",isbn:"978-1-83969-545-2",printIsbn:"978-1-83969-544-5",pdfIsbn:"978-1-83969-546-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"c77f99db5569e8d0325b856cb7d75b17",bookSignature:"Prof. Maged Marghany",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10854.jpg",keywords:"Optical, Radar, Algorithm, Programming, Big Data, Deep Learning, Image Processing, Time Series Data Analysis, Large Scale Methods, Signal Processing, Computer Vision, Remote Sensing",numberOfDownloads:756,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:1,numberOfTotalCitations:1,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 18th 2021",dateEndSecondStepPublish:"March 18th 2021",dateEndThirdStepPublish:"May 17th 2021",dateEndFourthStepPublish:"August 5th 2021",dateEndFifthStepPublish:"October 4th 2021",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:'Prof. Marghany was recently ranked among the top two percent scientists in a global list compiled by the prestigious Stanford University. A pioneering scientist in microwave remote sensing invented a new theory Quantum Nonlinear Ocean Dynamics " Quantized Marghany\'s Front".',coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"96666",title:"Prof.",name:"Prof.Dr. Maged",middleName:null,surname:"Marghany",slug:"prof.dr.-maged-marghany",fullName:"Prof.Dr. Maged Marghany",profilePictureURL:"https://mts.intechopen.com/storage/users/96666/images/system/96666.png",biography:"Prof.Dr. Maged Marghany, is figured in 2020 and 2021 among the top two per cent scientists in a global list compiled by the prestigious Stanford University. Besides, the prestigious Universidade Estadual de Feira de Santana, Universidade Federal da Bahia, and Universidade Federal de Pernambuco, Brazil ranked him as the first global scientist in the field of oil spill detection and mapping during the last fifty years. 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1. Introduction
Membrane processes, including Ultrafiltration, Nanofiltration and Reverse Osmosis, are widely used for the treatment of water and wastewater. Main advantage of these processes are well known operational conditions and wide application areas. But, main disadvantage of these processes is concentrate management. Mainly high amount of salt content in concentrate stream is limiting the discharge of these streams to water bodies.
Starting from evaporation to ion exchange, most of these processes transfer the pollutants from one phase to other phase. It means more concentrated streams can be created from these processes. Therefore, applicable and valuable product production techniques are urgently needed for membrane concentrates. Electrodialysis Bipolar Membrane (EDBM) Processes are promising technique for the disposal of membrane concentrates.
EDBM technique has too many advantages against other techniques such as, valuable product formation and low cost operation. On the other hand, there is still great limitations on application point such as limited company production, alkali element fouling on membranes, high capital cost etc.,
Briefly, technological opportunities may solve the application disadvantages of EDBM processes in near future. In this chapter, principles and potentials of EDBM processes are discussed.
2. Electrodialysis bipolar membrane: principles and definitions
Industrial wastewater differs in industrial pollutant components depending on the types of industries in which they are formed. This difference plays a major role in the selection of wastewater treatment technologies.
Treatment technologies applied for wastewater recycling; Secondary Treatment (IA), Nutrient Removal, Filtration, Surface Filtration, Microfiltration (MF), Ultrafiltration (UF), Flotation, Nanofiltration (NF), Reverse Osmosis (TO), Electrodialysis (ED), Carbon Adsorption, Ion Exchange, Advanced Oxidation and Disinfection [1]. Figure 1 shows the corresponding pore sizes of the pressure-operated membranes and their ability to hold specific wastewater components.
Figure 1.
Pressure operated membrane technology [2].
Membrane Processes (mainly reverse osmosis (RO) systems) and desalination plants are increasing day by day. In last two decades, over 10.000 membrane treatment plants have been established in most countries [3]. Daily treatment capacity of these plants may access 100 million m3/day in 2020.
With the introduction of low cost membrane modules in the 1960s and 1970s, membranes were widely used in industrial areas [4]. RO process (pore diameter < 0.0001 μm) can remove dissolved solids, bacteria, viruses and other microorganisms present in water [5]. By operating RO systems, which is one of the wastewater recycling processes, both high quality process water (filtrate flow) production is provided, and concentrate flow with high pollution load but low flow (silk) is formed. In RO systems with flow and concentrate modifications, approximately almost 90% filtrate and 10% concentrate can be formed from the inlet flow at high pressure [3].
The disposal of the concentrate from Membrane systems is still the main focus of most scientific research. This is an important issue for most country for the protection of water bodies and soil. As well known, discharged wastewater streams are still being used for irrigation. High salt content in concentrate streams means desertification of most valuable agricultural areas. The concentrate originating from membrane processes should be disposed or treated with feasible system.
Bipolar membranes are a type of ion-selective membranes first introduced in the 1950s (Figure 2). Bipolar membranes are composite membranes consisting of a Cation exchange membrane and an Anion exchange membrane [7]. Cation exchange membrane and anion exchange membranes, which are among ion exchange membranes, are heterogeneous, while bipolar membranes are homogeneous. Homogeneous bipolar membranes can be prepared from many different materials. The properties of bipolar membranes formed from different materials are given in the table below (Table 1).
Figure 2.
Water splitting function of a bipolar membrane [6].
Polymer(s)
İon exchange group
Remarks
Anion exchange layer
Poly-styrene-co- divinylbenzene
Tertiary and quaternary amines
Crosslinked resin, heterogeneous
Poly-sulfone
Di-amines
Crosslinked homogeneous
Poly-sulfone
Quaternary amines
Homogeneous
Poly-vinylidene fluoride blend with poly-vinyl benzyl chloride
Ion exchange polymers of bipolar membrane layers [8].
Earlier studies on electrodialysis began before the World War II in Germany. Industrial and pilot scale applications have been developed since 1950. The first applications were about obtaining drinking water from sea water. Later, in applications in the food industry, it was tried to produce demineralized sugarcane sugar. If we consider the electrodialysis system as a black box, as a result of natural brine feeding, acid and base are formed at the output of the system, this picture is shown in the picture below [8] (Figure 3).
Figure 3.
Schematic illustration of EDBM process as a black-box [8].
Electrodialysis processes is one of the membrane process that the driving force is an electrical field. EDBM system consist of anionic, cationic and bipolar membranes [9]. EDBM systems are widely used in chemical industry, in food industry, biochemistry industry and environmental protection technologies [9].
Using bipolar membranes together with ion exchange membranes in electrodialysis processes, high quality process water production can be possible and EDBM may become a more viable method for industrial wastewater treatment applications [10].
In the EDBM process, direct current (DC) is supplied to the electrodes to electrolyse the water molecules. Electrical potential between anode and cathode works as a driving force for the movement of electrons in electrolyte solution [8]. In EDBM process, bipolar membranes realizes the acid and base production in electrolyte solution.
Organic acids such as lactic acid, ascorbic acid, salicylic acid, amino acid and inorganic acids such as hydrofluoric (HF) acid, sulfuric acid (H2SO4), hydrochloric acid (HCl) can be produced using EDBM systems. Alkali bases potassium hydroxide (KOH), Sodium Methoxide (CH3NaO) can also be produced in this systems [11].
In electrodialysis systems that separate water with bipolar membranes, an acid - base is formed from a very efficient energy-related salt concentration due to the accumulation of hundreds of cell units between 2 electrodes, such as conventional electrodialysis processes [7].
Some catalytic reactions take place in electrodialysis systems using bipolar membranes. Reactions between water molecules and functional chemical groups occur as Eq. (1), (2), (3), (4) [12]. The catalytic mechanism is underlined by chemical reaction model of water dissociation, that is, the water splitting could be considered as some type of proton-transfer reaction between water molecules and the functional groups or chemicals [7]:
B+H2O↔BH+…OH−↔BH++OH−E1
BH++H2O↔B…H3O↔B+H3OE2
A−+H2O↔AH…OH−↔AH+OH−E3
AH+H2O↔A−…H3O+↔A−+H3OE4
where BH+ and A− refer to the catalytic centers. The catalytic sites provide an alternative path with low effective activation energy for water splitting into hydrogen and hydroxyl ions [7]. EDBM configurations including acid base production schematic diagrams are given in Figure 4 [12].
Figure 4.
Bipolar membrane and EDBM: BP, bipolar membrane; A, anion selective membrane; C, cation selective membrane; M +, cation; X- anion; H +, hydrogen ion; R, OH− or CH3O. (a) Bipolar membrane and its functions; (b) acid and base production; (c) acid production; (d) base production [12].
3. Usage areas of EDBM process
The bipolar membrane electrodialysis process is used in the latest technological way as an integrated process for the supply of potable water and industrial salt water and recovery of industrial effluent. On the other hand, both in chemical processes and environmental protection processes, they have been successfully applying in recent years. Another field of use of bipolar membrane is the chemical industry, where new products such as H2SO4 and NaOH are produced from a salt such as Na2SO4. Indeed, this method has become widespread recently and is used successfully. Especially, the production of acid and base without producing waste and the production of organic - inorganic acids increased the interest in this method. Many researchers have worked on this subject. It is possible to find many studies especially on acetic acid, propionic acid, gluconic acid, citric acid and lactic acid. In fact, some model studies have started to be carried out recently. Biotechnological research is ongoing to reduce costs in the electrodialysis process in order to reduce the cost in order to ensure acid recovery.
When ED and EDBM processes are compared with other treatment methods, it is an important advantage that it provides recovery from pollutants in wastewater and salt water. Studies show that it is possible to recover pollutants from solutions with one or more contaminants. In addition to this, the process of making acid and base production possible with EDBM process takes another step forward [13].
4. Recovery of concentrated wastes by EDBM process
An important advantage of the electrodialysis process over other processes is the possibility of recovery of concentrated waste. When the electrodialysis studies in the literature are taken into consideration, recovery has been proved possible. Electrodialysis studies are mainly in the form of recovery of those pollutants from aqueous solutions with single or multiple pollutants.
The process characteristics and economic evaluations of some studies in the literature are given in Table 2.
Application
Scale
Process characteristics
Economic evaluations
References
HF and HNO3 Recovery
Industrial Scale
3 compartments, M. Area; 3x105 m2, BM Service Life; 2 years, Efficiency 90–95%
Total $ 2,950,000 Annual Business Administration Cost: $ 870,000
Recovery of concentrated wastes by EDBM process [14].
In addition to treatment and recovery, it is frequently encountered that electrodialysis method is used directly in acid and base production.
5. Advantages and disadvantages of EDBM process
Main advantage of EDBM systems is energy efficiency. In most cases high energy needed for most treatment processes mainly for pumping. But in EDBM process, system works with low pressure pumps (0.5–0.8 Bar). On the other hand direct current usage makes the EDBM systems advantageous against the other advanced treatment processes. Beside the most treatment processes, by products of EDBM are valuable materials such as acids and bases. Additionally, the inlet concentrated stream with a high salt content is deionized and water can be recovered. Briefly, salt content can be converted to valuable materials and water content can be reduced and recovered. Actually, it turns out that the EDBM system is a process capable of very high approach to zero waste practice.
The biggest advantages of using bipolar membranes in EDBM processes is that BPMs increase ionization by 50 million times compared to the self-hydrolysis of water. In addition, the anionic and cationic membranes inside the EDBM systems prevent the OH− and H+ ions formed in the system from reaching the anodes and cathodes, and no O2 and H2 gas output is observed in the BPMs [3].
The first disadvantage of EDBM systems meets the mark in acid and base production from membrane process concentrates. Concentrates consisting of membrane processes from wastewater treatment processes, generally contain mixed ion groups instead of single ion groups. This is due to the type and variety of wastewater they treat. Mixed acids and bases may remain low in commercial value. Another problem is the permanent damage left in the membrane structure of the multivalent ions in the concentrated stream. For this, +2 and + 3 valence cations can be removed from the water by nanofiltration, ion exchange, evaporation etc., before reverse osmosis process. Or + 2-valued (especially calcium compounds) ions can be removed from the reverse osmosis concentrate content by processes such as precipitation. However, in both cases, the operating costs of the processes will increase and will lead to reductions in acid and base concentrations resulting from the decrease in ion concentration in the feed water to EDBM systems.
Another problem to be encountered in EDBM systems may be the locking of the system at low acid and base concentrations (1–2%) with the increase of osmotic pressure in the system due to the increasing ion content. As it is known, high acid and base levels are important in these systems both commercially and in terms of water recovery. The most important solution related to this lies in the separate collection and purification of the salt content in the wastewater source. In other words, these systems can be paved with clean production. In other words, the disadvantages of the EDBM system in mixed wastewater streams can be prevented by interventions at the source. Thus, the operating life of EDBM systems is preserved and operating costs and product quality are increased.
It is certain that the advantages mentioned so far will lead the EDBM systems to attract more attention in the future. However, the biggest obstacle to the implementation of EDBM systems is the high cost of the membranes used in the system. This is thought to be in favor of the price decrease of the balances in the market due to the widespread use of EDBM and increased membrane production over time. Because the vast majority of existing wastewater treatment systems transfer existing pollutants to another phase or make them more concentrated and present them as an even bigger problem. However, EDBM systems promise us to use new products from our waste. This; It plays an important role in the solution of many environmental problems from efficient use of resources to global warming.
6. Conclusions
For further usage of membrane processes without any problematic concrete flows on environment, new concentrate disposal technologies will be needed such as EDBM process. The main advantage of the EDBM process is the commercially obtaining precious product from environmentally problematic products. However, the most important problem at the moment is high initial investment costs. But, similar high investment problems are valid for many processes that are widely used today, and with the spread of manufacturing, this problem has disappeared and the possibility of widespread use has increased. Finally, membrane concentrate flows are waiting an urgent solution, and the spread of EDBM or similar technologies will not take too long.
\n',keywords:"electrodialysis, electrodialysis bipolar membrane, concentrate, reuse, recovery",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/73677.pdf",chapterXML:"https://mts.intechopen.com/source/xml/73677.xml",downloadPdfUrl:"/chapter/pdf-download/73677",previewPdfUrl:"/chapter/pdf-preview/73677",totalDownloads:486,totalViews:0,totalCrossrefCites:1,totalDimensionsCites:3,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:54,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"April 10th 2020",dateReviewed:"September 11th 2020",datePrePublished:"October 20th 2020",datePublished:"December 9th 2020",dateFinished:"October 20th 2020",readingETA:"0",abstract:"In most cases traditional and advanced treatment technologies transfers and concentrates the pollutants from one phase to other phase. However, nowadays, these concentrated flows containing heavy pollution are rapidly moving away from being manageable. In particular, membrane concentrate flows await immediate solutions to this issue. Electrodialysis Bipolar Membrane (EDBM) Processes are becoming a serious and potential solution technique for similar concentrate streams. In this chapter, principles and potentials of EDBM processes for the recycling or recovery of membrane concentrates are discussed.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/73677",risUrl:"/chapter/ris/73677",book:{id:"10026",slug:"electrodialysis"},signatures:"Taner Yonar",authors:[{id:"190012",title:"Associate Prof.",name:"Taner",middleName:null,surname:"Yonar",fullName:"Taner Yonar",slug:"taner-yonar",email:"yonar@uludag.edu.tr",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190012/images/system/190012.png",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Electrodialysis bipolar membrane: principles and definitions",level:"1"},{id:"sec_3",title:"3. Usage areas of EDBM process",level:"1"},{id:"sec_4",title:"4. Recovery of concentrated wastes by EDBM process",level:"1"},{id:"sec_5",title:"5. Advantages and disadvantages of EDBM process",level:"1"},{id:"sec_6",title:"6. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'Visvanathan C, Asano T. The Potentıal for Industrıal Wastewater Reuse Environmental Engineering Program and Asian Institute of Technology. Department of Civil and Environmental Engineering, University of California; 2001. pp. 1-14'},{id:"B2",body:'Sadr SMK, Saroj DP. 14 - Membrane Technologies for Municipal Wastewater Treatment, In: Basile a, Cassano a, Rastogi N.K, Editors. Advances in Membrane Technologies for Water Treatment: Woodhead Publishing; 2015. pp. 443-446'},{id:"B3",body:'Badruzzaman M, Oppenheimer JS, Kumar M. Innovative beneficial reuse of reverse osmosis concentrate using bipolar membrane electrodialysis and electrochlorination processes. J. Membr. Science. 2009;326:392-399'},{id:"B4",body:'Adham S, Burbano A, Chiu K, Kumar M. Development of a NF/RO knowledgebase, California Energy Commission. In: Public Interest Energy Research Program Report. 2005'},{id:"B5",body:'Heijman SGJ, Guo H, Li S, van Dijk JC, Wessels LP. Zero liquid discharge: Heading for 99% recovery in nanofiltration and reverse osmosis. Desalination. 2009;236(1-3):357-362'},{id:"B6",body:'Balster J. Membrane Module and Process Development for Monopolar and Bipolar Membrane Electrodialysis, PhD Thesis. The Netherland: University of Twente; 2006'},{id:"B7",body:'Xu T. Ion exchange membranes: State of their development and perspective. Journal of Membrane Science. 2005;263:1-29'},{id:"B8",body:'Wilhelm FG. Bipolar Membrane Electrodialysis. PhD. Thesis. Enschede: Twente University; 2001'},{id:"B9",body:'Aksangür I. Investigation of Disposal and Optimization of Concentrate with Edbm System Which Originates from. Msc. Thesis. Bursa: Uludağ University; 2014'},{id:"B10",body:'Strathmann H. Electrodialysis, a mature technology with a multitude of new applications. Desalination. 2010;264:268-288'},{id:"B11",body:'Wilhelm FG, Punt IGM, Vegt NFA, Der V, Strathmann H, Wessling M. Cation permeable membranes from blends of sulfonated poly(ether ether ketone) and poly(ether sulfone). Journal of Membrane Science. 2002;199:167-176'},{id:"B12",body:'Yazıcı S. Analysis of Fouling Mechanism and Prevention Works of Electrodialysis with Bipolar Membrane Processes: Leachate Sample, Msc. Thesis. Istanbul: Yıldız Teknik University; 2012'},{id:"B13",body:'Yuzer B. Wastewater Treatment by Bipolar Membrane Electrodialysis Process and Evaluation of Reuse Alternatives. PhD. Thesis. Istanbul: İstanbul University-Cerrahpasa; 2018'},{id:"B14",body:'Ilhan F. Investigation of Treatability and Recycling of Landfill Leachate by Electrodialysis Process, PhD Thesis. Istanbul: Yıldız Teknik University; 2012'},{id:"B15",body:'Pourcelly, G. Gavach, C., (2000). Electrodialysis water splitting-application of electrodialysis with bipolar membranes, In Handbook on Bipolar Membrane Technology; Kemperman, A. J. B., Ed., Twente University Press: Enschede, The Netherlands, 17-46'},{id:"B16",body:'Graillon, S.; Persin, F.; Pourcelly, G. ve Gavach, C., (1996). “Development of electrodialysis with bipolar membrane for the treatment of concentrated nitrate effluents”, Desalination, 107: 159-169'},{id:"B17",body:'Aritomi T., Nago S. ve Hanada F., (2001). “Performance of an improved bipolar membrane”, Membrane Technology, 135: 11-13'},{id:"B18",body:'Novalic, S. ve Kulbe, K. D., (1998). “Separation and concentration of citric acid by means of electrodialytic bipolar membrane technology”, Food Technology and Biotechnology, 36: 193-195'},{id:"B19",body:'Yu, L. X., Guo, Q. F., Hao, J. H. ve Jiang, W. J., (2000). “Recovery of acetic acid from dilute wastewater by means of bipolar membrane electrodialysis”, Desalination, 129: 283-288'},{id:"B20",body:'Wakamatsu Y., Matsumoto H., Minigawa M. ve Tanioka A., (2006), “Effect of ionexchange nanofiber fabrics on water splitting in bipolar membrane”, Journal of Colloid and Interface Science, 300(1): 442-445'},{id:"B21",body:'Xu T. Electrodialysis processes with bipolar membranes (BMED) in environmental protection—A review. Resources Conservation Recycling. 2002;37(1)'},{id:"B22",body:'Alvarez, F., Alvarez, R., Coca, J., Sandeaux, J., Sandeaux, R. ve Gavach, C. (1997). “Salicylic acid production by electrodialysis with bipolar membranes”, Journal of Membrane Science, 123: 61-69'},{id:"B23",body:'Trivedi G.S., Shah B.G., Adhikary S.K., Indusekhar V.K. ve Rangarajan R., (1997). “Studies on bipolar membranes. part ıı – conversion of sodium acetate to acetic acid and sodium hydroxide”, Reactive & Functional Polymers, 32: 209-215'},{id:"B24",body:'Ferrer, J.S.J., Laborie, S., Durand, G. ve Rakib, M., (2006). “Formic acid regeneration by electromembrane process”, Journal of Membran Science, 280(1-2): 509-516'},{id:"B25",body:'Cifuentes, L., Garci’a, I., Ortiz, R. ve Casas, J. M., (2006). “The use of electrohydrolysis for the recovery of sulphuric acid from coppercontaining”, Separation and Purification Technology, 50(2): 167-174'},{id:"B26",body:'Pourcelly, G. Bazinet, L. (2007). In handbook of membrane separations: Chemical, pharmaceutical and biotechnological applications, Pabby, A. K., Rizvi, S. S. H., Sastre, A. M., Eds.; CRC Pr I Llc:, Florida'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Taner Yonar",address:"yonar@uludag.edu.tr",affiliation:'
Environmental Engineering Department, Bursa Uludag University, 16059 Gorukle, Bursa, Turkey
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1. Introduction
Extracellular vesicles (EVs) are traditionally classified into three types: exosomes (Exo), microvesicles (MVs), and apoptotic vesicles. Several theories exist on how tumor cells alter their neighboring cells and matrix ultimately changing their behavior into an invasive one. This typically would involve the transport of materials from tumor cells to their adjacent surroundings. These materials include a wide range of soluble cytokines, RNA species, enzymes, and proteins. Most of which are carried in nano-sized carriers such as EVs. EVs are classified according to their size and the mechanism of genesis. The first class of EVs known as MVs or when secreted from cancer cells, are called oncosomes [1]. MVs formation is originated by the outward budding of the cell surface at specific regions along the plasma membrane enriched with high concentrations of lipids, such as cholesterol and glycosphingolipids, and proteins such as Flotillin-1 and 2 [2]. Exo represent the second major class of EVs [3]. They are formed when multivesicular bodies (MVBs) in the endo-lysosomal pathway accumulate intraluminal vesicles (ILVs) that consist of proteins and nucleic acids. Exo are smaller in size and range from 30 to 50 nm.
EVs can function in an autocrine, paracrine, and even endocrine fashion, and were shown to impact various cancer cell phenotypes, increasing their cell growth and promoting metastasis [4]. This secretome is released into the microenvironment and acts as cell-cell communicators. Tumor derived Exo (TDE) has appeared as imperative facilitators in cancer initiation, progression, metastasis, host immune suppression, and drug resistance [5]. TDE typically consists of high sphingolipids and cholesterol contents that contain major histocompatibility complex (MHC) molecules, heat shock proteins, and tetraspanin (CD63, CD81, and CD9). Additionally, tumor antigens such as Mart1, gp100, TRP, and Her2-neu have been discovered in TDE [5]. TDE also contains surface and soluble proteins and RNA species such as mRNAs and miRNAs. mRNAs conveyed in EVs result in proteins synthesis in target cells, while miRNAs alter their gene expression [6]. The protein cargo of TDE includes extracellular matrix (ECM) proteins, cell adhesion proteins, cell-surface receptor tyrosine kinases, chaperones, cytosolic and nuclear signaling proteins, as well as DNA and RNA binding proteins. Several types of nucleic acids that have been identified in EVs include RNA transcripts, microRNAs, long non-coding RNAs (lncRNAs), and DNA [7].
2. The role of MVs/TDE regional preconditioning
Tumor development is a multistep process that starts by cellular reprogramming of cells to acquire the hallmarks of cancer cells to gain and maintain abnormal growth and invasive capacity [8]. The complex process of tumor formation and spreading additionally requires a rewiring of the surrounding stromal cells. This can be induced by intrinsic cell events such as genetic or epigenetic aberrations or by external factors from direct or indirect cell communication [9]. In cancer, EVs especially Exo, have been shown to be essential for various steps during tumor initiation and progression. EVs disrupt signaling and gene expression regulation in the recipient cell by horizontally transferring bioactive chemicals between cancer cells and the surrounding stroma. As a result, malignant cells can change the phenotype of surrounding benign cells to one that supports tumor growth and metastasis, creating a favorable environment for cancer progression and spread. EVs play several roles in priming the surrounding environment preparing it for metastasis and invasion. The role of EVs in promoting tumor progression has been elucidated in studies on mixed populations of EVs. The function of EVs largely depends on their bioactive cargo, in particular the shuttling of tumor-specific proteins to the surrounding cells. While researchers have mainly studied the RNA content of EVs, however, the focus is starting to shift towards the EVs proteome [10].
The protein content of MVs within mixed populations of EVs was discovered to be significantly diverse from that of the Exo proteome, and is supplemented in proteins involved in microtubule, actin, and cytoskeleton networks, ARF6, its effector phospholipase D2, and parts of the endosomal sorting complex required for transport family (ESCRT-I) [11] By transporting these molecules, MVs can impact nearby tumor cells and stromal cells.
2.1 MVs mediated tumor-invasion
One example in which MVs shed by the cancer cells were shown to enhance tumor cell proliferation is in multiple myeloma. This effect was shown to be related to the amelioration of the Extracellular Matrix Metalloproteinase Inducer (EMMPRIN/CD147) on the tumor MVs. This protein is known to be overexpressed in solid tumors, some lymphomas, and leukemias [12]. Another study in breast cancer cells found that the highly glycosylated version of EMMPRIN exists in high quantities in breast cancer cell-derived MVs and enhances tumor invasion through activation of p38/MAPK signaling [11]. Interestingly, it was found that MVs from patient Blood with metastatic breast cancer had a similar high-EMMPRIN expression, along with the tumor marker Mucin-1 (MUC1/CA 15-3) [11]. Additionally, the truncated oncogenic form of the epidermal growth factor receptor (EGFR), EGFRvIII, commonly expressed in aggressive brain tumor cells, is associated with pro-tumorigenic tumor–tumor crosstalk via MVs. It was discovered that EGFRvIII was present in MVs released by U373 glioma cells, allowing them to transfer malignant features from highly aggressive tumor cells to the more benign tumor cells, EGFRvIII-negative, thereby facilitating their oncogenic transformation [11]. Hence, MVs are convenient communicators within the TME, as they can either mediate the horizontal transfer of oncogenic material or activate oncogenic signaling pathways in neighboring cancer cells, enhancing their survival, proliferative, and angiogenic potential and triggering their transformation into an aggressive phenotype.
2.2 Tumor-immune cells crosstalk
Alongside the tumor–tumor communication, MVs were proven to facilitate the crosstalk between the tumor and its surrounding stroma and immune cells which ultimately leads to cancer immune evasion. In breast cancer cells, the secretion of both tumor MV and TDE induced the expression of Wnt5a in tumor-associated macrophages. Macrophage Wnt5a promoted ß-catenin-independent Wnt signaling in breast cancer cells when delivered by macrophage-derived MVs and Exo, resulting in enhanced tumor invasion. This shows how EV-based cell-cell communication can drive tumor-associated immune cells to stimulate tumor growth [11]. MVs-enriched preparations induced the differentiation of monocytes producing anti-inflammatory cytokines such as IL-10. In line with this, early stimulation with tumor MV triggered macrophage polarization towards an anti-inflammatory phenotype with decreased anti-tumor cytotoxic potential. Additionally, as T cells represent the first line of the immune defense, tumor cells appear to suppress T cell activity and diminish antitumoral immune response via MVs-mediated cell-cell communication. For instance, leukemia-derived MVs deliver miRNAs to T cells, which alters T cell phenotype [13] (Figure 1). Moreover, MVs released by irradiated breast cancer cells were shown to carry abundant immune-suppressive proteins, such as programmed cell death ligand 1 (PD-L1) which inhibited cytotoxic T cell activity and enabled tumor growth (Figure 1)[14].
Figure 1.
Exosome PD-L1 (similar to tumor PD-L1) can bind to PD-1 on T cells, induce T cell apoptosis, and inhibit T cell activation and proliferation [15].
TDEs, through their miRNAs proteins, DNAs, mRNAs lncRNAs, initiate the transformation of epithelial cells to mesenchymal cells. This transformation was due to the loss of epithelial E-cadherin expression, cell-cell adhesion and cell polarity, and gaining of vimentin expression [16].
3. Pre-metastatic niche formation
The complex and heterogeneous microenvironment of both primary or metastatic tumor is comprised of a network of cellular and acellular constituents. The cellular compartment consists of tumor cells and assorted non-transformed cells, such as cancer-associated fibroblasts (CAFs), macrophages, and endothelial cells. The non-cellular part is formed by secreted factors and components of the ECM. The tumor microenvironment modulates tumor progression by providing inhibitory or stimulatory growth signals [17]. Thus pre-metastatic niche refers to the microenvironment, that is primed to allow tumor cells to colonize in and disseminate to distant sites. The main machineries of the premetastatic niche formation include tumor-derived secreted factors (TDSFs), EVs bone marrow-derived cells (BMDCs), suppressive immune cells and host stromal cells [4], and inflammation. Chronic inflammation is a driving force for tumor development and metastasis. Thus, the local inflammatory microenvironment is one of the essential factors for the pre-metastatic niche formation and driving force for metastasis.
3.1 TDE in upregulation of inflammatory molecules and premalignant niche formation
Tumor development and metastasis are aided by chronic inflammation. As a result, one of the most important variables in the establishment of a pre-metastatic niche is the local inflammatory microenvironment. Tumor cells can be induced to create TDSFs such as vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-α), transforming growth factor (TGF-β), and interleukin-2 by the local inflammatory microenvironment. These TDSFs then exert a paracrine effect on myeloid cells, initiating their migration to potential pre-metastatic niche formation sites [18]. Host stromal cells in the pre-metastatic niche may upregulate the expression of inflammatory factors in response to TDSF activation. The recruitment of BMDCs or immune cells to the pre-metastatic niche speeds up the release of inflammatory factors. Exo from tumors also transport inflammatory substances into the bloodstream, where they reach the pre-metastatic niche. In the pre-metastatic niche, an inflammatory milieu supportive to tumors is eventually generated [18].
In a study conducted by Hoshino, he showed that the proinflammatory cytokine s100 was upregulated up to four folds when Kupffer cells were treated with integrin intact Exo, as compared to those treated with integrin knocked out Exo. Hoshino speculated that the activation of Src, and its phosphorylation might be a causative pathway [19].
3.2 Cellular compartment of the pre-metastatic niche
3.2.1 Cancer-associated fibroblasts
TDE and MV were also shown to modify fibroblasts in the tumor stroma. When normal human fibroblasts were exposed to oral squamous carcinoma derived MV [20] the fibroblasts were altered into a cancer phenotype. This switch to CAFs was largely mediated via metabolic reprogramming of the fibroblasts to aerobic glycolysis, with an increase in glucose uptake and lactate secretion. Some TDEs contain surface TGF-β along with betaglycan, which could trigger SMAD-dependent signaling and regulate the differentiation of fibroblasts to myofibroblasts [21]. This was further proved by co-culturing the generated CAF with cancer cells which led to enhanced cancer cell invasion and migration, creating a bidirectional cross-talk that favors tumor promotion and spread. The MVs-induced fibroblast activation and spreading seem to occur in the matrix milieu in the tumor periphery [22]. In prostate cancer, TDE were shown to induce the expression of RANKL and Metalloproteinases in CAFs, through miR-100, -21, and -139, further promoting its metastasis [23]. Hypoxia seems to stimulate prostate cancer cells to release protein-rich Exo which further induces activation of CAFs [24], promotes epithethelial mesenchymal transition (EMT), stemness, and angiogenesis by prostate cancer cells.
Additionally, TDE were also described as regulators of metabolism in the tumor microenvironment, for example, breast cancer tumors could suppress glucose uptake by lung fibroblasts, via secretion of Exo containing miR-122, increasing glucose availability and facilitating metastasis [25]. The cell-to-cell communication mediated by Exo is also affected by the genetic profile of the recipient fibroblasts. For example, fibroblasts lacking the BRCA1, a tumor suppressor gene, internalize larger amounts of serum-derived Exo when compared to BRCA1 containing fibroblasts [26]. Furthermore, these cells were found to undergo a malignant transformation when exposed to Exo derived from sera of cancer patients, implying that oncosuppressor genes can prevent exosome information from tumor cells from being integrated and thus shelter these cells from their pro-oncogenic signals [26].
3.2.2 Macrophages and immune cells
Tumor MVs extravasate through the vessel wall in pancreatic cancer, reach the liver microcirculation and are picked up by perivascular macrophages to prime the liver metastatic niche in a CD36-dependent manner. Furthermore, tumor MVs produced from the B16F10 melanoma cell line was discovered to cause metastases in BALB/c mice, which are generally resistant to the B1610 tumor cell line [27]. TDEs also protect cancer cells from apoptosis by selectively effluxing apoptosis inducer proteins that are delivered by T cells or natural killer (NK) cells. TDEs also reduce the effects of therapy by preventing drug efflux or concealing the binding site of monoclonal antibodies, which could lead to the emergence of chemotherapy-resistant cell populations [28].
Exosome-derived programmed death receptor 1 (PD-1) and programmed death-ligand 1 have been linked to an immunological escape mechanism in recent years. PD-1 is mostly found on macrophages, activated T cells, and B cells, whereas PD-L1 is abundant in tumor tissues, antigen-presenting cells (APCs), and stromal cells [29]. T lymphocytes can recognize and destroy tumor cells in normal circumstances. When PD-1 attaches to PD-L1, however, it sends an inhibitory signal to T cells, causing them to die and inhibiting their activation and proliferation. As a result, blocking the PD-1/PD-L1 pathway may boost the immune response by increasing the killing effect of T cells [30]. T lymphocytes can recognize and destroy tumor cells in normal circumstances. When PD-1 attaches to PD-L1, however, it sends an inhibitory signal to T cells, causing them to die and inhibiting their activation and proliferation (Figure 1). As a result, blocking the PD-1/PD-L1 pathway may boost the immune response by increasing the killing effect of T cells. As a result, Exo containing PD-L1 suppress the immune system in the pre-metastatic milieu and promote the establishment of a pre-metastatic niche [31].
3.2.3 Endothelial cells and vascular barriers
Angiogenesis within the primary tumor is also influenced by tumor MVs and TDE. Normal endothelial cells (ECs) were shown to endocytose tumor EVs, which triggered PI3K/Akt signaling and increased EC motility and tube formation ability [32]. Tumor MVs and TDE also release VEGF, a pro-angiogenic substance that stimulates ECs [33]. Similarly, MVs produced from multiple myeloma cells have been demonstrated to transfer CD138, a myeloma cell marker, to ECs, promoting their proliferation, invasion, and production of the angiogenic mediators IL-6 and VEGF, resulting in tube formation [50] (Figure 2). MVs change the environment around the main tumor and create pre-metastatic niches from afar. This was originally attributed to their procoagulant activity, which encouraged the production of microthrombi and facilitated the extravasation of trapped circulating tumor cells. ECs are important components of the tumor microenvironment because they provide a pathway for nutrients and trophic substances [34].
Figure 2.
Possible mechanisms of pre-metastatic niche formation. The figure delineates how TDEs can modulate its surroundings of ECM, cancer-CAFs, immune cells, ECs, and MSCs all in favor of tumor support and progression. TDE can carry integrins to distant sites and create a pre-metastatic niche.
3.2.3.1 Neovascularization
TDE enriched in vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 has been demonstrated to regulate the process of neovascularization in myeloid leukemia [35]. Furthermore, enhanced vascularization has been linked to the packaging of miR-92a in Exo derived from leukemia[36] and CO-029/D6.1A Tetraspanin in Exo produced from pancreatic cancer [37]. Upregulation of Heparanase in tumor cells, such as myeloma and breast malignancies, has also been linked to increased exosome production and exosomal packing of Syndecan-1, VEGF, and hepatocyte growth factor, resulting in enhanced endothelial invasion through the ECM [38]. Exo produced from skin cancer can also enhance angiogenesis by transferring the EGFR [39] and miR-9 to ECs [26]. Furthermore, melanoma-derived Exo have been found to condition sentinel lymph nodes prior to the installation of melanoma cells and subsequent metastasis by upregulating Collagen 18 and Laminin 5, as well as producing angiogenic growth factors [26].
Another significant component in altering tumor-EC communication is hypoxia. Hypoxic glioblastoma cells, for example, release Exo that interact with ECs, promoting proliferation and angiogenesis both in vitro and in vivo [40], and also prompting tissue factor/Factor VIIa dependent activation of hypoxic ECs [26].
3.2.3.2 Vascular leakage
Exo from melanoma cause pulmonary vascular leakiness and upregulate tumor cell recruitment genes such Stabilin 1, Vitronectin, Integrins, and Ephrin receptor b4 in lymph nodes, forming pre-metastatic niches [41]. Furthermore, breast cancer-derived Exo enriched in miR-105 alter the expression of Claudin 5, Zonula Occludens protein 1, and Occludin, which promotes metastasis by disrupting vascular endothelial barriers [42]. Exo produced from brain tumors include miR-181c, which regulates EC actin dynamics and promotes the breakdown of the blood-brain barrier by three times. Protein Kinase-1 Degradation Requires Phosphoinositol [43]. Similarly, glioblastoma cells release Exo with high quantities of VEGF-A, which promote EC permeability and angiogenesis in vitro [44].
3.2.4 Tumor-stem/progenitor-non-transformed cell communication
TDE can promote pro-tumorigenic microenvironments via promoting tumor-stem/progenitor cell contact, in addition to its well-known actions in differentiated cells. Melanoma-derived Exo, for example, stimulate BMDCs by transferring the oncoprotein MET, resulting in the mobilization of vasculogenic and hematopoietic bone marrow progenitor cells to ensure vascular proliferation and immunosuppression at pre-metastatic niches [45]. Communication between tumor stem/progenitor cells is also critical in bone metastasis. Exo from bone metastatic prostate cancer PC3 cells were found to influence the process of bone metastasis by modulating both osteoclast genesis and osteoblast proliferation. Exo generated from osteoblasts, on the other hand, have been demonstrated to stimulate PC3 prostate cancer cell proliferation [46].
TDE was also demonstrated to influence the development of myeloid precursor cells into myeloid-derived suppressor cells (MDSCs), which are known to aid tumor progression by permitting immune escape [47]. Exo produced from breast carcinomas have been found to be taken up by bone marrow cells and to convert these cells\' development pathways toward MDSCs via Prostaglandin E2 and TGF-β, boosting COX2, IL6, VEGF, and Arginase1 accumulation by MDSCs [48].
TDE can also cause alterations in mesenchymal stem cells (MSCs), which help to promote and maintain tumor-promoting inflammatory environments. For example, HSP70+ lung tumor-derived exosomes (TDEs) activate NF-kB and cause MSCs to secrete IL-6, IL-8, and MCP1 via TLR2-mediated signaling, causing MSCs to become more inflammatory and tumor supportive [49]. According to De Veirman et al. [50], myeloma-derived Exo transfer miR-146a to mesenchymal cells, stimulating them to secrete numerous cytokines and chemokines including CXCL1, IL6, IL-8, IP-10, MCP-1, and CCL-5 (Figure 2). Another example is Exo produced by KMBC cholangiocarcinoma cells, which cause MSCs to upregulate IL-6, and hence KMBC cell proliferation [51].
4. Mechanisms of TDE in tumor metastasis
4.1 Tumor cell proliferation and anti-apoptotic effect
One of the proposed mechanisms of tumorigenicity of TDE is the induction of tumor cell proliferation. Studies involving various cancer cells such as, chronic myeloid leukemia and in human gastric cancer, showed that this proliferative potential is via an autocrine induction through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and MAPK/ERK signaling pathways. Additionally, through the transference of lncRNAs (reviewed in [49]).
In addition, glioblastoma-derived Exo were shown to induce proliferation of the human glioma U87 cell line [40] in a mechanism dependent on the chloride intracellular channel protein 1 (CLIC1) [52]. In a more specific context linked to prostate cancer treatment, prostate cancer LNCaP cells grown in the presence of androgens generate Exo high in CD9, which enhance the growth of androgen-depleted LNCaP cells. Another example involves the promotion of in vivo growth of murine melanomas by systemic treatment of mice with melanoma-derived Exo, which accelerated growth and inhibited apoptosis of melanoma tumors in vivo [26].
4.2 Invasiveness and motility
TDE can alter the migratory behavior of recipient malignant cells. Exo produced from nasopharyngeal cancer-bearing EMT-inducing signals such as TGF-β and hypoxia-inducible factor 1 alpha (HIF1a) [53], matrix metalloproteinases (MMPs) Notch1, LMP1 Casein Kinase II and Annexin A2, were shown to enhance the migratory capacity of the tumor recipient cells. Another example involves Exo derived from hypoxic prostate cancer cells, which prompted invasiveness and motility of naïve human prostate cancer cells (reviewed in [26]) through the neighboring stroma and to nearby cells.
4.3 Chemoresistance
Exo have been found to have a role in tumor-tumor communication by transferring chemoresistance. Exo have been linked to the transfer of Docetaxel resistance in prostate cancer since Corcoran and colleagues first discovered it [54]. The transfer of cisplatin resistance in lung cancer is achieved by donor resistant cells producing Exo with low levels of miR-100-5p, which leads to enhanced expression of the mammalian target of rapamycin (mTOR) protein and chemoresistance in recipient cells [55].
MiRNA packed in Exo from drug-resistant cells can modulate the expression of specific target genes in breast cancer, such as miR-23a targeting Sprouty2, miR-222 targeting PTEN, miR-452 targeting APC4, and miR-24 targeting p27, thereby modulating chemoresistance in recipient cells that integrate these Exo. In fact, exosomal miR-222 plays a key role in this process, as the silencing of miR-221/222 prevents the transmission of resistance [56].
In addition to miRNAs, the transfer of exosomal mRNAs that encode drug-resistant proteins may result in chemoresistance in the receiving cell. GSTP1 exosomal mRNA from Adriamycin-resistant breast cancer cells, for example, confers resistance to previously susceptible cells. The presence of GSTP1 in circulating Exo from patients\' peripheral blood was linked to a worse outcome in breast cancer patients receiving Adriamycin [57]. A supporting stroma is required for an optimum metabolic and physiological environment for tumor growth. Fibroblasts are the most abundant cells in most solid tissues, participating in environmental cue responses and being a common target of tumor-derived signals [58].
4.4 Integrins in metastasis
Integrins are a wide family of cell adhesion receptor proteins such as alpha3beta1, alpha6beta1, alpha6beta4, and alpha7beta1. Their roles have been implicated in tumor metastasis and mesenchymal transformation. TDE carry these integrins from primary tumor sites to distant sites such as lung, lymph nodes, brain, and bone creating pre-metastatic niches (Figure 2) [59].
5. Clinical applications of TDE
TDEs are involved in the advancement of several forms of cancer. Because of their abundance, TDEs may serve as noninvasive diagnostic and prognostic tools for various cancers. Additionally, blocking exosome secretion can slow the growth of some malignancies. Hence, Exo have been a popular target for developing cancer treatment techniques because of this property. Decreasing the expression of the exosomal proteins, Rab27a and Rab27b, inhibit exosome secretion without matching changes in soluble proteins secretions [60]. Several drugs used in the pharmaceutical industry such as Ketoconazole (an anti-fungal) sphingomyelinase (a hydrolase enzyme that is responsible for degrading sphingomyelin) [61], are additionally Rab27a inhibitors. These drugs can be re-directed as cancer modulators for their possible effects on attenuating TDE tumor progressive effects.
Furthermore, TDE owing to its small size, cancer-homing, and nontoxic nature, TDE can be re-directed to serve as a drug delivery system. Exo have been proven in several investigations to act as drug delivery vehicles, transporting anti-cancer chemicals to target cells [62]. For example, adriamycin and paclitaxel, target cancer cells via exosomal encapsulation and have low toxicity and immunogenicity [63].
6. Conclusions
EVs modulate the environment that favors tumor growth and progression. EVs provide a method of cell-cell communication, and through their rich cargo of ECM proteins, cell adhesion proteins, tyrosine kinases, chaperones, signaling proteins, DNA and RNA binding proteins, they create a pre-metastatic niche. By priming nearby and distant cells into becoming cancerous, they promote tumor metastasis. Several mechanisms have been discovered for their actions including, promotion of migratory behavior, chemoresistance, anti-apoptosis, vascular leakage, and immune modulation. Understanding how TDE and MVs create a pre-metastatic niche and how halting the trafficking of such vesicles can produce a revolutionizing new era in the field of cancer therapeutics. By preventing TDE-promoted metastasis and tumor progression, coupled with conventional radio and chemotherapy, the survival rates of cancer patients can significantly improve.
Conflict of interest
The author declares no conflicts of interest.
\n',keywords:"tumor microenvironment, exosomes, tumor progression, metastasis, targeted therapy",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81298.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81298.xml",downloadPdfUrl:"/chapter/pdf-download/81298",previewPdfUrl:"/chapter/pdf-preview/81298",totalDownloads:20,totalViews:0,totalCrossrefCites:0,dateSubmitted:"December 7th 2021",dateReviewed:"February 18th 2022",datePrePublished:"April 16th 2022",datePublished:null,dateFinished:"April 16th 2022",readingETA:"0",abstract:"Extracellular vesicles (EVs) are biological active vesicles and carriers of information in intercellular communication. In cancer settings, EVs especially exosomes (Exo), play a focal role in modulating the tumor microenvironment mainly by increasing tumor proliferation, facilitating the crosstalk between tumor and tumor-neighboring cells, and influencing the host immune response. Amongst these functions in tumor growth, Exo modulate fundamental steps of tumor progression, such as growth, invasion, and immune modulation. On the endocrine level, Exo released from tumors were shown to mediate distant cell-cell communication processes via secretory factors and miRNAs, which result in the set-up of pro-tumorigenic microenvironments supportive of metastatic dissemination. This is achieved through processes such as fibroblast activation, extracellular matrix ECM production, angiogenesis, and immune modulation.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81298",risUrl:"/chapter/ris/81298",signatures:"Eman Helmy Thabet",book:{id:"10796",type:"book",title:"Extracellular Vesicles - Role in Diseases Pathogenesis and Therapy",subtitle:null,fullTitle:"Extracellular Vesicles - Role in Diseases Pathogenesis and Therapy",slug:null,publishedDate:null,bookSignature:"Assistant Prof. Manash K. Paul",coverURL:"https://cdn.intechopen.com/books/images_new/10796.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-055-8",printIsbn:"978-1-80355-054-1",pdfIsbn:"978-1-80355-056-5",isAvailableForWebshopOrdering:!0,editors:[{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. The role of MVs/TDE regional preconditioning",level:"1"},{id:"sec_2_2",title:"2.1 MVs mediated tumor-invasion",level:"2"},{id:"sec_3_2",title:"2.2 Tumor-immune cells crosstalk",level:"2"},{id:"sec_4_2",title:"2.3 TDE-mediated epithethelial mesenchymal transition",level:"2"},{id:"sec_6",title:"3. Pre-metastatic niche formation",level:"1"},{id:"sec_6_2",title:"3.1 TDE in upregulation of inflammatory molecules and premalignant niche formation",level:"2"},{id:"sec_7_2",title:"3.2 Cellular compartment of the pre-metastatic niche",level:"2"},{id:"sec_7_3",title:"3.2.1 Cancer-associated fibroblasts",level:"3"},{id:"sec_8_3",title:"3.2.2 Macrophages and immune cells",level:"3"},{id:"sec_9_3",title:"3.2.3 Endothelial cells and vascular barriers",level:"3"},{id:"sec_9_4",title:"3.2.3.1 Neovascularization",level:"4"},{id:"sec_10_4",title:"3.2.3.2 Vascular leakage",level:"4"},{id:"sec_12_3",title:"3.2.4 Tumor-stem/progenitor-non-transformed cell communication",level:"3"},{id:"sec_15",title:"4. Mechanisms of TDE in tumor metastasis",level:"1"},{id:"sec_15_2",title:"4.1 Tumor cell proliferation and anti-apoptotic effect",level:"2"},{id:"sec_16_2",title:"4.2 Invasiveness and motility",level:"2"},{id:"sec_17_2",title:"4.3 Chemoresistance",level:"2"},{id:"sec_18_2",title:"4.4 Integrins in metastasis",level:"2"},{id:"sec_20",title:"5. Clinical applications of TDE",level:"1"},{id:"sec_21",title:"6. Conclusions",level:"1"},{id:"sec_25",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Raposo G, Stoorvogel W. Extracellular vesicles: Exosomes, microvesicles, and friends. Journal of Cell Biology. 2013;200(4):373-383'},{id:"B2",body:'Sezgin E, Levental I, Mayor S, Eggeling C. The mystery of membrane organization: Composition, regulation and roles of lipid rafts. Nature Reviews Molecular Cell Biology. 2017;18(6):361-374'},{id:"B3",body:'Desrochers LM, Antonyak MA, Cerione RA. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},subseries:[{id:"7",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",annualVolume:11403,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:null,institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda",middleName:"R.",surname:"Gharieb",fullName:"Reda Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. Osma",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSDv7QAG/Profile_Picture_1626602531691",institutionString:null,institution:{name:"Universidad de Los Andes",institutionURL:null,country:{name:"Colombia"}}},{id:"69697",title:"Dr.",name:"Mani T.",middleName:null,surname:"Valarmathi",fullName:"Mani T. Valarmathi",profilePictureURL:"https://mts.intechopen.com/storage/users/69697/images/system/69697.jpg",institutionString:"Religen Inc. | A Life Science Company, United States of America",institution:null},{id:"205081",title:"Dr.",name:"Marco",middleName:"Vinícius",surname:"Chaud",fullName:"Marco Chaud",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSDGeQAO/Profile_Picture_1622624307737",institutionString:null,institution:{name:"Universidade de Sorocaba",institutionURL:null,country:{name:"Brazil"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/163037",hash:"",query:{},params:{id:"163037"},fullPath:"/profiles/163037",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()