinct traits and functions of microvesicles and exosomes. Proc Natl Acad Sci U S A 2015; 112 (12): 3589–90.  Back to cited text no. 46
Desrochers LM, Antonyak MA, Cerione RA. Extracellular vesicles: satellites of information transfer in cancer and stem cell biology. Dev Cell 2016; 37 (4): 301–9.  Back to cited text no. 47
Kreger BT, Dougherty AL, Greene KS, Cerione RA, Antonyak MA. Microvesicle cargo and function changes upon induction of cellular transformation. J Biol Chem 2016; 291 (38): 19774–85.  Back to cited text no. 48
Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, Azzam DJ, Twyman-Saint Victor C, Wiemann BZ, Ishwaran H, Ter Brugge PJ, Jonkers J, Slingerland J, Minn AJ. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 2014; 159 (3): 499–513.  Back to cited text no. 49
Al-Nedawi K, Meehan B, Kerbel RS, Allison AC, Rak J. Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc Natl Acad Sci U S A 2009; 106 (10): 3794–9.  Back to cited text no. 50
Anderson JD, Johansson HJ, Graham CS, Vesterlund M, Pham MT, Bramlett CS, Montgomery EN, Mellema MS, Bardini RL, Contreras Z, Hoon M, Bauer G, Fink KD, Fury B, Hendrix KJ, Chedin F, El-Andaloussi S,6, Hwang B, Mulligan MS, Lehtiö J, Nolta JA. Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-kappaB signaling. Stem Cells 2016; 34 (3): 601–13.  Back to cited text no. 51
You Y, Shan Y, Chen J, Yue H, You B, Shi S, Li X, Cao X. Matrix metalloproteinase 13-containing exosomes promote nasopharyngeal carcinoma metastasis. Cancer Sci 2015; 106 (12): 1669–77.  Back to cited text no. 52
Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, Singh S, Williams C, Soplop N, Uryu K, Pharmer L, King T, Bojmar L, Davies AE, Ararso Y, Zhang T, Zhang H, Hernandez J, Weiss JM, Dumont-Cole VD, Kramer K, Wexler LH, Narendran A, Schwartz GK, Healey JH, Sandstrom P, Labori KJ, Kure EH, Grandgenett PM, Hollingsworth MA, de Sousa M, Kaur S, Jain M, Mallya K, Batra SK, Jarnagin WR, Brady MS, Fodstad O, Muller V, Pantel K, Minn AJ, Bissell MJ, Garcia BA, Kang Y, Rajasekhar VK, Ghajar CM, Matei I, Peinado H, Bromberg J, Lyden D. Tumour exosome integrins determine organotropic metastasis. Nature 2015; 527 (7578): 329–35.  Back to cited text no. 53
Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, Becker A, Hoshino A, Mark MT, Molina H, Xiang J, Zhang T, Theilen TM, García-Santos G, Williams C, Ararso Y, Huang Y, Rodrigues G, Shen TL, Labori KJ, Lothe IM, Kure EH, Hernandez J, Doussot A, Ebbesen SH, Grandgenett PM, Hollingsworth MA, Jain M, Mallya K, Batra SK, Jarnagin WR, Schwartz RE, Matei I, Peinado H, Stanger BZ, Bromberg J, Lyden D. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol 2015; 17 (6): 816–26.  Back to cited text no. 54
King HW, Michael MZ, Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer 2012; 12: 421.  Back to cited text no. 55
Kucharzewska P, Christianson HC, Welch JE, Svensson KJ, Fredlund E, Ringnér M, Mörgelin M, Bourseau-Guilmain E, Bengzon J, Belting M. Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci U S A 2013; 110 (18): 7312–7.  Back to cited text no. 56
Ramteke A, Ting H, Agarwal C, Mateen S, Somasagara R, Hussain A, Graner M, Frederick B, Agarwal R, Deep G. Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol Carcinog 2015; 54 (7): 554–65.  Back to cited text no. 57
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373 (2): 123–35.  Back to cited text no. 58
Zhang HG, Grizzle WE. Exosomes and cancer: a newly described pathway of immune suppression. Clin Cancer Res 2011; 17 (5): 959–64.  Back to cited text no. 59
Whiteside TL. Tumour-derived exosomes or microvesicles: another mechanism of tumour escape from the host immune system? Br J Cancer 2005; 92 (2): 209–11.  Back to cited text no. 60
Clayton A, Mitchell JP, Court J, Mason MD, Tabi Z. Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res 2007; 67 (15): 7458–66.  Back to cited text no. 61
Jakobsen KR, Paulsen BS, Bæk R, Varming K, Sorensen BS, Jørgensen MM. Exosomal proteins as potential diagnostic markers in advanced non-small cell lung carcinoma. J Extracell Vesicles 2015; 4: 26659.  Back to cited text no. 62
Ueda K, Ishikawa N, Tatsuguchi A, Saichi N, Fujii R, Nakagawa H. Antibody-coupled monolithic silica microtips for highthroughput molecular profiling of circulating exosomes. Sci Rep 2014; 4: 6232.  Back to cited text no. 63
Silva J, García V, Zaballos Á, Provencio M, Lombardía L, Almonacid L, García JM, Domínguez G, Peña C, Diaz R, Herrera M, Varela A, Bonilla F. Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival. Eur Respir J 2011; 37 (3): 617–23.  Back to cited text no. 64
Adi Harel S, Bossel Ben-Moshe N, Aylon Y, Bublik DR, Moskovits N, Toperoff G, Azaiza D, Biagoni F, Fuchs G, Wilder S, Hellman A, Blandino G, Domany E, Oren M. Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth. Cell Death Differ 2015; 22 (8): 1328–40.  Back to cited text no. 65
Safaei R, Larson BJ, Cheng TC, Gibson MA, Otani S, Naerdemann W, Howell SB. Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Mol Cancer Ther 2005; 4 (10): 1595–604.  Back to cited text no. 66
Ciravolo V, Huber V, Ghedini GC, Venturelli E, Bianchi F, Campiglio M, Morelli D, Villa A, Della Mina P, Menard S, Filipazzi P, Rivoltini L, Tagliabue E, Pupa SM. Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. J Cell Physiol 2012; 227 (2): 658–67.  Back to cited text no. 67


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