Abstract
The solid tumor microenvironment possesses a hypoxic condition, which promotes aggressiveness and resistance to therapies. Hypoxic tumor cells undergo broadly metabolic and molecular adaptations and communicate with surrounding cells to provide conditions promising for their homeostasis and metastasis. Extracellular vesicles such as exosomes originating from the endosomal pathway carry different types of biomolecules such as nucleic acids, proteins, and lipids; participate in cell-to-cell communication. The exposure of cancer cells to hypoxic conditions, not only, increases exosomes biogenesis and secretion but also alters exosomes cargo. Under the hypoxic condition, different signaling pathways such as HIFs, Rab-GTPases, NF-κB, and tetraspanin are involved in the exosomes biogenesis. Hypoxic tumor cells release exosomes that induce tumorigenesis through promoting metastasis, angiogenesis, and modulating immune responses. Exosomes from hypoxic tumor cells hold great potential for clinical application and cancer diagnosis. Besides, targeting the biogenesis of these exosomes may be a therapeutic opportunity for reducing tumorigenesis. Exosomes can serve as a drug delivery system transferring therapeutic compounds to cancer cells. Understanding the detailed mechanisms involved in biogenesis and functions of exosomes under hypoxic conditions may help to develop effective therapies against cancer.
Similar content being viewed by others
Background
Hypoxia, a condition of insufficient oxygen, is a common feature of numerous solid tumors, related to tumor development, therapy resistance, and mortality [1]. Tumor cells in the microenvironment encounter low oxygen levels because of insufficient oxygen flow and physiological anomalies in tumor vessels, resulting in normoxic, hypoxic, and also necrotic regions [2]. In most solid tumors, the average concentration of oxygen is near 10 mmHg, whereas in the other tissues it reaches 40 and 60 mmHg [3]. Tumor cells juxtaposed to the normal vessels are functional, whereas cells situated around 150 μm from the vasculature bed may undergo necrosis and atresia [4], however, cells are located between these two cell populations habituate to an insufficient oxygen environment, hypoxia. Generally, cells located in a diameter of approximately 1 mm undergo genetic, molecular, and metabolic changes. These cells could reorganize the microenvironment appropriate for growth, metastasis, and therapy resistance [5]. In this situation, by the production of pro-angiogenic factors, tumor cells can induce angiogenesis for supplying nutrients and oxygen and removing waste. Besides, increased angiogenesis in tumor mass provides a way for tumor cells to migrate and metastasize [6].
In response to a hypoxic condition, the transcription profile of tumor cells such as hypoxia-inducible factors (HIFs), the key factor involved in regulating hypoxic condition, are altered [7]. HIFs, the dimeric proteins, are composed of a constitutive subunit named HIF-1β and an oxygen-regulated α-subunit (HIF-1, 2, 3α) [8]. The activity of HIF-1α is dynamic and related to the availability of oxygen. In the presence of oxygen, HIF-1 α is degraded by the proteasome system; so that, HIF-1α is hydroxylated by prolyl hydroxylases (PHD), in kee**, von Hippel-Lindau (VHL) recognizes the hydroxylated HIF-1α. This event subsequently ubiquitinates HIF-1α for degradation by the 26S proteasome [9, 10]. PHDs are inactive in a hypoxic condition and allow HIF-1α to link to the HIF-1β subunit.
According to previous studies, HIFs are active in almost solid tumors. HIFs regulate different signaling pathways, which are implicated in the cell viability, proliferation, epithelial-to-mesenchymal transition (EMT), angiogenesis, metastasis, and therapy resistance [11]. However, other pathways including mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinases (PI3K)-Akt, Wnt/β-catenin, nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPK), and NADPH oxidase (NOX) facilitate the adaption of tumor cells to hypoxia [1, 12, 13]. Besides, HIFs have been shown to facilitate exosomes biogenesis and secretion [14]. Exosomes a subfamily of extracellular vesicles (EVs) mediate intercellular communication by carrying different biological molecules among cells. These vesicles contain various biological molecules like proteins, RNAs (coding and non-coding RNAs), DNAs, and lipids, regulating activation of different signaling pathways in recipient cells located nearby or distant tissues [15, 16]. It has been shown that exosomes derived from tumor cells participate in modulating the tumor microenvironment and promoting tumorigenesis [17, 18]. Confirmed that, hypoxia induces exosomes biogenesis and secretion and thereby promotes tumor intercellular communication, representing the key role of exosomes in hypoxic tumors [14, 19]. The majority of experiments discussed in this review used 1% O2 as a hypoxic model that generally called the hypoxic condition, if not, we explained the condition. In the present review, we discuss exosomes biogenesis and loading and also possible underlying mechanisms under hypoxic. Also, we describe the key roles of hypoxic in tumorigenesis and tumor-therapy.
Tumor microenvironment
The tumor microenvironment is a dynamic environment around a tumor, containing the blood vessels, fibroblasts, immune cells, the extracellular matrix (ECM), and signaling molecules that support proliferation, growth, metastasis, and therapy resistance of tumor cells. Tumor cell proliferation, death, invasion, migration, angiogenesis, metabolic reprogramming, immune evasion, are all regulated by the complex interaction inside the tumor microenvironment. In this regard, autocrine, paracrine, and juxtacrine communication network orchestrate these biological functions. Paracrine-mediated communication plays pivotal roles in signal transduction between neighboring and distant cells [20,21,22].
Non-tumor cells including fibroblasts, endothelial cells (ECs), and immune cells contribute to tumor microenvironment interaction and are affected by tumor soluble factors, and their fate goes through tumor-like modifications, persistently accommodate to the tumor microenvironment and support tumor growth. In the tumor microenvironment, fibroblasts are motivated into cancer-associated fibroblasts (CAFs), these cells are the most resident stromal cells in the tumor microenvironment, producing an ECM that vary common ECM in inflexibility and arrangement properties that facilities migration and invasion of tumor cells [23]. In the tumor microenvironment, hypoxia induces tumor cells to produce angiogenic factors, which in turn affect ECs and up-regulate angiogenesis [24, 25]. In the tumor microenvironment, the resident immune cells demonstrate multiplicity and could suppress the immune responses. Also, anti-inflammatory molecules can inhibit the immune system, which is involved in the suppression of cancer cells [99]. More recently, Mo et al. [100] found that exosomes derived from hypoxic A549 lung cancer cells contain angiopoietin-like 4 protein that induces angiogenesis in HUVECs. Also, exosomal miR-210 released from hypoxic leukemia cells induced tubulogenesis in ECs [101]. These data show exosomes from hypoxic tumor cells can promote angiogenesis, thus these exosomes may serve as a novel target for cancer treatment.
Diagnostic application of hypoxic exosomes
Early diagnosis of cancer is the hallmark of cancer therapy that improves the survival rate and quality of a patient’s life [102]. As exosomes released from tumor cells can be distributed to several bio-fluids, thus, a simple liquid-biopsy from plasma, serum, urine, and CSF is a non-invasive way for acquiring detailed information about tumor environment/status [15]. As exosomes originate directly from tumor cells, they may serve as a diagnostic tool for predicting the extent of the physiological and pathological status of tumor cells. Exosomes cargo like proteins and nucleic acids are altered upon the change in the dynamic of parental cells, suggesting a prognostic and diagnostic tool for the treatment of cancer [103]. Analyzing exosomal cargoes (miRs and proteins) gives a chance for scientists to predict the status of a pathological condition like tumor progression. Therefore, as under hypoxia condition tumor cells release more exosomes with distinct cargoes; they may be potentially used as a biomarker for hypoxia tumors. Exosomal biomarker represents superiority against other approaches evaluating hypoxia. Currently, some of the approaches have clinical challenges in estimating hypoxia. For instance, pimonidazole and immunohistochemistry techniques are invasive and necessitate surgical elimination of tumors. Consequently, the application of tumor-derived exosomes from bio-fluids to obtain evidence of hypoxia standing in various cancers could be noteworthy. In this regard, exosomal miRs and protein obtained from bio-fluids have biomarker potential for the diagnosis of different cancers [104, 105]. For example, Matsumura et al. [106] reported that expression of miR-19a in exosomes isolated from the serum of CRC patients was up-regulated, which could be considered as a relapse biomarker of CRC. In the case of hypoxic tumors, confirmed that HIF-1 mRNA molecules are enriched within tumor-derived exosomes that are commonly considered as a typical biomarker for diagnosing cancer development as well as therapy consequences [79]. A study conducted by Kucharzewska et al. [107] demonstrated that exosomes obtained from both Glioblastoma multiform (GBM) cells culture medium and isolated from the GBM patients plasma abundantly contain hypoxia-regulated proteins and mRNAs including PDGFs, Caveolin 1, IL- 8, MMPs, and LOX. The authors conclude that the mRNA and proteome content of these exosomes reflect the hypoxic status of cancer and have biomarker potential for GBM. Also, miRs and metabolites cargo of hypoxic exosome would be useful as a biomarker for diagnosis and prognosis of different cancers such as prostate, colorectal, and pancreatic cancers [108,109,110]. For example, the expression pattern of exosomal miR-210 from the serum of CRC patients may function as a promising non-invasive biomarker for the diagnosis and prognosis of CRC [108]. During the hypoxic condition, miR-210 is the most extensively and consistently up-regulated miR that commonly shows tumorigenesis properties in different tumors [111]. Similar to hypoxic exosomes from prostate tumor cells (PCa and LNCaP), exosomes obtained from the serum of PCa patients contain a high level of miR-885 and miR-521 [109]. Besides, proteins cargo (VLA-4, TYRP2, HSP90, and HSP70) of exosomes derived from the plasma of melanoma patients are significantly increased in comparison with healthy persons [112]. VLA-4 and TYRP2 are up-regulated under the hypoxic condition and their high expression in exosomes correlates with stage 3 melanoma [113, 114]. Previous studies have shown that HSP90 and HSP70 are hypoxic related proteins and play roles in hypoxic condition [115, 116]. In this regard, exosomal proteins have diagnostic and prognostic value for the melanoma tumor development and hypoxic status. Therefore, hypoxic exosomes may be a useful tool for predicting the hypoxic status of solid tumors, however, it seems that this evidence is not sufficient and further scrutiny is essential to examine and confirm the potential application of hypoxic exosomes to quantify the degree of hypoxia to detect stages of tumor development.
Possible therapeutic application of exosomes
Exosomes can reach target cells and alter the function, fate, and morphology through different signaling pathways. As mentioned, tumor cells under hypoxic conditions produce more exosomes, promoting tumorigenesis. Thus, it seems that targeting exosomes formation and secretion particularly from the hypoxic tumor may provide us with a tool that reduces tumorigenesis. Recent findings have shown that it is possible to inhibit the exosomes biogenesis and secretion from different cells. For example, Manumycin A and GW4869 have been shown to inhibit exosome biogenesis and release from cells [117]. Datta et al. [118] reported that Manumycin A inhibited exosomes biogenesis and secretion from aggressive prostate cells mainly by suppression of Ras/Raf/ERK1/2 signaling and hnRNP H1. They concluded that Manumycin A is a potential drug candidate to inhibit exosome biogenesis and secretion. Suppression of Rab27a, a protein involved in exosomes secretion, has been shown to inhibit exosome-dependent and -independent tumor cells growth [119]. Inhibition of Rab proteins involved in intracellular trafficking of exosomes/MVB may inhibit exosomes biogenesis and release, thus they may be a target to inhibit exosome biogenesis. For example, Rab5a has been involved in the early step of exosomes biogenesis, while Rab11, Rab27a, and Rab35 regulate the MVBs-plasma membrane fusion and exosomes secretion. Moreover, inhibition of sphingomyelinase, an enzyme catalyzes the formation of ceramide from sphingomyelin, may lessen exosomes biogenesis and loading, thus prevents tumor growth [120]. In human prostate cancer (PC3) cells, it was shown that Imipramine profoundly inhibited the biogenesis of both microvesicles and exosomes [121]. A fascinating approach has been proposed by Marleau and colleagues based on the effective elimination of blood exosomes of breast cancer patients by extracorporeal hemofiltration associated with affinity agents like exosome-trap** antibodies and lectins. This approach was proposed to trap particles < 200 nm from the whole circulatory system [122]. Considering the existence of numerous experiments on exosomes inhibition, there are challenges regarding analyzing and conclusions of findings, because as various methods are used to isolate and characterize exosomes. Moreover, some researchers did not include ISEV guidelines regarding the exosomes confirmation and validation, as exosome-based studies had been performed before the 2014 and 2018 declaration of ISEV guidelines about exosome-based studies [30, 123]. Besides, it is vital to discover the non-toxic doses of the drugs for target cells to confirm that any decrease in exosomes secretion resulting from exosomes inhibition not from cell death. The majority of these experiments were pre-clinical performed, thus, clinical trials are essential for the approval. Furthermore, the non-targeting effects of these drugs on exosomes biogenesis from normal cells remain an important concern. At least, in the field of cancer, key studies must still be necessary to investigate their effects on exosomes production from both healthy and tumor cells and to progress methods to specifically deliver drugs into tumor cells.
Another approach that exosomes can be used as a therapeutic agent is the drug delivery potential of them. According to previous studies, exosomes can be used as a drug delivery system in two ways: (I); direct loading by which therapeutic agents directly sorted into exosomes; and (II); indirect loading where source cells co-cultured with therapeutic agents or manipulated genetically to produce optional exosomes. In this regard, different approaches for producing optional exosomes have been examined, which comprise: incubating exosomes with the agents, electroporation, sonication, sensitive fusogenic peptide, and cationic lipid, liposome, and exosome-coated metal–organic nanoparticle [124, 125]. An example of the direct method, Zhuang et al. [131]. Collectively, exosomes may serve as a new avenue to overcome cancer, however, translation of pre-clinical results into the clinic needs more experiments regarding exosomes biology and bio-applications in disease models.
Conclusion
Hypoxia increases exosome biogenesis and secretion in tumor cells. Moreover, it can alter exosomes cargo. Exosomes released from tumor cells play a pivotal role in promoting growth, metastasis, and resistance of hypoxic tumors. Furthermore, exosomes from hypoxic tumors have been suggested to be a promising non-invasive biomarker for cancer diagnosis through analyzing their components such as proteins and miRs. Inhibition of exosomes biogenesis and secretion may help to reduce tumorigenesis. Exosomes can be used as a drug delivery system for the treatment of cancer. However, despite many experiments, translation of the preclinical findings into the clinic requires additional examinations in this field. Therefore, further scrutiny is essential for a better understanding of the mechanisms behind exosome loading and production under hypoxic conditions, which could be useful in targeting exosomes biogenesis and prevent tumorigenesis.
Availability of data and materials
The primary data for this study is available from the authors on direct request.
Abbreviations
- ABs:
-
Apoptotic bodies
- AMPK:
-
AMP-activated protein kinase
- CAFs:
-
Cancer-associated fibroblasts
- CMA:
-
Chaperone-mediated autophagy
- CML:
-
Chronic myeloid leukemia
- d-GalN/LPS:
-
D-galactosamine and Lipopolysaccharide
- GBM:
-
Glioblastoma multiform
- ECM:
-
Extracellular matrix
- ECs:
-
Endothelial cells
- EMT:
-
Epithelial-to-mesenchymal transition
- ESCRT:
-
Endosomal sorting complex required for transport
- EVs:
-
Extracellular vesicles
- HIFs:
-
Hypoxia-inducible factors
- HRE:
-
Hypoxia-responsive element
- HR-MM:
-
Hypoxia-resistant multiple myeloma
- HUVECs:
-
Human umbilical vein endothelial cells
- ILVs:
-
Intraluminal vesicles
- ISEV:
-
International Society for Extracellular Vesicles Protein type 2A
- LOX:
-
Protein-lysine 6-oxidase
- MAPK:
-
Mitogen-activated protein kinases
- MHC:
-
Major histocompatibility complex
- MMPs:
-
Matrix metalloproteinase
- MSCs:
-
Mesenchymal stem cells
- MSDCs:
-
Myeloid-derived suppressor cells
- mTOR:
-
Mammalian target of rapamycin
- MV:
-
Microvesicles
- MVBs:
-
Multivesicular bodies
- nSMase2:
-
Sphingomyelinase 2
- NSCLC:
-
Non-small cell lung cancer
- NOX:
-
NADPH oxidase
- NPC:
-
Nasopharyngeal carcinoma
- PI3K:
-
Phosphatidylinositol 3-kinases
- PHD:
-
Prolylhydroxylase
- PKM2:
-
Pyruvate kinase 2
- PLP:
-
Proteolipid proteins
- PM:
-
Plasma membrane
- PTX:
-
Paclitaxel
- ROCK:
-
RHO-associated protein kinase
- ROS:
-
Reactive oxygen species
- SNAREs:
-
Soluble NSF attachment protein receptors
- TLR:
-
Toll-like receptors
- VHL:
-
Von Hippel-Lindau
References
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.
Al Tameemi W, Dale TP, Al-Jumaily RMK, Forsyth NR. Hypoxia-modified cancer cell metabolism. Front Cell Dev Biol. 2019;7:4.
McKeown S. Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response. Br J Radiol. 2014;87:20130676.
Tomes L, Emberley E, Niu Y, Troup S, Pastorek J, Strange K, Harris A, Watson PH. Necrosis and hypoxia in invasive breast carcinoma. Breast Cancer Res Treat. 2003;81:61–9.
Balkwill FR, Capasso M, Hagemann T: The tumor microenvironment at a glance. The Company of Biologists Ltd; 2012.
Folkman J: Role of angiogenesis in tumor growth and metastasis. In Seminars in oncology. Elsevier; 2002: 15–18.
Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148:399–408.
Harada H, Inoue M, Itasaka S, Hirota K, Morinibu A, Shinomiya K, Zeng L, Ou G, Zhu Y, Yoshimura M. Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels. Nature communications. 2012;3:1–12.
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–8.
Tukmechi A, Rezaee J, Nejati V, Sheikhzadeh N. Effect of acute and chronic toxicity of paraquat on immune system and growth performance in rainbow trout, O ncorhynchus mykiss. Aquacult Res. 2014;45:1737–43.
Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–32.
Mitani T, Harada N, Nakano Y, Inui H, Yamaji R. Coordinated action of hypoxia-inducible factor-1α and β-catenin in androgen receptor signaling. J Biol Chem. 2012;287:33594–606.
Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38–47.
Zhang W, Zhou X, Yao Q, Liu Y, Zhang H, Dong Z. HIF-1-mediated production of exosomes during hypoxia is protective in renal tubular cells. American Journal of Physiology-Renal Physiology. 2017;313:F906–13.
Kowal J, Tkach M, Théry C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol. 2014;29:116–25.
Jabbari N, Akbariazar E, Feqhhi M, Rahbarghazi R, Rezaie J. Breast cancer-derived exosomes: tumor progression and therapeutic agents. J Cell Physiol. 2020. https://doi.org/10.1002/jcp.29668.
Lu X, Kang Y. Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res. 2010;16:5928–35.
Filipazzi P, Bürdek M, Villa A, Rivoltini L, Huber V. Recent advances on the role of tumor exosomes in immunosuppression and disease progression. In: Seminars in cancer biology. Elsevier; 2012, p. 342–349.
Park JE, Tan HS, Datta A, Lai RC, Zhang H, Meng W, Lim SK, Sze SK. Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol Cell Proteomics. 2010;9:1085–99.
Giraldo NA, Sanchez-Salas R, Peske JD, Vano Y, Becht E, Petitprez F, Validire P, Ingels A, Cathelineau X, Fridman WH. The clinical role of the TME in solid cancer. Br J Cancer. 2019;120:45–53.
Yuan Y, Jiang Y-C, Sun C-K, Chen Q-M. Role of the tumor microenvironment in tumor progression and the clinical applications. Oncol Rep. 2016;35:2499–515.
Khaksar M, Sayyari M, Rezaie J, Pouyafar A, Montazersaheb S, Rahbarghazi R. High glucose condition limited the angiogenic/cardiogenic capacity of murine cardiac progenitor cells in in vitro and in vivo milieu. Cell Biochem Funct. 2018;36:346–56.
Petrova V, Annicchiarico-Petruzzelli M, Melino G, Amelio I. The hypoxic tumour microenvironment. Oncogenesis. 2018;7:1–13.
Lucero R, Zappulli V, Sammarco A, Murillo OD, Cheah PS, Srinivasan S, Tai E, Ting DT, Wei Z, Roth ME. Glioma-derived miRNA-containing extracellular vesicles induce angiogenesis by reprogramming brain endothelial cells. Cell Rep. 2020;30(2065–2074):e2064.
Varricchi G, Loffredo S, Galdiero MR, Marone G, Cristinziano L, Granata F, Marone G. Innate effector cells in angiogenesis and lymphangiogenesis. Curr Opin Immunol. 2018;53:152–60.
**e F, Zhou X, Fang M, Li H, Su P, Tu Y, Zhang L, Zhou F. Extracellular vesicles in cancer immune microenvironment and cancer immunotherapy. Adv Sci. 2019;6:1901779.
Whiteside TL. Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment. In: Seminars in immunology. Elsevier; 2018, p. 69–79.
Jarosz-Biej M, Smolarczyk R, Cichoń T, Kułach N. Tumor microenvironment as A “Game Changer” in cancer radiotherapy. Int J Mol Sci. 2019;20:3212.
Peng J, Yang Q, Shi K, **ao Y, Wei X, Qian Z. Intratumoral fate of functional nanoparticles in response to microenvironment factor: Implications on cancer diagnosis and therapy. Adv Drug Deliv Rev. 2019;143:37–67.
Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. Journal of extracellular vesicles. 2018;7:1535750.
Record M, Silvente-Poirot S, Poirot M, Wakelam MJ. Extracellular vesicles: lipids as key components of their biogenesis and functions. J Lipid Res. 2018;59:1316–24.
Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2:569–79.
McKelvey KJ, Powell KL, Ashton AW, Morris JM, McCracken SA. Exosomes: mechanisms of uptake. J Circulating Biomarkers. 2015;4:7.
Hassanpour M, Rezaie J, Nouri M, Panahi Y. The role of extracellular vesicles in COVID-19 virus infection. Infect Genet Evol. 2020. https://doi.org/10.1016/j.meegid.2020.104422.
Shen B, Fang Y, Wu N, Gould SJ. Biogenesis of the posterior pole is mediated by the exosome/microvesicle protein-sorting pathway. J Biol Chem. 2011;286:44162–76.
Yang J-M, Gould SJ. The cis-acting signals that target proteins to exosomes and microvesicles. London: Portland Press Ltd.; 2013.
Mulcahy LA, Pink RC, Carter DRF. Routes and mechanisms of extracellular vesicle uptake. J Extracellular Vesicles. 2014;3:24641.
Morelli AE, Larregina AT, Shufesky WJ, Sullivan ML, Stolz DB, Papworth GD, Zahorchak AF, Logar AJ, Wang Z, Watkins SC. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood. 2004;104:3257–66.
Hassanpour M, Rahbarghazi R, Nouri M, Aghamohammadzadeh N, Safaei N, Ahmadi M. Role of autophagy in atherosclerosis: foe or friend? J Inflamm. 2019;16:8.
Wang T, Gilkes DM, Takano N, **ang L, Luo W, Bishop CJ, Chaturvedi P, Green JJ, Semenza GL. Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc Natl Acad Sci USA. 2014;111:E3234-3242.
King HW, Michael MZ, Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer. 2012;12:421.
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 USA. 2013;110:7312–7.
Liu W, Li L, Rong Y, Qian D, Chen J, Zhou Z, Luo Y, Jiang D, Cheng L, Zhao S. Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126. Acta Biomater. 2020;103:196–212.
Liu W, Rong Y, Wang J, Zhou Z, Ge X, Ji C, Jiang D, Gong F, Li L, Chen J. Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization. J Neuroinflammation. 2020;17:1–22.
Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29:625–34.
Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, Cole RN, Pandey A, Semenza GL. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011;145:732–44.
Vaupel P, Harrison L. Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist. 2004;9:4–9.
Wei Y, Wang D, ** F, Bian Z, Li L, Liang H, Li M, Shi L, Pan C, Zhu D. Pyruvate kinase type M2 promotes tumour cell exosome release via phosphorylating synaptosome-associated protein 23. Nat Commun. 2017;8:1–12.
Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, Coscia C, Iessi E, Logozzi M, Molinari A. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem. 2009;284:34211–22.
Ban J-J, Lee M, Im W, Kim M. Low pH increases the yield of exosome isolation. Biochem Biophys Res Commun. 2015;461:76–9.
Jordens I, Marsman M, Kuijl C, Neefjes J. Rab proteins, connecting transport and vesicle fusion. Traffic. 2005;6:1070–7.
Stenmark H, Olkkonen VM. The rab gtpase family. Genome Biol. 2001;2(reviews3007):3001.
Dorayappan KDP, Wanner R, Wallbillich JJ, Saini U, Zingarelli R, Suarez AA, Cohn DE, Selvendiran K. Hypoxia-induced exosomes contribute to a more aggressive and chemoresistant ovarian cancer phenotype: a novel mechanism linking STAT3/Rab proteins. Oncogene. 2018;37:3806–21.
Panigrahi GK, Praharaj PP, Peak TC, Long J, Singh R, Rhim JS, Abd Elmageed ZY, Deep G. Hypoxia-induced exosome secretion promotes survival of African-American and Caucasian prostate cancer cells. Sci Rep. 2018;8:3853.
Wang Z, ** N, Ganguli S, Swartz DR, Li L, Rhoades RA. Rho-Kinase activation is involved in hypoxia-induced pulmonary vasoconstriction. Am J Respir Cell Mol Biol. 2001;25:628–35.
Li B, Antonyak MA, Zhang J, Cerione RA. RhoA triggers a specific signaling pathway that generates transforming microvesicles in cancer cells. Oncogene. 2012;31:4740–9.
Yang JCS, Lin MW, Rau CS, Jeng SF, Lu TH, Wu YC, Chen YC, Tzeng SL, Wu CJ, Hsieh CH. Altered exosomal protein expression in the serum of NF-κB knockout mice following skeletal muscle ischemia-reperfusion injury. J Biomed Sci. 2015;22:40.
Hedlund M, Nagaeva O, Kargl D, Baranov V, Mincheva-Nilsson L. Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells. PLoS ONE. 2011;6:e16899.
Kim B, Boo K, Lee JS, Kim KI, Kim WH, Cho H-J, Park Y-B, Kim H-S, Baek SH. Identification of the KAI1 metastasis suppressor gene as a hypoxia target gene. Biochem Biophys Res Commun. 2010;393:179–84.
Chairoungdua A, Smith DL, Pochard P, Hull M, Caplan MJ. Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling. J Cell Biol. 2010;190:1079–91.
Hervera A, De Virgiliis F, Palmisano I, Zhou L, Tantardini E, Kong G, Hutson T, Danzi MC, Perry RBT, Santos CX. Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons. Nat Cell Biol. 2018;20:307–19.
Zhang W, Zhou Q, Wei Y, Da M, Zhang C, Zhong J, Liu J, Shen J. The exosome-mediated PI3k/Akt/mTOR signaling pathway in cervical cancer. Int J Clin Exp Pathol. 2019;12:2474.
Jung KO, Youn H, Lee C-H, Kang KW, Chung J-K. Visualization of exosome-mediated miR-210 transfer from hypoxic tumor cells. Oncotarget. 2017;8:9899.
Ding L, Zhao L, Chen W, Liu T, Li Z, Li X. miR-210, a modulator of hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cell. Int J Clin Exp Med. 2015;8:2299–307.
Huang X, Ding L, Bennewith KL, Tong RT, Welford SM, Ang KK, Story M, Le Q-T, Giaccia AJ. Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. Mol Cell. 2009;35:856–67.
Huang Z, Yang M, Li Y, Yang F, Feng Y. Exosomes derived from hypoxic colorectal cancer cells transfer Wnt4 to normoxic cells to elicit a prometastatic phenotype. Int J Biol Sci. 2018;14:2094.
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;54:554–65.
Kore RA, Edmondson JL, Jenkins SV, Jamshidi-Parsian A, Dings RPM, Reyna NS, Griffin RJ. Hypoxia-derived exosomes induce putative altered pathways in biosynthesis and ion regulatory channels in glioblastoma cells. Biochem Biophys Rep. 2018;14:104–13.
Umezu T, Tadokoro H, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH. Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. Blood. 2014;124:3748–57.
Chiang AC, Massagué J. Molecular basis of metastasis. N Engl J Med. 2008;359:2814–23.
Chowdhury R, Webber JP, Gurney M, Mason MD, Tabi Z, Clayton A. Cancer exosomes trigger mesenchymal stem cell differentiation into pro-angiogenic and pro-invasive myofibroblasts. Oncotarget. 2015;6:715.
Huber MA, Kraut N, Beug H. Molecular requirements for epithelial–mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17:548–58.
Tan EJ, Olsson A-K, Moustakas A. Reprogramming during epithelial to mesenchymal transition under the control of TGFβ. Cell Adhesion Migration. 2015;9:233–46.
Peng Z, Wang C-X, Fang E-H, Wang G-B, Tong Q. Role of epithelial-mesenchymal transition in gastric cancer initiation and progression. World J Gastroenterol. 2014;20:5403–10.
Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Can Res. 2008;68:3645.
Xue M, Chen W, **ang A, Wang R, Chen H, Pan J, Pang H, An H, Wang X, Hou H, Li X. Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1. Mol Cancer. 2017;16:143.
Li L, Li C, Wang S, Wang Z, Jiang J, Wang W, Li X, Chen J, Liu K, Li C, Zhu G. Exosomes derived from hypoxic oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a prometastatic phenotype. Can Res. 2016;76:1770.
Takahashi K, Yan IK, Haga H, Patel T. Modulation of hypoxia-signaling pathways by extracellular linc-RoR. J Cell Sci. 2014;127:1585.
Aga M, Bentz GL, Raffa S, Torrisi MR, Kondo S, Wakisaka N, Yoshizaki T, Pagano JS, Shackelford J. Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene. 2014;33:4613–22.
Wang Y, Yi J, Chen X, Zhang Y, Xu M, Yang Z. The regulation of cancer cell migration by lung cancer cell-derived exosomes through TGF-β and IL-10. Oncol Lett. 2016;11:1527–30.
Sceneay J, Parker BS, Smyth MJ, Möller A. Hypoxia-driven immunosuppression contributes to the pre-metastatic niche. Oncoimmunology. 2013;2:e22355–e22355.
Filipazzi P, Bürdek M, Villa A, Rivoltini L, Huber V. Recent advances on the role of tumor exosomes in immunosuppression and disease progression. Semin Cancer Biol. 2012;22:342–9.
Liu C, Yu S, Zinn K, Wang J, Zhang L, Jia Y, Kappes JC, Barnes S, Kimberly RP, Grizzle WE, Zhang H-G. Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J Immunol. 2006;176:1375–85.
Ye SB, Zhang H, Cai TT, Liu YN, Ni JJ, He J, Peng JY, Chen QY, Mo HY, Jun-Cui, et al: Exosomal miR-24-3p impedes T-cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma. J Pathol 2016, 240:329–340.
Wen SW, Sceneay J, Lima LG, Wong CSF, Becker M, Krumeich S, Lobb RJ, Castillo V, Wong KN, Ellis S, et al. The biodistribution and immune suppressive effects of breast cancer-derived exosomes. Can Res. 2016;76:6816.
Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, Lovat F, Fadda P, Mao C, Nuovo GJ. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci. 2012;109:E2110–6.
Theodoraki M-N, Hoffmann TK, Jackson EK, Whiteside TL. Exosomes in HNSCC plasma as surrogate markers of tumour progression and immune competence. Clin Exp Immunol. 2018;194:67–78.
Liu Y, **ang X, Zhuang X, Zhang S, Liu C, Cheng Z, Michalek S, Grizzle W, Zhang H-G. Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. The American journal of pathology. 2010;176:2490–9.
Chen X, Ying X, Wang X, Wu X, Zhu Q, Wang X. Exosomes derived from hypoxic epithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization. Oncol Rep. 2017;38:522–8.
Hasina R, Lingen MW. Angiogenesis in oral cancer. J Dent Educ. 2001;65:1282–90.
Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia. 2015;3:83.
Hsu YL, Hung JY, Chang WA, Lin YS, Pan YC, Tsai PH, Wu CY, Kuo PL. Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene. 2017;36:4929–42.
Mao G, Liu Y, Fang X, Liu Y, Fang L, Lin L, Liu X, Wang N. Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer. Angiogenesis. 2015;18:373–82.
Zhang P, Lim SB, Jiang K, Chew TW, Low BC, Lim CT. Cancer exosomes harbor diverse hypoxia-targeted mRNAs and contribute toward tumor angiogenesis. bioRxiv 2020.
Mao Y, Wang Y, Dong L, Zhang Y, Zhang Y, Wang C, Zhang Q, Yang S, Cao L, Zhang X. Hypoxic exosomes facilitate angiogenesis and metastasis in esophageal squamous cell carcinoma through altering the phenotype and transcriptome of endothelial cells. J Exp Clin Cancer Res. 2019;38:389.
Guo Z, Wang X, Yang Y, Chen W, Zhang K, Teng B, Huang C, Zhao Q, Qiu Z. Hypoxic tumor-derived exosomal long noncoding RNA UCA1 promotes angiogenesis via miR-96-5p/AMOTL2 in pancreatic cancer. Mol Ther Nucleic Acids. 2020;22:179–95.
Li J, Yuan H, Xu H, Zhao H, **ong N. Hypoxic cancer-secreted exosomal miR-182-5p promotes glioblastoma angiogenesis by targeting Kruppel-like factor 2 and 4. Mol Cancer Res. 2020;18:1218–31.
Matsuura Y, Wada H, Eguchi H, Gotoh K, Kobayashi S, Kinoshita M, Kubo M, Hayashi K, Iwagami Y, Yamada D. Exosomal miR-155 derived from hepatocellular carcinoma cells under hypoxia promotes angiogenesis in endothelial cells. Dig Dis Sci. 2019;64:792–802.
Wu F, Li F, Lin X, Xu F, Cui R-R, Zhong J-Y, Zhu T, Shan S-K, Liao X-B, Yuan L-Q. Exosomes increased angiogenesis in papillary thyroid cancer microenvironment. Endocr Relat Cancer. 2019;26:525–38.
Mo F, Xu Y, Zhang J, Zhu L, Wang C, Chu X, Pan Y, Bai Y, Shao C, Zhang J. Effects of hypoxia and radiation-induced exosomes on migration of lung cancer cells and angiogenesis of umbilical vein endothelial cells. Radiat Res. 2020. https://doi.org/10.1667/RR15555.1/436363.
Tadokoro H, Umezu T, Ohyashiki K, Hirano T, Ohyashiki JH. Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells. J Biol Chem. 2013;288:34343–51.
Schiffman JD, Fisher PG, Gibbs P. Early detection of cancer: past, present, and future. Am Soc Clin Oncol Educ Book. 2015;35:57–65.
Duijvesz D, Luider T, Bangma CH, Jenster G. Exosomes as biomarker treasure chests for prostate cancer. Eur Urol. 2011;59:823–31.
Hildonen S, Skarpen E, Halvorsen TG, Reubsaet L. Isolation and mass spectrometry analysis of urinary extraexosomal proteins. Sci Rep. 2016;6:36331.
Duijvesz D, Burnum-Johnson KE, Gritsenko MA, Hoogland AM, Vredenbregt-van den Berg MS, Willemsen R, Luider T, Paša-Tolić L, Jenster G. Proteomic profiling of exosomes leads to the identification of novel biomarkers for prostate cancer. PLoS ONE. 2013;8:e82589.
Matsumura T, Sugimachi K, Iinuma H, Takahashi Y, Kurashige J, Sawada G, Ueda M, Uchi R, Ueo H, Takano Y. Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. Br J Cancer. 2015;113:275.
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. 2013;110:7312–7.
Wang W, Qu A, Liu W, Liu Y, Zheng G, Du L, Zhang X, Yang Y, Wang C, Chen X. Circulating miR-210 as a diagnostic and prognostic biomarker for colorectal cancer. Eur J Cancer Care. 2017;26:e12448.
Panigrahi GK, Ramteke A, Birks D, Ali HEA, Venkataraman S, Agarwal C, Vibhakar R, Miller LD, Agarwal R, Elmageed ZYA. Exosomal microRNA profiling to identify hypoxia-related biomarkers in prostate cancer. Oncotarget. 2018;9:13894.
Altadill T, Campoy I, Lanau L, Gill K, Rigau M, Gil-Moreno A, Reventos J, Byers S, Colas E, Cheema AK. Enabling metabolomics based biomarker discovery studies using molecular phenoty** of exosome-like vesicles. PLoS ONE. 2016;11:e0151339.
Dang K, Myers KA. The role of hypoxia-induced miR-210 in cancer progression. Int J Mol Sci. 2015;16:6353–72.
Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, García-Santos G, Ghajar CM. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012;18:883.
Zhao XP, Wang M, Song Y, Song K, Yan TL, Wang L, Liu K, Shang ZJ. Membrane microvesicles as mediators for melanoma-fibroblasts communication: roles of the VCAM-1/VLA-4 axis and the ERK1/2 signal pathway. Cancer Lett. 2015;360:125–33.
Zbytek B, Peacock DL, Seagroves TN, Slominski A. Putative role of HIF transcriptional activity in melanocytes and melanoma biology. Dermato Endocrinol. 2013;5:239–51.
Zhou J, Schmid T, Frank R, Brüne B. PI3K/Akt is required for heat shock proteins to protect hypoxia-inducible factor 1α from pVHL-independent degradation. J Biol Chem. 2004;279:13506–13.
Jain K, Suryakumar G, Ganju L, Singh SB. Differential hypoxic tolerance is mediated by activation of heat shock response and nitric oxide pathway. Cell Stress Chaperones. 2014;19:801–12.
Zhou X, Zhang W, Yao Q, Zhang H, Dong G, Zhang M, Liu Y, Chen J-K, Dong Z. Exosome production and its regulation of EGFR during wound healing in renal tubular cells. Am J Physiol Renal Physiol. 2017;312:F963–70.
Datta A, Kim H, Lal M, McGee L, Johnson A, Moustafa AA, Jones JC, Mondal D, Ferrer M, Abdel-Mageed AB. Manumycin A suppresses exosome biogenesis and secretion via targeted inhibition of Ras/Raf/ERK1/2 signaling and hnRNP H1 in castration-resistant prostate cancer cells. Cancer Lett. 2017;408:73–81.
Bobrie A, Krumeich S, Reyal F, Recchi C, Moita LF, Seabra MC, Ostrowski M, Théry C. Rab27a supports exosome-dependent and-independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Can Res. 2012;72:4920–30.
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;319:1244–7.
Kosgodage US, Trindade RP, Thompson PR, Inal JM, Lange S. Chloramidine/bisindolylmaleimide-I-mediated inhibition of exosome and microvesicle release and enhanced efficacy of cancer chemotherapy. Int J Mol Sci. 2017;18:1007.
Marleau AM, Chen C-S, Joyce JA, Tullis RH. Exosome removal as a therapeutic adjuvant in cancer. J Transl Med. 2012;10:134.
Lötvall J, Hill AF, Hochberg F, Buzás EI, Di Vizio D, Gardiner C, Gho YS, Kurochkin IV, Mathivanan S, Quesenberry P. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. Milton: Taylor & Francis; 2014.
Bunggulawa EJ, Wang W, Yin T, Wang N, Durkan C, Wang Y, Wang G. Recent advancements in the use of exosomes as drug delivery systems. J Nanobiotechnol. 2018;16:1–13.
Johnsen KB, Gudbergsson JM, Skov MN, Pilgaard L, Moos T, Duroux M. A comprehensive overview of exosomes as drug delivery vehicles—endogenous nanocarriers for targeted cancer therapy. Biochimica et Biophysica Acta (BBA) Reviews Cancer. 2014;1846:75–87.
Zhuang X, **ang X, Grizzle W, Sun D, Zhang S, Axtell RC, Ju S, Mu J, Zhang L, Steinman L. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther. 2011;19:1769–79.
Aryani A, Denecke B. Exosomes as a nanodelivery system: a key to the future of neuromedicine? Mol Neurobiol. 2016;53:818–34.
Jiang X-C, Gao J-Q. Exosomes as novel bio-carriers for gene and drug delivery. Int J Pharm. 2017;521:167–75.
Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJA. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29:341–5.
Pascucci L, Coccè V, Bonomi A, Ami D, Ceccarelli P, Ciusani E, Viganò L, Locatelli A, Sisto F, Doglia SM. Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery. J Control Release. 2014;192:262–70.
Jung KO, Jo H, Yu JH, Gambhir SS, Pratx G. Development and MPI tracking of novel hypoxia-targeted theranostic exosomes. Biomaterials. 2018;177:139–48.
Chen X, Zhou J, Li X, Wang X, Lin Y, Wang X. Exosomes derived from hypoxic epithelial ovarian cancer cells deliver microRNAs to macrophages and elicit a tumor-promoted phenotype. Cancer Lett. 2018;435:80–91.
Mace TA, Collins AL, Wojcik SE, Croce CM, Lesinski GB, Bloomston M. Hypoxia induces the overexpression of microRNA-21 in pancreatic cancer cells. J Surg Res. 2013;184:855–60.
Umezu T, Tadokoro H, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH. Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. Blood J Am Soc Hematol. 2014;124:3748–57.
Schlaepfer IR, Nambiar DK, Ramteke A, Kumar R, Dhar D, Agarwal C, Bergman B, Graner M, Maroni P, Singh RP. Hypoxia induces triglycerides accumulation in prostate cancer cells and extracellular vesicles supporting growth and invasiveness following reoxygenation. Oncotarget. 2015;6:22836.
Panigrahi GK, Praharaj PP, Peak TC, Long J, Singh R, Rhim JS, Elmageed ZYA, Deep G. Hypoxia-induced exosome secretion promotes survival of African-American and Caucasian prostate cancer cells. Scientific reports. 2018;8:1–13.
Huang Z, Feng Y. Exosomes derived from hypoxic colorectal cancer cells promote angiogenesis through Wnt4-induced β-catenin signaling in endothelial cells. Oncol Res Featuring Preclin Clin Cancer Therapeutics. 2017;25:651–61.
Svensson KJ, Kucharzewska P, Christianson HC, Sköld S, Löfstedt T, Johansson MC, Mörgelin M, Bengzon J, Ruf W, Belting M. Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2–mediated heparin-binding EGF signaling in endothelial cells. Proc Natl Acad Sci. 2011;108:13147–52.
Horie K, Kawakami K, Fujita Y, Sugaya M, Kameyama K, Mizutani K, Deguchi T, Ito M. Exosomes expressing carbonic anhydrase 9 promote angiogenesis. Biochem Biophys Res Commun. 2017;492:356–61.
Shan Y, You B, Shi S, Shi W, Zhang Z, Zhang Q, Gu M, Chen J, Bao L, Liu D. Hypoxia-induced matrix metalloproteinase-13 expression in exosomes from nasopharyngeal carcinoma enhances metastases. Cell Death Dis. 2018;9:1–13.
Ye SB, Zhang H, Cai TT, Liu YN, Ni JJ, He J, Peng JY, Chen QY, Mo HY, Zhang XS. Exosomal miR-24-3p impedes T-cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma. J Pathol. 2016;240:329–40.
Berchem G, Noman MZ, Bosseler M, Paggetti J, Baconnais S, Le Cam E, Nanbakhsh A, Moussay E, Mami-Chouaib F, Janji B. Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-β and miR23a transfer. Oncoimmunology. 2016;5:e1062968.
Xue M, Chen W, **ang A, Wang R, Chen H, Pan J, Pang H, An H, Wang X, Hou H. Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1. Mol Cancer. 2017;16:143.
Li L, Li C, Wang S, Wang Z, Jiang J, Wang W, Li X, Chen J, Liu K, Li C. Exosomes derived from hypoxic oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a prometastatic phenotype. Can Res. 2016;76:1770–80.
Acknowledgements
Not applicable.
Funding
Not applicable.
Author information
Authors and Affiliations
Contributions
RJ and JR conceived the ideas. JR, MA and MH collected data. RR and JR designed and reviewed the manuscript. All authors reviewed the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Jafari, R., Rahbarghazi, R., Ahmadi, M. et al. Hypoxic exosomes orchestrate tumorigenesis: molecular mechanisms and therapeutic implications. J Transl Med 18, 474 (2020). https://doi.org/10.1186/s12967-020-02662-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s12967-020-02662-9