Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\n
Seeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\n
Over these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\n
We are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\n
Thank you all for being part of the journey. 5,000 times thank you!
\\n\\n
Now with 5,000 titles available Open Access, which one will you read next?
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n
"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\n
Seeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\n
Over these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\n
We are excited about the present, and we look forward to sharing many more successes in the future.
\n\n
Thank you all for being part of the journey. 5,000 times thank you!
\n\n
Now with 5,000 titles available Open Access, which one will you read next?
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"588",leadTitle:null,fullTitle:"Ceramic Coatings - Applications in Engineering",title:"Ceramic Coatings",subtitle:"Applications in Engineering",reviewType:"peer-reviewed",abstract:"The main target of this book is to state the latest advancement in ceramic coatings technology in various industrial fields. 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\r\n
\r\n\tThe main focus of this book aims to be on the development of a novel method of nanopore fabrication, applications, and analysis of nanopore data. The secondary purpose of this book aims to be dedicated to a thorough discussion of the complexities involved in analyzing nanopores as well as the development of several tools that address the characterization of nanopores.
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She is the recipient of the Best Researcher Award and member of the Society for Semiconductor Devices, Indian Society for Analytical Chemist Member of IEEE Photovoltaic Specialists Society, member of KICHE (Korean Institute of Chemical Engineering), member of SPIE, International Society for Optics and Photonics.",coeditorOneBiosketch:"Professor M. Shaheer Akhtar is an associate professor at the New & Renewable Energy Materials Development Center (NewREC). His research interests constitute the photo-electrochemical characterizations of thin-film semiconductor nanomaterials, composite materials, polymer-based solid-state films, solid polymer electrolytes and electrode materials for dye-sensitized solar cells (DSSCs), hybrid organic-inorganic solar cells, small molecules based organic solar cells, and photocatalytic reactions.",coeditorTwoBiosketch:"Professor Hyung-Shik Shin received his Ph.D. in the kinetics of the initial oxidation Al (111) surface from Cornell University, USA, in 1984. and also President of Korea Basic Science Institute (KBSI), Gwahak-ro, Yuseong-gu, Daejon, Republic of Korea. He is an active executive member of various renowned scientific committees such as KiChE, copyright protection, KAERI, etc.",coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"52613",title:"Dr.",name:"Sadia",middleName:null,surname:"Ameen",slug:"sadia-ameen",fullName:"Sadia Ameen",profilePictureURL:"https://mts.intechopen.com/storage/users/52613/images/system/52613.jpeg",biography:"Professor Sadia Ameen obtained her Ph.D. in Chemistry (2008) and then moved to Jeonbuk National University. Presently she is working as an Assistant Professor in the Department of Bio-Convergence Science, Jeongeup Campus, Jeonbuk National University. Her current research focuses on dye-sensitized solar cells, perovskite solar cells, organic solar cells, sensors, catalyst, and optoelectronic devices. She specializes in manufacturing advanced energy materials and nanocomposites. She has achieved a gold medal in academics and is the holder of a merit scholarship for the best academic performance. She is the recipient of the Best Researcher Award. She has published more than 130 peer-reviewed papers in the field of solar cells, catalysts and sensors, contributed to book chapters, edited books, and is an inventor/co-inventor of patents.",institutionString:"Jeonbuk National University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Jeonbuk National University",institutionURL:null,country:{name:"Korea, South"}}}],coeditorOne:{id:"218191",title:"Dr.",name:"M. Shaheer",middleName:null,surname:"Akhtar",slug:"m.-shaheer-akhtar",fullName:"M. Shaheer Akhtar",profilePictureURL:"https://mts.intechopen.com/storage/users/218191/images/system/218191.jpg",biography:"Professor M. Shaheer Akhtar completed his Ph.D. in Chemical Engineering, 2008, from Jeonbuk National University, Republic of Korea. Presently, he is working as Associate Professor at Jeonbuk National University, the Republic of Korea. His research interest constitutes the photo-electrochemical characterizations of thin-film semiconductor nanomaterials, composite materials, polymer-based solid-state films, solid polymer electrolytes and electrode materials for dye-sensitized solar cells (DSSCs), hybrid organic-inorganic solar cells, small molecules based organic solar cells, and photocatalytic reactions.",institutionString:"Jeonbuk National University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Jeonbuk National University",institutionURL:null,country:{name:"Korea, South"}}},coeditorTwo:{id:"36666",title:"Prof.",name:"Hyung-Shik",middleName:null,surname:"Shin",slug:"hyung-shik-shin",fullName:"Hyung-Shik Shin",profilePictureURL:"https://mts.intechopen.com/storage/users/36666/images/system/36666.jpeg",biography:"Professor Hyung-Shik Shin received a Ph.D. in the kinetics of the initial oxidation Al (111) surface from Cornell University, USA, in 1984. He is a Professor in the School of Chemical Engineering, Jeonbuk National University, and also President of Korea Basic Science Institute (KBSI), Gwahak-ro, Yuseong-gu, Daejon, Republic of Korea. He has been a promising researcher and visited several universities as a visiting professor/invited speaker worldwide. He is an active executive member of various renowned scientific committees such as KiChE, copyright protection, KAERI, etc. He has extensive experience in electrochemistry, renewable energy sources, solar cells, organic solar cells, charge transport properties of organic semiconductors, inorganic-organic solar cells, biosensors, chemical sensors, nano-patterning of thin film materials, and photocatalytic degradation.",institutionString:"Jeonbuk National University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Jeonbuk National University",institutionURL:null,country:{name:"Korea, South"}}},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"17",title:"Nanotechnology and Nanomaterials",slug:"nanotechnology-and-nanomaterials"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"259492",firstName:"Sara",lastName:"Gojević-Zrnić",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/259492/images/7469_n.png",email:"sara.p@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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1. Introduction
As a result of anthropogenic activities, toxic chemicals have become ubiquitous contaminants of soils and groundwater worldwide. Thus, they are omnipresent in the environment due to rapid industrialization, urbanization, and modernization. This type of pollution is now being taken seriously by various industries, governments, environmental agencies, and non-governmental organizations. They are now always looking for an eco-friendly and cost-effective approach toward the removal of emerging environmental contaminants. Consequently, biodegradation is recognized as an efficient, economic, and versatile alternative to physico-chemical treatment of oil contaminants. Hence, microbial biodegradation plays a crucial role in the removal of polycyclic aromatic hydrocarbons (PAHs) specifically actinobacteria, which are a group of diverse bacteria, having the ability to degrade a wide range of organic compounds particularly hydrophobic compounds as PAH polychlorinated biphenyls (PCB), BTEX, pesticides, and so on [1]. Members of the genus Mycobacterium are of great interest due to their multiple PAH degradation capability, specifically high molecular weight (HMW), especially polycyclic aromatic hydrocarbons (PAHs) containing four or more fused benzene rings [2].
These compounds are persistent in environment due to high hydrophobicity and high stereochemical stability. They are known to possess mutagenic, genotoxic, and carcinogenic properties, causing deleterious effects on plants, aquatic organisms, animals, and humans. In contrast to low molecular weight (LMW) PAHs that can be degraded by various microorganisms (bacteria, actinobacteria, etc.), enrichment culture methods with HMW PAHs as sole sources of carbon and energy often lead to the isolation of Mycobacterium spp.
The goal of this chapter is to provide an outline of the current knowledge about biodegradation of PAHs using Mycobacterium. Moreover, various conditions as physiology of mycobacteria, environmental habitat, degradation behavior, enzymatic mechanisms, and ecological survival strategies toward organic compounds such as PAHs have also been discussed.
2. Calligraphy
2.1. Polycyclic aromatic hydrocarbons
Polycyclic aromatic hydrocarbons (PAHs) are a class of organic compounds that are widely distributed in the environment. PAHs is a predominant term describing hundreds of individual chemical compounds containing two or more fused aromatic rings and are known to persist or accumulate in the environment. PAHs in the soil have recently become a matter of great concern due to their potential toxicity, mutagenicity, and carcinogenicity. Therefore, 16 PAH compounds have been identified by the United States Environmental Protection Agency (USEPA) as priority pollutants [3, 4]. They are ubiquitous compounds that are formed either naturally during thermal geological reactions, fossilization, and biological reactions or anthropogenically during mineral production, combustion of fossil fuels, refuse burning, forest and agricultural fires, and so on. On the basis of physical and chemical properties of PAHs, they are classified into two groups: low molecular weight (LMW PAHs, including 2–3 rings) and high molecular weight (HMW PAHs, including four or more rings). Table 1 shows the physico-chemical properties of 16 PAHs as a number of benzene rings, vapor pressure, aqueous solubility, and octanol-water partitioning coefficient (Kow) values. Therefore, LMW PAHs are greatly more soluble and volatile as compared to HMW PAHs due to their higher hydrophobicity than the LMW PAHs [5]. The Kow values also reflect the hydrophobicity of the PAHs. These properties regulate the environmental behavior of PAHs. Therefore, HMW PAHs are persistent in the environment specifically in soil due to their high hydrophobicity.
Sr. no.
PAH
No. of rings
Mr
Melting point (°C)
Boiling point (°C)
Water solubility (mg L−1)
Vapor pressure (Pa)
Kow value
1
Naphthalene
2
128.17
80.6
218
31
10.4
3.37
2
Acenaphthene
3
154.21
95
279
3.47
3.0 × 10 −1
3.92
3
Acenaphthylene
3
152.20
93.5–94.5
265
3.93
8.93 × 10 −1
4.07
4
Fluorene
3
166.22
116
295
0.190
8.0 × 10−2
4.18
5
Anthracene
3
178.23
217.5
340
0.0434
1.0 × 10−3
4.54
6
Phenanthrene
3
178.23
99.5
340
1.18
2.0 × 10 −2
4.57
7
Fluoranthene
4
202.26
110.8
375
0.265
1.23 × 10−3
5.22
8
Pyrene
4
202.26
156
404
0.013
6.0 × 10−4
5.18
9
Benz[a]anthracene
4
228.29
159.8
437.6
0.014
2.8 × 10−5
5.91
10
Chrysene
4
228.29
255.8
448
0.0018
5.70 × 10 −−7
5.86
11
Benzo[k]fluoranthene
5
252.31
215.7
480
0.00055
7.0 × 10−7
6.04
12
Dibenz[a,h]anthracene
5
278.35
266
524
0.0005
1.33 × 10 −8
7.16
13
Benzo[a]pyrene
5
252.31
176.5
495
0.0038
1.40 × 10−8
6.25
14
Indeno[1,2,3-cd]pyrene
6
276.34
162.5
536
0.0620
1.0 × 10−10
6.58
15
Benzo[b]fluoranthene
6
252.31
167
357
0.0012
6.67 × 10 −5
6.57
16
Benzo[g,h,i]perylene
6
276.34
278.3
500
0.00026
1.39 × 10−8
7.10
Table 1.
Physico-chemical properties of 16 PAHs as classified by USEPA.
Generally, the rate of degradation of PAHs is inversely proportional to the number of rings in PAH molecule [6]. LMW PAHs, such as naphthalene, fluorene, phenanthrene, and anthracene, are more easily degraded and usually utilized as the model PAHs for further understanding the degradative mechanisms on the HMW PAHs. HMW PAHs are more persistent in the environment as they exhibit higher hydrophobicity and toxicity [7] than LMW PAHs.
With increase in the number of benzene rings, PAH solubility decreases while hydrophobicity increases. The Kow values of the 16 PAH priority pollutants are in the range from 3.37 to 6.5, which is generally considered moderate-to-higher lipophilic (Table 1). Thus, PAHs tend to adsorb onto organic fractions in soil sediment and biota and are also accumulated in the food chain [8].
2.2. Characteristics of Mycobacterium
The genus Mycobacterium comprises aerobic, rod-shaped, acid-fast, mycolic acid (lipid moieties)-containing bacteria; they are common saprophytes, distributed in different environmental pools. The distinguishing characteristic of all Mycobacterium species is that the cell wall is thicker than in many other bacteria, being hydrophobic, waxy, and rich in mycolic acid content. As per the Floyd et al. [9] data collection, the abundance of Mycobacterium genera accounted for 2.6% of total soil microbial diversity present in the environment. On the basis of growth cycle, they are divided into two categories such as slow and fast growers exhibiting growth within seven and after seven days, respectively. These phenomena are further supported by the difference in 16S rRNA sequences. Fast growing strains have two copies of the 16S rRNA gene, whereas slow growing strains normally have a single copy of the gene [10]. Moreover, properties of one or two 16S rRNA genes are assumed to be comparatively slow growth and lower metabolic activities, which require more time for adaptation into the environment [11].
Mycobacteria are high G + C-containing genera; they possess many properties that make them good candidates for application in bioremediation of soils contaminated with organic pollutants. Mycobacterium sp. is frequently found in environmental habitats including PAHs-contaminated soil. Nocardio-forming Actinobacteria has a unique enzymatic mechanism that degrades a wide range of complex organic compounds and their spores are resistant to desiccation. In addition, these groups of microorganisms have the ability to degrade a wide range of hydrophobic compounds and produce biosurfactants. Biosurfactant is useful for the adhesion of microbial cells to the hydrophobic compound. Therefore, many mycobacterial stains have the capability to degrade organic compounds as pesticides, PAHs, polychlorinated biphenyls (PCB), and so on. The nocardio-forming actinomycetes such as Mycobacterium sp., Rhodococcus sp., Gordonia sp., and so on have been reported to possess hydrocarbon degradation capability in PAHs-contaminated soil. Many Mycobacterium species have been reported as high molecular weight (HMW) PAH degraders, specifically pyrene, fluoranthene, benzo[b]pyrene, and so on. Thus, they are promising candidates for environmental bioremediation because of their ubiquitous presence in soils and their ability to catabolize aromatic compounds. Mycobacterium sp. has an ability to operate the unique catabolic pathway of HMW PAHs as compared to gram-negative bacteria. Cerniglia [12] has reported the Mycobacterium sp. PYR-l in enhanced degradation of four aromatic rings of PAHs when inoculated into microcosms-containing sediment. The scientific community worked on biodegradation of PAHs in different habitats as marine sediment, agriculture soil, and soil with alkaline or acidic conditions [1, 4, 13, 14] as listed in Table 2.
Global scenario of PAH degradation in different environments by Mycobacterium strain.
3. PAH biodegradation using Mycobacterium
3.1. Mycobacterium degradation ability
Our laboratory has worked on degradation of HMW PAHs as pyrene and fluoranthene using M. litorale on solid agar and liquid medium. Multiple PAHs-degrading bacterial strains were isolated from the PAHs-contaminated site near Bhavnagar. Preliminary culture was enriched in Bushnell Haas (BH) broth and further isolated on PAH-coated BH agar plate. Isolate showed a zone of clearance on PAH (fluoranthene)-coated BH plate and growth of bacteria in liquid culture (BH broth) supplemented with PAHs as the carbon source (Figure 1), which indicated that Mycobacterium litorale had the ability to utilize fluoranthene, a four-ring HMW PAH, as the sole source of carbon and energy [3]. Similar results have also been reported by Bogan et al. [15] who reported that M. austroafricanum utilized phenanthrene, pyrene, and fluoranthene as the sole source of carbon and energy.
Figure 1.
Fluoranthene degradation by Mycobacterium litorale.
Many Mycobacterium strains have been isolated from different environmental habitats (Table 2). Recently, culture-independent molecular techniques and PCR-based amplification of 16S rRNA gene were used to compare the diversity and abundance of indigenous Mycobacterium populations in different historically contaminated soils [16]. A wide variety of Mycobacteriumgenera are extensively used for removal of PAHs from contaminated sites by bioremediation techniques. It has been well established that Mycobacteria have exceptionally lipophilic surfaces which makes them a suitable candidate for the uptake of complex bound pollutants (i.e., PAHs) from the heavy contaminated soil particles. Thus, they have good catabolic properties toward the PAH molecule up to five benzene rings [17, 18]. Therefore, it indicates the PAH-degrading Mycobacterium strains are diversely distributed in the environmental soil.
The ability of the soil microbial community to degrade hydrocarbons depends on the number of microbes and its catabolic activity. Mycobacteria are metabolically versatile and are able to metabolize LMW and HMW PAHs. They have been reported to degrade HMW PAHs as pyrene, fluoranthene, and benzo[a]pyrene. Zeng et al. [19] demonstrated that Mycobacterium sp. NJ1 has an ability to degrade anthracene, pyrene, fluoranthene, and benzo[a]pyrene to various extents. Pagnout et al. [20] described Mycobacterium sp. SNP11 as possessing unique characteristics such as a cell wall rich with mycolic acids and the capacity to adhere strongly to hydrophobic compounds such as the HMW PAHs. This adhesion strongly facilitates the mass transfer of PAHs into the cells. Furthermore, Vila et al. [21] also reported that Mycobacterium sp. AP1 has the ability to degrade pyrene and produce intermediate metabolites.
3.2. Microcosm study
Soil microcosm is an approach to study microbial interactions with organic pollutants, in controlled and reproducible environmental conditions. Laboratory microcosms permit measuring of biodegradation and mineralization (CO2 production) rates and can be used to study the effect of bioaugmentation and biostimulation on bioremediation process [22, 23]. Dave et al. [23], in our laboratory have constructed an efficient microcosm system for the enhancement of soil bioremediation process, which resulted in the improvement of HMW PAH degradation in simulated soil conditions (Figure 2). Addition of glucose, Triton X-100, and beta-cyclodextrin in presence of chrysene resulted in enhanced biodegradation of LMW and HMW PAHs up to six rings. In our previous study (unpublished work), we conducted a microcosm experiment in the laboratory using M. litorale as a bioaugmenting agent and addition of various biostimulating agents such as Triton X-100, agricultural compost, Bushnell Haas medium, and mixture of all agents, which exhibited significant biodegradation of PAHs (phenanthrene, anthracene, pyrene, fluoranthene, and chrysene) from PAH spiked soil. Actinomycetes are well known to grow under conditions ranging from obstructive to unfavorable environmental conditions for a long time. Mycobacterium AP1 is able to utilize pyrene, fluoranthene, and phenanthrene as a carbon source. Mycobacterium sp. AP1 plays a significant role in degradation of PAHs such as phenanthrene in soil microcosm conditions [22]. All over, bioaugmentation treatments showed better results than monitored natural attenuation treatments in remediating PAH-contaminated soils.
Figure 2.
Microcosm system constructed in the laboratory [23]. Air pump (A), 2 M NaOH (B), activated charcoal (C), rotameter (D), 0.2 μ cellulose acetate filter (E), glass manifold (F), air regulator (G), sterile MilliQ water bottle to maintain humidity (H), microcosm flask (I) and CO2 trap (J).
3.3. Bacterial enzymatic routes
In the aerobic degradation, cytochrome P-450 monooxygenases are complex multicomponent systems present generally in fungi and are like the bacterial aromatic ring dioxygenases. These enzymes are generally membrane bound and have broad substrate specificities. PAH is converted into arene oxide by addition by one atom of molecular oxygen by the monooxygenase (Figure 3), while the other atom is reduced to water.
Figure 3.
Microbial metabolisms of PAHs by various routes [17].
The bacterial aerobic degradation of PAHs is generally initiated by the action of multicomponent dioxygenases that can catalyze the incorporation of both atoms of oxygen and two electrons from NADH to form cis-dihydrodiol. These multicomponent dioxygenases usually consist of reductase, a ferredoxin, and a third component consisting of two proteins, large and small iron-sulfur proteins [24]. Subsequent dehydrogenation by dehydrogenase forms dihydroxylated intermediates, which can further be degraded through ortho- or meta- (intradiol or extradiol) ring cleavage pathway which then eventually enters the TCA cycle (Figure 3). Dioxygenases have a number of applications such as in various clean-up technologies for wastewater treatments, biodegradation/bioremediation of PAHs, and other organic compounds in various contaminated niches.
Majority of dioxygenase enzymes were studied with Gram-negative bacteria but certain reports are also on gram-positive bacteria, specifically actinobacteria [25]. Silva et al. [26] reported that M. fortuitum has an ability to degrade anthracene maximally and increase their metabolic activity by changing various physical conditions, that is, pH and temperature. The other route of PAH degradation is accomplished by the action of monooxygenases. Initial oxidation by monooxygenases in bacteria forms trans-dihydrodiols; this activity is slower than dioxygenases. The cytochrome P-450 monooxygenase is a complex multi-enzyme protein of fungal origin that shares similarities to its bacterial counterparts.
Figure 3 represents the major routes for the degradation of PAHs by various enzyme systems. Among these, degradation of PAHs by dioxygenase-dehydrogenase enzyme system is commonly used by bacteria. Bacterial genera, capable of degrading PAHs commonly, include species of Rhodococcus, Nocardia, and Mycobacterium. This is a relatively small range of genera considering the prevalence of PAHs in the environment. Gram-positive actinobacteria as Mycobacterium spp. have been reported for the degradation of PAHs containing four or more fused aromatic rings at various extents. This is probably due to the hydrophobic cell surface which allows their adhesion to hydrophobic PAHs, thus facilitating mass transfer of the substrates inside the cells [27].
3.4. Biotransformation by Mycobacterium species
Many Mycobacterial species as M. vanbaalenii PYR-1 have been elucidated for the degradation of naphthalene, phenanthrene, anthracene, fluoranthene, pyrene, benz[a]anthracene, and benzo[a]pyrene, which produces key intermediate metabolites during degradation [28]. These results are significant because they have expanded our understanding of the enzymatic capabilities of bacteria to biodegrade HMW PAHs.
Mycobacterium strains have ability to degrade PAHs via either monooxygenase or dioxygenase enzymatic mechanisms, which form trans- and cis-dihydrodiol as an intermediate metabolite. Dean-Ross [29] recognized biodegradation of fluoranthene via fortuitous metabolism by an M. flavescens strain through meta-cleavage.
M. holderi was isolated from PAH-contaminated soil and was reported to grow on fluoranthene and co-oxidize pyrene in the presence of fluoranthene. It produced 29 metabolites during fluoranthene biodegradation [30]. Therefore, generated intermediate metabolite by Mycobacterium sp. showed a significant reduction of genotoxic potential after biodegradation of pyrene, fluoranthene, and phenanthrene [20, 31, 32].
M. vanbaalenii PYR-1 has been studied in detail with respect to enzymatic functions of various genes involved in PAH degradation [33, 34, 35, 36]. Gene-encoding PAHs ring-hydroxylating oxygenases as nidA, nidB, and nidD are involved in PAH biodegradation [33]. These genes are expressed in Mycobacterium cells, which actively participated in phenanthrene, pyrene, and fluoranthene degradation. Guo et al. [37] also described that the dioxygenase nidA genes are involved in biodegradation of PAHs such as phenanthrene, pyrene, and fluoranthene.
4. Conclusion
Organic pollutants such as PAHs, PCB, and pesticides are resistant to degradation and are predominantly present in the environment; thus, they cause severe toxicological effects on humans as well as marine biota. Therefore, there has been growing interest in mycobacterial strains as potential bioremediation agents and as important components of indigenous PAH and other xenobiotic compound degradation. Various researchers reported the use of Mycobacterium for PAH degradation in different environmental conditions. Mycobacterium possesses peculiar characteristics for degradation of HMW PAHs due to their potential enzymatic mechanisms, which encoded the PAH ring-hydroxylating oxygenases genes, participating in PAH biodegradation. A member of the genus Mycobacterium is responsible for HMW PAH removal and their catabolic enzyme like monooxygenase/dioxygenase, which is converted into less harmful and simpler end products. Thus, mycobacteria, isolated from different habitats in the environment, can be exploited for their potential to remediate contaminated sediment/soil. Based on the study, interpretations will aid notable information to the scientific community for future research on bioremediation of recalcitrant high molecular weight (HMW) PAHs. Based on the previous study Mycobacterium has tremendous capability to remediate the contaminated sites and transform them to less toxic end products. Biodegradation is considered as the best approach to restore PAH-contaminated soils. Therefore, bioremediation is a feasible option for cleaning up PAHs because it is simple, applicable over large areas, cost-effective, and eco-friendly green approach.
Acknowledgments
Authors are thankful to Department of Science and Technology, Government of India, New Delhi, for providing SERB-National Post-Doctoral Fellowship (PDF/2016/003007) and Gujarat State Biotechnology Mission (GSBTM), Gandhinagar, Gujarat, for financial assistance to carry out this research.
\n',keywords:"mycobacterium, PAHs, microcosm, bioremediation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/59150.pdf",chapterXML:"https://mts.intechopen.com/source/xml/59150.xml",downloadPdfUrl:"/chapter/pdf-download/59150",previewPdfUrl:"/chapter/pdf-preview/59150",totalDownloads:670,totalViews:225,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"August 1st 2017",dateReviewed:"January 5th 2018",datePrePublished:null,datePublished:"June 20th 2018",dateFinished:null,readingETA:"0",abstract:"The genus Mycobacterium has the ability to degrade various environmental pollutants including polycyclic aromatic hydrocarbons (PAHs). Mycobacterium has an ability to withstand adverse environmental conditions and it has been considered for future bioremediation applications for the removal of PAH contaminants from crude oil–polluted sites. The degradation of PAHs using a cost-effective laboratory microcosm system was discussed. The various conditions such as environmental habitat, degradation behavior, enzymatic mechanisms, and ecological survival are thoroughly discussed in this chapter. Based on the above study, Mycobacterium has proved to be a better candidate in bioremediation of PAH-contaminated sites.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/59150",risUrl:"/chapter/ris/59150",book:{slug:"mycobacterium-research-and-development"},signatures:"Dushyant R. Dudhagara and Bharti P. Dave",authors:[{id:"219060",title:"Prof.",name:"Bharti",middleName:null,surname:"Dave",fullName:"Bharti Dave",slug:"bharti-dave",email:"bpd8256@gmail.com",position:null,institution:{name:"Bhavnagar University",institutionURL:null,country:{name:"India"}}},{id:"225052",title:"Dr.",name:"Dushyant",middleName:null,surname:"Dudhagara",fullName:"Dushyant Dudhagara",slug:"dushyant-dudhagara",email:"dushyant.373@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Calligraphy",level:"1"},{id:"sec_2_2",title:"2.1. Polycyclic aromatic hydrocarbons",level:"2"},{id:"sec_3_2",title:"2.2. Characteristics of Mycobacterium",level:"2"},{id:"sec_5",title:"3. PAH biodegradation using Mycobacterium",level:"1"},{id:"sec_5_2",title:"3.1. Mycobacterium degradation ability",level:"2"},{id:"sec_6_2",title:"3.2. Microcosm study",level:"2"},{id:"sec_7_2",title:"3.3. Bacterial enzymatic routes",level:"2"},{id:"sec_8_2",title:"3.4. Biotransformation by Mycobacterium species",level:"2"},{id:"sec_10",title:"4. Conclusion",level:"1"},{id:"sec_11",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Pizzul L, Sjögren Å, del Pilar Castillo M, Stenström J. Degradation of polycyclic aromatic hydrocarbons in soil by a two-step sequential treatment. Biodegradation. 2007;18(5):607-616'},{id:"B2",body:'Kanaly RA, Harayama S. Biodegradation of high-molecular-weight polycyclic aromatic hydrocarbons by bacteria. 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Physiological characterization of Mycobacterium sp. strain 1B isolated from a bacterial culture able to degrade high-molecular-weight polycyclic aromatic hydrocarbons. Journal of Applied Microbiology. 2004;97(2):246-255'},{id:"B42",body:'Habe H, Kanemitsu M, Nomura M, Takemura T, Iwata K, Nojiri H, Yamane H, Omori T. Isolation and characterization of an alkaliphilic bacterium utilizing pyrene as a carbon source. Journal of Bioscience and Bioengineering. 2004;98(4):306-308'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Dushyant R. Dudhagara",address:null,affiliation:'
Analytical and Environmental Science Division and Centralized Instrument Facility, CSIR-Central Salt and Marine Chemicals Research Institute, India
Department of Life Sciences, Maharaja Krishnakumarsinhji Bhavnagar University, India
'},{corresp:"yes",contributorFullName:"Bharti P. Dave",address:"bpd8256@gmail.com",affiliation:'
Department of Life Sciences, Maharaja Krishnakumarsinhji Bhavnagar University, India
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Sánchez-Pérez, Anaximandro Gómez-Velasco, G. Leal, A.\nBencomo-Alerm, N. Romero-Sandoval and M. Martín-Mateo",authors:[{id:"159383",title:"Ph.D.",name:"Héctor Javier",middleName:null,surname:"Sánchez-Pérez",fullName:"Héctor Javier Sánchez-Pérez",slug:"hector-javier-sanchez-perez"}]},{id:"48279",title:"Molecular Epidemiology of Tuberculosis",slug:"molecular-epidemiology-of-tuberculosis",signatures:"Magda Lorena Orduz and Wellman Ribón",authors:[{id:"88491",title:"Dr.",name:"Wellman",middleName:null,surname:"Ribón",fullName:"Wellman Ribón",slug:"wellman-ribon"},{id:"172842",title:"Prof.",name:"Magda Lorena",middleName:null,surname:"Orduz",fullName:"Magda Lorena Orduz",slug:"magda-lorena-orduz"}]},{id:"47934",title:"Regulation of the Immune Response by Mycobacterium tuberculosis Beijing Genotype",slug:"regulation-of-the-immune-response-by-mycobacterium-tuberculosis-beijing-genotype",signatures:"Marcia Campillo-Navarro, Isabel Wong-Baeza, Jeanet Serafín-López,\nRogelio Hernández-Pando, Sergio Estrada-Parra, Iris Estrada-García\nand Rommel Chacón-Salinas",authors:[{id:"86616",title:"Dr.",name:"Iris",middleName:null,surname:"Estrada-García",fullName:"Iris Estrada-García",slug:"iris-estrada-garcia"},{id:"86892",title:"Dr.",name:"Jeanet",middleName:null,surname:"Serafin-Lopez",fullName:"Jeanet Serafin-Lopez",slug:"jeanet-serafin-lopez"},{id:"86894",title:"Dr.",name:"Sergio",middleName:null,surname:"Estrada-Parra",fullName:"Sergio Estrada-Parra",slug:"sergio-estrada-parra"},{id:"86896",title:"Dr.",name:"Rommel",middleName:null,surname:"Chacon-Salinas",fullName:"Rommel Chacon-Salinas",slug:"rommel-chacon-salinas"},{id:"89110",title:"Dr.",name:"Rogelio",middleName:null,surname:"Hernandez-Pando",fullName:"Rogelio Hernandez-Pando",slug:"rogelio-hernandez-pando"},{id:"172811",title:"MSc.",name:"Marcia",middleName:null,surname:"Campillo-Navarro",fullName:"Marcia Campillo-Navarro",slug:"marcia-campillo-navarro"},{id:"172817",title:"Dr.",name:"Isabel",middleName:null,surname:"Wong-Baeza",fullName:"Isabel Wong-Baeza",slug:"isabel-wong-baeza"}]},{id:"48040",title:"Early Exposure of Human Neutrophils to Mycobacteria Triggers Cell Damage and Pro-Inhibitory Molecules, but not Activation",slug:"early-exposure-of-human-neutrophils-to-mycobacteria-triggers-cell-damage-and-pro-inhibitory-molecule",signatures:"M. Orozco-Uribe, L. Donis-Maturano, J. Calderón-Amador, R.\nChacón-Salinas, J. Castañeda-Casimiro, S. Estrada-Parra, I. Estrada-\nGarcía and L. Flores-Romo",authors:[{id:"85769",title:"Dr.",name:"Leopoldo",middleName:null,surname:"Flores-Romo",fullName:"Leopoldo Flores-Romo",slug:"leopoldo-flores-romo"}]},{id:"48603",title:"Vaccines – Recent advances and clinical trials",slug:"vaccines-recent-advances-and-clinical-trials",signatures:"Marisol Ocampo C.",authors:[{id:"172190",title:"Ph.D.",name:"Marisol",middleName:null,surname:"Ocampo",fullName:"Marisol Ocampo",slug:"marisol-ocampo"}]},{id:"47940",title:"Tuberculosis Vaccine Development — Its History and Future Directions",slug:"tuberculosis-vaccine-development-its-history-and-future-directions",signatures:"Elizabeth M. MacDonald and Angelo A. 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Besra",authors:[{id:"81479",title:"Prof.",name:"David",middleName:null,surname:"Minnikin",fullName:"David Minnikin",slug:"david-minnikin"},{id:"88527",title:"Prof.",name:"Gurdyal",middleName:null,surname:"Besra",fullName:"Gurdyal Besra",slug:"gurdyal-besra"},{id:"88529",title:"Dr.",name:"Helen",middleName:"Dorothy",surname:"Donoghue",fullName:"Helen Donoghue",slug:"helen-donoghue"},{id:"173387",title:"Dr.",name:"Houdini",middleName:null,surname:"Wu",fullName:"Houdini Wu",slug:"houdini-wu"},{id:"173388",title:"Dr.",name:"Luke",middleName:null,surname:"Alderwick",fullName:"Luke Alderwick",slug:"luke-alderwick"},{id:"173389",title:"Dr.",name:"Apoorva",middleName:null,surname:"Bhatt",fullName:"Apoorva Bhatt",slug:"apoorva-bhatt"},{id:"173392",title:"Dr.",name:"Oona Ying-Chi",middleName:null,surname:"Lee",fullName:"Oona Ying-Chi Lee",slug:"oona-ying-chi-lee"},{id:"173393",title:"Mr.",name:"Nataraj",middleName:null,surname:"Vijayashankar",fullName:"Nataraj Vijayashankar",slug:"nataraj-vijayashankar"},{id:"173394",title:"Prof.",name:"Malin",middleName:null,surname:"Ridell",fullName:"Malin Ridell",slug:"malin-ridell"},{id:"173395",title:"Dr.",name:"Motoko",middleName:null,surname:"Watanabe",fullName:"Motoko Watanabe",slug:"motoko-watanabe"}]},{id:"48058",title:"ENT Manifestations in Tuberculosis",slug:"ent-manifestations-in-tuberculosis",signatures:"Luiz Alberto Alves Mota, Paula Cristina Alves Leitão and Ana Maria\ndos Anjos Carneiro-Leão",authors:[{id:"88874",title:"Prof.",name:"Luiz",middleName:"Alberto Alves",surname:"Mota",fullName:"Luiz Mota",slug:"luiz-mota"},{id:"172369",title:"Dr.",name:"Ana Maria",middleName:"Dos Anjos",surname:"Carneiro-Leão",fullName:"Ana Maria Carneiro-Leão",slug:"ana-maria-carneiro-leao"},{id:"172496",title:"Ms.",name:"Paula",middleName:null,surname:"Leitão",fullName:"Paula Leitão",slug:"paula-leitao"}]},{id:"48019",title:"Molecular Diagnostic Testing on Post Mortem Inspection and Rulings on Bovine Tuberculosis — An Experience Report in Brazil",slug:"molecular-diagnostic-testing-on-post-mortem-inspection-and-rulings-on-bovine-tuberculosis-an-experie",signatures:"Ricardo César Tavares Carvalho, Leone Vinícius Furlanetto, Rafael\nda Silva Duarte, Luciano Nakazato, Walter Lilenbaum, Eduardo\nEustáquio de Souza Figueiredo and Vânia Margaret Flosi Paschoalin",authors:[{id:"97533",title:"Dr.",name:"Vania",middleName:null,surname:"Paschoalin",fullName:"Vania Paschoalin",slug:"vania-paschoalin"},{id:"126657",title:"Dr.",name:"Eduardo Eustáquio De Souza",middleName:null,surname:"Figueiredo",fullName:"Eduardo Eustáquio De Souza Figueiredo",slug:"eduardo-eustaquio-de-souza-figueiredo"},{id:"126658",title:"MSc.",name:"Leone Vinicius",middleName:"Vinicius",surname:"Furlanetto",fullName:"Leone Vinicius Furlanetto",slug:"leone-vinicius-furlanetto"},{id:"126662",title:"Dr.",name:"Rafael Silva",middleName:null,surname:"Duarte",fullName:"Rafael Silva Duarte",slug:"rafael-silva-duarte"},{id:"126663",title:"Dr.",name:"Walter",middleName:null,surname:"Lilenbaum",fullName:"Walter Lilenbaum",slug:"walter-lilenbaum"},{id:"172843",title:"MSc.",name:"Ricardo",middleName:null,surname:"César Tavares Carvalho",fullName:"Ricardo César Tavares Carvalho",slug:"ricardo-cesar-tavares-carvalho"},{id:"172844",title:"Dr.",name:"Luciano",middleName:null,surname:"Nakazato",fullName:"Luciano Nakazato",slug:"luciano-nakazato"}]},{id:"47964",title:"Application of High Performance Liquid Chromatography for Identification of Mycobacterium spp",slug:"application-of-high-performance-liquid-chromatography-for-identification-of-mycobacterium-spp",signatures:"Carlos Adam Conte Junior, César Aquiles Lázaro de la Torre,\nEduardo Eustáquio de Souza Figueiredo, Walter Lilenbaum and\nVânia M. Flosi Paschoalin",authors:[{id:"126659",title:"Dr.",name:"Carlos Adam",middleName:null,surname:"Conte Junior",fullName:"Carlos Adam Conte Junior",slug:"carlos-adam-conte-junior"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"65567",title:"CTCs as Liquid Biopsy: Where Are We Now?",doi:"10.5772/intechopen.84366",slug:"ctcs-as-liquid-biopsy-where-are-we-now-",body:'\n
\n
1. Introduction
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A few years ago, the analysis of circulating tumor cells (CTCs) in the blood of patients with cancer was defined by the term “liquid biopsy” [1]. Blood samples can be obtained and analyzed at the time of diagnosis and during the systemic treatment. Detection of CTCs in circulation gives important information on the molecular properties of tumor lesions. This information contributes to the early detection of metastatic lesions and participates in the personalized treatment of cancer patients such as prognostic evaluation, stratification of patients for targeted therapies, real-time monitoring of treatment efficacy, identification of therapeutic target, and resistance mechanism.
\n
The analysis of the liquid biopsy has provided new insights into the biology of metastasis with important implications for the clinical management of cancer patients (Figure 1). Numerous clinical studies and meta-analyses including large cohorts of patients have shown that the number of CTCs is an important indicator of the risk of progression or death in patients with metastatic solid cancer (e.g., breast, prostate, colon, etc.) [2, 3, 4, 5, 6].
\n
Figure 1.
From the blood sample toward the precision medicine in cancer patients.
\n
Despite the remarkable advances made in recent years, so far, liquid biopsy analyses are rarely implemented in routine patient testing. In-depth investigation of CTCs remains technically challenging. CTCs occur at the very low concentrations of one tumor cell in the background of millions of blood cells. Their identification and characterization require extremely sensitive and specific analytic methods. Moreover, up to now, results obtained with liquid biopsy analysis did not lead yet to validated guidelines for treatment and patient management. Nevertheless, technical advances and encouraging clinical studies demonstrated that liquid biopsy holds great promise for revolutionizing cancer diagnostics in a soon future.
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Here, we will outline the advantages and challenges of CTCs as liquid biopsy in oncology by discussing the strategies for enrichment, detection, and characterization linked to the biology of these cells. Moreover, the potential of CTC analysis for clinical utility will be argued as well as other circulating biomarkers.
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\n
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2. Technical strategies for enrichment, detection, and characterization of CTCs
\n
At the moment, in-depth investigation of CTCs still remains technically challenging as they are every rare events in blood circulation. Their identification and characterization require extremely sensitive and specific analytic methods, which are usually a combination of enrichment and detection procedures (Figure 2). The different strategies to analyze CTCs are described in this chapter, and all the advantages/disadvantages plus the commercial status are summarized in Table 1.
\n
Figure 2.
Strategies for enrichment, detection, and characterization of CTCs.
\n
Table 1.
Advantages, disadvantages, and commercial status of technologies for enrichment, detection, and characterization of CTCs.
\n
\n
2.1 Strategies for CTC enrichment
\n
Up to date, a large panel of technologies was designed to enrich CTCs from the surrounding normal hematopoietic cells. These enrichment methods rely on different properties of CTCs: (a) biological properties (e.g., surface protein expression) and (b) physical properties (e.g., size, density, electric charges, and deformability).
\n
Biological properties are mainly used in immunological procedures with antibodies against either tumor-associated antigens (positive selection) or common leukocytes antigen CD45 (negative selection). Positive enrichment typically attains high cell purity, which depends on antibody specificity. Among the current positive systems, most of the technologies targeted the epithelial cell adhesion molecule (EpCAM) antigen, as the FDA-cleared CELLSEARCH® system which is frequently compared for all new CTC detection methods as the gold standard. However, capturing CTCs lacking EpCAM expression has involved the use of cocktails of antibodies against various other epithelial cell surface antigens (e.g., EGFR, MUC1) or against tissue-specific antigen (e.g., PSA, HER2) and against mesenchymal or stem-cell antigens (e.g., Snail, ALDH1) [7]. Positive selection of CTCs requires an assumption about the unknown nature of CTCs in an individual blood sample. This bias is avoided by negative selection in which the blood sample is depleted of unwanted cells. Indeed, negative enrichment targets and removes background cells, such as leukocytes, using antibodies against CD45 (which is not expressed on carcinomas or other solid tumors) and other leukocyte antigens, to achieve a CTC-enriched sample. Moreover, negative enrichment technologies evade some of the pitfalls of positive enrichment; for example, CTCs are not tagged with a difficult-to-remove antibody, they are not activated or modified via an antibody-protein interaction, and antibody selection does not bias the subpopulation of CTCs captured. However, these advantages come at the cost of purity, as negative enrichment strategies typically have a much lower purity than positive enrichment [8, 9, 10] and require a suitable CTC detection step.
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These last years, numerous marker-independent techniques have been developed for CTC isolation and detection. Label-free enrichment process based on physical properties, such as density, size, deformability, and electric charge, have come to avoid molecular bias induced by variability of cell biomarker expression associated with tumor heterogeneity. Mostly used, size and density technologies like microfiltration technologies, based on the precedent that CTCs generally exhibit a larger morphology than leukocytes, or microfluidic devices using inertial focusing to separate CTCs from blood are developed by several companies such as ScreenCell® [11], ISET® [12], CellSieve™ [13, 14], Parsortix™ [15], or Vortex [16]. Such technologies or approaches have the advantages of being less complicated, sometimes rapid, and require minimal equipment. However, some of these approaches may be prone to clogging, and the release of the CTCs into suspension for further analysis is challenging.
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\n
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2.2 Strategies for CTC detection
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After enrichment, the CTC fraction still contains a substantial number of leukocytes, and CTCs need to be specifically identified at the single-cell level by a robust and reproducible method that can distinguish them from normal blood cells.
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Immunological technologies are the most frequent methods used for CTC detection using a combination of membrane and/or intracytoplasmic anti-epithelial, anti-mesenchymal, and anti-tissue-specific marker or antitumor-associated antibodies [7]. However, many CTC assays use the same identification step as the CELLSEARCH® system: cells are fluorescently stained for cytokeratins (CK), the common leukocyte antigen CD45, and a nuclear dye (DAPI).
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Nucleic acid-based CTC detection methods are the most widely used alternatives to immunological assays to identify CTCs. These techniques identify specific tumor DNA or mRNA to confirm the presence of CTCs indirectly [17]. Detection involves designing specific primers supposedly associated with CTC-specific genes. These genes either code for tissue-, organ-, or tumor-specific proteins or, more specifically, contain known mutations, translocations, or methylation patterns found in cancer cells [18]. These methods have the highest sensitivity but lack specificity, owing to the potential of captured noncancerous cells to generate false-positive signals, thus decreasing the overall accuracy. Considering the genetic heterogeneity of CTCs, multiplex PCR, such as the AdnaTest kit (AdnaGen AG), could overcome this limitation [19, 20].
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Furthermore, functional assays that exploit aspects of live cellular activity for CTC detection have the particularity to focus on the discovery of the “metastasis-competent cells.” The functional epithelial immunospot (EPISPOT) assay was introduced for in vitro CTC detection and focuses only in viable CTCs [21]. This technology assesses the presence of CTCs based on secretion, shedding, or release of specific proteins during 24–48 h of short-term culture [22]. More recently, Tang et al. described a high-throughput metabolic-based assay for rapid detection of rare metabolically active tumor cells in pleural effusion and peripheral blood of lung cancer patients [23]. In vivo, important information can be obtained by transplantation of patient-derived CTCs into immunodeficient mice: tumors that could grow after xenotransplantation of enriched CTCs have the characteristics of metastasis-initiator cells [8].
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\n
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2.3 Strategies for CTC characterization
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CTCs hold the key to understand the biology of metastasis and provide a biomarker to noninvasively measure the evolution of tumor subclone during treatment and disease progression. Improvements in technologies to yield purer CTC populations make better cellular and molecular investigation. Characterization of CTCs allows better insight into tumor heterogeneity, within most assays, including immunofluorescence, array CGH, next-generation sequencing (NGS) of both DNA and RNA, and fluorescence in situ hybridization.
\n
Protein analyses on single CTCs are currently performed by immunostaining with antibodies directed against protein of interest. Multiple labeling is possible but usually restricted to a few proteins of interest for tumor cell biology and cancer therapy. This may help to identify signaling pathways relevant to metastasis development and treatment responses. In breast cancer patient, the HER2 status of CTCs could be assessed and shows discrepancies with primary tumor status [24, 25]. More recently, immune checkpoint regulators such as programmed death-ligand 1 (PD-L1) have become exciting new therapeutic targets and could be used for liquid biopsy in future clinical trials on patients undergoing immune checkpoint blockage [26, 27].
\n
Immunological detection and characterization offer the advantage of allowing isolation of stained CTCs for subsequent molecular characterization. While manual isolation by micromanipulation of CTCs is possible [28], it is rather arduous and time-consuming. An alternative automated single-cell selection device has been therefore developed. The DEPArray™ technology based on a dielectrophoresis strategy by trapping single cells in DEP cages [29] is designed for single-cell recovery of CTCs. Multiple clinical studies have used DEPArray™ to detect and recover single CTCs for subsequent genetic analyses [30, 31, 32].
\n
Among single-cell sequencing to identify genomic and transcriptomic characteristics of CTCs, most studies have focused on genomic analyses and carried out whole genome amplifications (WGAs) to increase the amount of DNA, which is subsequently subjected to the analyses of specific mutations and copies number variations using conventional and next-generation sequencing technologies [28, 33, 34]. As an example, CTCs with mutated KRAS genes will escape anti-EGFR therapy, and their early detection might help to guide therapy in individual patients. Besides isolation of single CTCs, a 3–4 log units enrichment step are enough to detect CTCs based on recently developed highly sensitive technologies (e.g., droplet digital PCR) [35].
\n
Another approach is fluorescence in situ hybridization (FISH) analysis of single CTCs identified by immunocytochemistry [36, 37]. Such an immuno-FISH approach can be combined with automated detection of CTCs and might be easier to implement in future clinical diagnostics. Recently, padlock probe technology, which enables in situ analysis of AR-V7 in CTCs, showed that 71% (22 of 31) of CRPC patients had detectable AR-V7 expression ranging from low to high expression [38]. Patients with AR-V7-positive circulating tumor cells (CTCs) have greater benefit of taxane-based chemotherapy than novel hormonal therapies, indicating a treatment-selection biomarker [39, 40].
\n
Finally, these last years, many teams tried to obtain CTC lines by culturing CTCs ex vivo. The establishment of in vitro cultures and permanent lines from CTCs has become a challenging task. Indeed, CTC lines could be used to identify proteins and pathways involved in cancer cell stemness and dissemination and also to test new drugs to inhibit metastasis-competent CTCs. Ex vivo CTC cultures have been established for breast [41, 42], prostate [43], lung [44], colon [22], and head and neck cancer [45]. To our knowledge, permanent CTC lines have been described only from circulating colon cancer cells: one before (CTC-MCC-41) [22, 46] and eight after the initiation of the anticancer treatment [47].
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\n
\n
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3. Biology of CTCs
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3.1 Epithelial to mesenchymal plasticity
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Epithelial to mesenchymal transition (EMT), which is characterized by the downregulation of epithelial proteins and upregulation of mesenchymal proteins, is a complex process that supports the migratory capacity of epithelial tumor cells and is thought to play a crucial role in promoting cancer metastasis. EMT led to increased motility via rearrangements of cellular contact junctions and loss of cell adhesion (i.e., E-cadherin, N-cadherin, claudins), plus epithelial cell morphology through cytoskeleton modification (i.e., cytokeratin, vimentin, fibronectin, etc.) [48]. This invasive phenotype enables cancer cells to pass through the basal membrane and endothelial barriers of blood vessels to reach bloodstream. However, it is still unclear what degree of EMT is needed in tumor cells to attain the circulation.
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Despite the wealth of experimental data, the exact role of EMT in cancer patients remains more controversial. Over the past 10 years, the development of sensitive technologies that allow the detection and molecular characterization of CTCs helped to shed new light into the importance of EMT for human tumor cell dissemination [7, 49]. All these data lead now to a new trend, focused on plasticity of tumor cell: epithelial to mesenchymal plasticity (EMP) associated with stemness. This process is today considered as a central actor of the metastatic cascade, providing tumor cells the ability to adapt to the different microenvironments encountered during metastatic spread to colonized organs (i.e., adjacent stroma, blood, newly colonized organs).
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CTCs with mesenchymal and stemness features can be attributed in some clinical studies to higher disease stages and metastasis [50, 51, 52] and even to therapy response and worse outcome [53, 54, 55]. However, the published studies addressing the impact of mesenchymal-like CTCs show heterogeneity with regard to assay specificity, size of cancer and control groups, and endpoint parameters.
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To conclude, evaluation of the EMT and stem-cell markers in CTCs may provide information of clinical interest, and using these markers to classify CTCs can elucidate CTC heterogeneity. Nevertheless, studies still suffer from lack of standardized procedures and small sample sizes. Therefore, larger well-designed clinical trials are needed to further illuminate the potential values of EMT markers in CTCs.
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3.2 Anoikis resistance
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In normal tissue, adhesion to appropriate extracellular matrix proteins is essential for survival. Loss of this adhesion induces cell death which has been termed “anoikis.” Anoikis is a physiologically relevant process for tissue homeostasis and development because it prevents detached epithelial cells from colonizing elsewhere, thereby inhibiting dysplastic cell growth or attachment to an inappropriate matrix [56]. Dysregulation of anoikis, such as anoikis resistance, is a critical mechanism in tumor metastasis. If cells acquire oncogenic signals that are able to overcome this machinery, they gain the ability to survive outside their normal environment in the absence of adhesion to the extracellular matrix. The tumor cells that acquire anoikis resistance can survive detachment from their primary site, traveling through the circulatory and lymphatic systems to disseminate to ectopic locations [57]. Different studies have shown that the death receptor pathway of caspase activation mediates anoikis; thus, defects in this pathway such as overexpression of the caspase-8 inhibitor FLIP can turn cell resistant to anoikis. Similarly, resistance to anoikis can be conferred by roadblocks in the mitochondrial pathway, such as overexpression of the Bcl-2 family of anti-apoptotic proteins [57].
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The investigation of molecular mechanisms involved in cancer cell survival while they are leaving the adherent microenvironment of the tumor to the circulatory system is important to understand the process by which cancer can spread to distant organs, as well as to design new therapeutics to inhibit the spread of the disease.
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3.3 Escape to the immune system
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Once in the bloodstream, CTCs face several natural obstacles that hinder the metastatic process. One of the main obstacles that CTCs face in the blood is the attack of the immune system. Lots of work was done to understand mechanisms involve in the battle between the immune system’s capabilities to fight cancer and the immune-suppressive processes that promote tumor growth. Several biomarkers showed up from this work; for example, in colorectal cancer, immune escape was observed by the upregulation of CD47, a “don’t eat me signal” that prevents CTCs from macrophage and dendritic cell attack [58]. The most clinically advanced biomarkers are the programmed death-1 (PD-1) and its ligand (PD-L1). PD-L1 expressed in tumors has been highlighted to function as a key component of the cancer-immunity cycle by preventing the immune system from destroying cancer cells. PD-1 receptor is a surface protein expressed on activated T-cells, and its ligand PD-L1 is expressed on the surface of antigen-presenting cells. The formation of the PD-1/PD-L1 complex induces a strong inhibitory signal in the T-cell, which leads to a reduction of cytokine production and a suppression of T-cell proliferation [59]: the immune system is misled by the cancer cells expressing PD-L1 and does not destroy them. That understanding led to the development of immune checkpoint inhibitor therapies, antibodies against both PD-1 and PD-L1, and remarkable clinical responses which have been seen in several different malignancies including, but not limited to, melanoma, lung, kidney, and bladder cancers [59].
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However, CTCs can use several mechanisms to survive in the circulatory system. For example, these cells can couple to reactive platelets. Several hypotheses propose that the surface coating of platelets may serve as a shield against immune assault or that platelets may load the major histocompatibility complex to CTCs to imitate host cells and therefore avoid immune surveillance [60]. The aggregation of CTCs with platelets, stromal fibroblasts, and leukocytes leads to the formation of floating complexes and increases the survival of CTCs in the bloodstream by avoiding anoikis and killing by immune cells [61]. In addition, the vascular endothelial growth factor (VEGF), secreted by platelets, is able to affect the maturation of dendritic cells that play a key role in antigen presentation [62].
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3.4 CTC microemboli
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An alternative mechanism for metastasis has emerged from recent studies, the collective migration of tumor cells by clusters of CTCs. CTC clusters are defined as groups of tumor cells (more than two or three cells, varied among studies) that travel together in the bloodstream. Thus, in the blood circulation, CTCs can be found both as single tumor cells and clusters of tumor cells in patients with an advanced stage of the cancer. Study using mouse models with tagged mammary tumors demonstrates that these clusters arise from oligoclonal tumor cell groupings and not from intravascular aggregation events [63]. Moreover, CTC clusters have 23- to 50-fold increased metastatic potential. Even fewer in number, clusters of CTCs possess much higher metastatic potential than individual CTCs.
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Patients with CTC microemboli or clusters in their bloodstream have significantly worse overall and progression-free survival than those with only individually migrating single CTCs [63]. The prognostic value of CTC clusters can be estimated by clinical observations.
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Current studies have partially elucidated the reasons for CTC clusters to have higher potential of metastasis. First, tumor cells within CTC clusters showed prolonged survival and decreased apoptosis [64]. Second, the physical specialty of CTC clusters allows for a greater likelihood of it residing in distant organs. Microvasculature of viscera can retain large CTCs; thus, it can retain CTC clusters more easily [65].
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4. Clinical relevance of CTCs
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Despite many clinical validation studies, CTCs have not been included yet into the clinical guidelines (e.g., ASCO guidelines at http://www.asco.org/practice-guidelines/quality-guidelines/guidelines). Although CTC enumeration can improve current tumor staging and contribute to the early assessment of therapy effects, the clinical utility of CTCs remains to be addressed in interventional studies (i.e., its capacity to decide adopting or to rejecting a therapeutic action).
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In this chapter, we highlighted the clinical relevance of CTCs in breast, prostate, colon, and lung cancer. Figure 3 illustrates how CTCs as liquid biopsy can guide clinicians to personalized medicine.
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Figure 3.
CTC as liquid biopsy for precision medicine.
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4.1 Breast
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More advanced studies, regarding clinical utility of CTCs, are related to metastatic breast cancer (MBC). Sequential CTC enumeration has been shown in a large multicenter prognostic study to be superior to conventional serum protein markers (CA-15-3, CEA) for early detection of therapy failure in MBC [5]. However, in the interventional trial SWOG 0500 (NCT00382018), although the prognostic significance of CTCs was confirmed, the CTC-driven switch to an alternate cytotoxic therapy was not effective in prolonging overall survival for MBC patients with persistently increased CTCs after 21 days of therapy [66]. The inconvenient of these kinds of interventional biomarker-driven studies is the fact that the result is dependent of the therapy efficacy. This strategy can only work if there is an efficient therapy for the cohort identified by the test.
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Another promising approach is the stratification of patients to chemotherapy or hormonal therapy based on CTC enumeration like in the interventional STIC CTC METABREAST clinical trial (NCT0 1,710,605) for MBC patients [67]. Besides CTC enumeration, stratification based on CTC phenotype might become also an important strategy. Stratification of MBC patients based on HER2 status of CTCs is currently tested in the DETECT III trial [67].
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Other possible uses for CTC detection include prognostication in early stage patients, identifying patients requiring adjuvant therapy. The SUCCESS study provides strong evidence of the prognostic relevance of CTCs in early breast cancer before and after adjuvant chemotherapy in a large patient cohort [68]. This study outlines the potential of the CTC analysis at primary diagnostic to evaluate individual risk and points that they may use for treatment management in early stage of cancer. These data have been confirmed by Bidard et al. who conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of CTC detection as a prognostic marker [69]. They showed that CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by NCT. Liquid biopsy complements current prognostic models based on tumor characteristics and response to therapy. Moreover, Trapp et al. demonstrated recently that the presence of CTCs 2 years after chemotherapy was associated with decreased OS and DFS. Based on these results, active individualized surveillance strategies for breast cancer survivors based on biomarkers should be reconsidered [70].
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4.2 Prostate
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For men with metastatic castration-resistant prostate cancer (mCRPC), the CELLSEARCH® system method for CTCs enumeration is the only FDA-cleared CTC test available clinically. The CTC count has been shown to provide prognostic value and was associated with treatment response in mCRPC patients, in several recent studies [4, 71, 72, 73], indicating a clear value as a patient-level indicator of survival. However, despite increasing evidence that CTCs could be used to monitor disease progression in mCRPC [18], CTC use is still limited to clinical trials in academic centers. Clinical utility of CTCs, reflecting the ability of this test to favorably change outcomes, is still an unmet clinical need in prostate cancer [74]. The first interventional clinical trial in prostate cancer that will show the clinical utility of CTCs should start in 2019 (TACTIK project—NCT03101046).
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Moreover new data suggest that CTCs may harbor genetic information (such as the androgen receptor splice variant 7, AR-V7) relevant to changing clinical management and predicting treatment sensitivity or resistance to cancer therapies such as enzalutamide, abiraterone, and taxane-based chemotherapies [39].
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Regarding nonmetastatic cancer patient, a recent European TRANSCAN study CTC-SCAN investigated the feasibility of detecting CTCs in nonmetastatic high-risk prostate cancer (PCa) patients by combining the CELLSEARCH® platform, the in vivo CellCollector® capture system, and the EPISPOT assay. The observed correlation, with established risk factors and the persistence of CTCs 3 months after surgery, suggested a potential clinical relevance of CTCs as markers of minimal residual disease (MRD) in PCa [75]. CTC-based liquid biopsies have the potential to monitor MRD in patients with nonmetastatic prostate cancer although follow-up evaluations are now required to assess how to provide independent prognostic information. A new European project (Transcan—PROLIPSY) will assess whether CTCs in combination with exosomes and ctDNA as noninvasive liquid biopsy allow the diagnosis of prostate cancer and the evaluation of its aggressiveness.
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4.3 Colon
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In 2008, Cohen et al. demonstrated the independent prognostic and predictive value of CTCs for patients initiating chemotherapy for metastatic colorectal cancer (mCRC) [2]. Since this first publication defining a cutoff of three CTCs, different meta-analyses have confirmed that baseline levels of CTC count is an important prognostic factor for PFS and OS in patients with mCRC [76, 77, 78].
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Despite the strong evidence of a prognostic significance of CTC count, there is no solid evidence demonstrating the interest of CTC count for therapeutic strategy, and this biomarker is rarely used in the management of patients with mCRC. However, patients with high CTC counts recruited in a phase II study could benefit from a more intense chemotherapeutic regimen [79]. These preliminary data require validation in randomized trials. Moreover, Lalmahomed et al. failed to show a prognostic effect of CTCs for early relapse after the resection of colorectal liver metastases [80].
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4.4 Lung
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The role of CTCs in non-small cell lung cancer (NSCLC) has been addressed in several clinical trials. More specifically, the prediction of the outcome of patients with early and advanced NSCLC based on the CTC enumeration has been explored. The CTC count with the CELLSEARCH® system in advanced NSCLC patients who received standard chemotherapy was associated with a shorter PFS and OS, but standardize cutoff could not be observed [81, 82, 83, 84]. Furthermore, analysis of CTCs from patients with metastatic NSCLC identified the expected EGFR-activating mutation in CTCs from 11 of 12 patients (92%) and in matched free plasma DNA from 4 of 12 patients (33%) [85]. The T790 M mutation, which confers drug resistance, was revealed in CTCs from patients who had received tyrosine kinase inhibitors, suggesting the strong potential gain of noninvasive liquid biopsy. Moreover, serial increases in CTC counts were associated with tumor progression, with the emergence of additional EGFR mutations in some cases. Recently, KRAS and EGFR mutations, relevant for treatment decisions, could be detected in CTCs and in the corresponding primary tumors of the same patients [86].
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5. Other circulating biomarkers as liquid biopsy
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Even if the term “liquid biopsy” was originally used for CTC analysis, currently, it includes all different circulating biomarkers like circulating cell-free DNA (cfDNA), microRNA (miRNA), and exosomes that are shed into the bloodstream by tumors and/or metastatic deposits, as well as tumor-educated platelets which are described to have a role in tumor metastasis. Like CTCs, all these other circulating biomarkers need to be validated in clinical trials. Table 2 summarizes observational and interventional clinical trials on breast, lung, prostate, and colorectal cancer registered in clinical.gov (A) and the applications (B).
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Table 2.
(A) Number of observational and interventional clinical trials (clinical.gov) involving liquid biopsy in the main cancer types and (B) the applications of each circulating biomarkers (CTCs, circulating DNA, exosomes, microRNA, and TEPs).
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5.1 Circulating tumor DNA
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Apoptotic and necrotic tumor cells are known to discharge cell-free nucleic acid fragments into the bloodstream of cancer patients. Although most circulating DNA is believed to originate from nonmalignant cells, an increased level of cfDNA was observed in blood of patients with late stage cancer [87]. Among the pool of total cfDNA, there is circulating tumor DNA (ctDNA) which cannot be specifically isolated from the total pool but can be detected by tumor-specific mutations [88]. In general, cfDNA can be analyzed from plasma by targeted or untargeted approaches. The targeted approaches involve the detection of known genetic changes, e.g., “druggable” mutations, with impact on therapy decisions [89]. The interest of cfDNA was demonstrated by Douillard et al. [90] by determining the EGFR mutational status in NSCLC and can represent a substitute for tissue biopsies when these are not available. Moreover, in 2016, the detection of EGFR gene mutations in cfDNA using the cobas EGFR Mutation Test v2 achieved FDA approval as a companion diagnostic for erlotinib, becoming the first blood-based biopsy test approved for implementation in clinical decisions [91].
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However, despite the evidence of potential clinical utility and even if it has been recommended (e.g., by the FDA) that the blood could be analyzed first to reduce the number of invasive biopsies in cancer patients, the lower sensitivity of ctDNA analyses prevents its use in clinical management for the moment, and the primary tumor analysis still remains the gold standard in NSCLC diagnostics of EGFR mutations.
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5.2 MicroRNAs
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MicroRNAs (miRNAs, miR-x), consisting in approximately 22 nucleotides, represent another potential blood biomarker in oncology. These noncoding small RNAs are master regulators of genic expression and consequently of many cellular processes. Alterations in the expression of microRNA genes have been shown to play in important role in human malignancies. These alterations can be caused by a variety of mechanisms, including deletions, amplifications, or mutations involving microRNA loci, by epigenetic silencing or by dysregulation of transcription factors targeting specific microRNAs [92]. The three major detection techniques for circulating cell-free miRNA (cfmiRNA) analysis, following RNA extraction, comprise quantitative RT-PCR, microarray analyses, and deep sequencing. The assessment of cfmiRNA has been suggested for early diagnosis, prognosis, therapy monitoring, and therapeutic response prediction in different cancer types (e.g., lung, breast, colon, prostate, and ovary cancers and melanoma), as reviewed by Armand-Labit and Pradines [93].
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5.3 Exosomes
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Tumor and normal cells are known to release microvesicles such as exosomes (40–150 nm) into the circulation, discharging cellular content. Currently, one challenge for the analyses of circulating cell-free nucleic acids in blood is their instability. Thus, due to their protective environment, the exosomes represent a valuable source for analysis of proteins, DNA, RNA, miRNA, lipids, and metabolites [94]. Ultracentrifugation, density-based separation, or immune-affinity capture using magnetic beads coated with anti-EpCAM antibodies can be used to isolate exosomes [95]. They are important regulators of the cellular niche, and their altered characteristics in many diseases, such as cancer, suggest their importance for diagnostic and therapeutic applications and as drug delivery vehicles. Hoshino et al. demonstrated that the composition of exosomal integrins could predict organ-specific metastasis and that tumor-derived exosomes participate in preparing the pre-metastatic niche [96]. Correspondingly, the same group shows that a pro-metastatic phenotype of bone marrow progenitor cells is promoted by education through melanoma exosomes [97].
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5.4 Tumor-educated platelets
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A new emerging class of components for liquid biopsy is tumor-educated platelets (TEPs). These anucleated blood cells (second most abundant cell type in circulation) could be educated by tumor cells by the transfer of tumor-associated biomolecules, mostly RNA. Platelets are isolated by centrifugation and RNA can be subjected to RT-PCR [45]. Performing mRNA sequencing on TEPs, Best and his colleagues showed that cancer patients with different tumor types could be discriminated from healthy individuals with 96% accuracy and that the primary tumor was correctly located with a precision of 71% [98]. Studies have shown that platelet count and platelet size can already provide clinically relevant information about the presence of cancer [99]. High platelet count is associated with increased mortality in a variety of cancers.
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Furthermore, biomarkers (MET or HER2 expression/KRAS, EGFR, and PIK3CA mutations) were identified in surrogate TEP mRNA profiles, which might be tested in future studies as potential predictors for targeted therapies. Recently, Diem et al. showed that elevated pretreatment platelet-to-lymphocyte ratios correlate with a reduced response rate to nivolumab anti-PD-L1 immunotherapy in NSCLC [100], indicating that circulating platelets may enhance a pro-tumorigenic effect in the presence of an antitumor immune response.
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6. Conclusion
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CTC as liquid biopsy represents a promising approach for personalized treatment in oncology. Lots of efforts have been made to overcome technical challenges for enrichment, detection, and characterization of these tumor cells. Nevertheless, low number (or even absence) of CTCs can weaken the reliability of CTC-based assays in some patients with current detection techniques. This points the need for further technological advances and procedure standardization. To introduce CTC tests into clinical trials, an intense validation of the technical aspects of the applied assays is currently executed in Europe by the EU-funded CANCER-ID network (www.cancer-id.eu) that will be continued by the European Liquid Biopsy Society (ELBS).
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Additionally, an extensive work has been made to understand biological processes of cancer dissemination and metastasis, underlying different aspects for CTCs survival in bloodstream. This knowledge could improve pharmaceutical drug researches and therapeutic strategies for better clinical management of cancer patients.
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Beside CTC analysis several other circulating biomarkers are under investigations and demonstrate real valuable data. It is now well accepted that there is not a perfect unique biomarker and that combining different circulating biomarkers can bring a huge benefit for precision medicine for cancer patients.
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In conclusion, liquid biopsy diagnostics might help to focus the current cancer screening modalities, which would reduce side and healthcare costs. However, despite promising first results and the enormous interest by diagnostic companies and the public press, disease monitoring and early detection of cancer face serious challenges of both sensitivity and specificity.
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Acknowledgments
\n
The authors received support from (1) the National Institute of Cancer (INCa, http://www.e-cancer.fr), (2) CANCER-ID, an Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115749, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) (www.cancer-id.eu) and EFPIA companies’ in-kind contribution, (3) ARC Foundation, (4) Ligue contre le cancer, and (5) the ELBA—Innovative Training Networks (ITN) H2020—European Liquid Biopsies Academy project—Toward widespread clinical application of blood-based diagnostic tools. H2020-MSCA-ITN-2017 (http://elba.uni-plovdiv.bg).
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\n',keywords:"circulating tumor cells, liquid biopsy, clinical relevance, circulating biomarkers, precision medicine",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65567.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65567.xml",downloadPdfUrl:"/chapter/pdf-download/65567",previewPdfUrl:"/chapter/pdf-preview/65567",totalDownloads:686,totalViews:0,totalCrossrefCites:0,dateSubmitted:"August 2nd 2018",dateReviewed:"January 14th 2019",datePrePublished:"May 10th 2019",datePublished:"November 6th 2019",dateFinished:null,readingETA:"0",abstract:"A few years ago, the analysis of circulating tumor cells (CTCs) in the blood of patients with cancer was defined by the term “real-time liquid biopsy.” Blood samples can be obtained and analyzed at the time of diagnosis and repeatedly during the systemic treatment. The analysis of the liquid biopsy has provided new insights into the biology of metastasis with important implications for the clinical management of cancer patients. In this review, we updated all technical strategies developed to improve enrichment, detection, and characterization of CTCs. We also focused on their biological properties as well as on their clinical relevance in different cancer types. At the end, we opened the discussion to all the other circulating biomarkers used as liquid biopsy.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65567",risUrl:"/chapter/ris/65567",signatures:"Laure Cayrefourcq and Catherine Alix-Panabières",book:{id:"8400",title:"Molecular Medicine",subtitle:null,fullTitle:"Molecular Medicine",slug:"molecular-medicine",publishedDate:"November 6th 2019",bookSignature:"Sinem Nalbantoglu and Hakima Amri",coverURL:"https://cdn.intechopen.com/books/images_new/8400.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"147712",title:"Dr.",name:"Sinem",middleName:null,surname:"Nalbantoglu",slug:"sinem-nalbantoglu",fullName:"Sinem Nalbantoglu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"270197",title:"Ph.D. Student",name:"Laure",middleName:null,surname:"Cayrefourcq",fullName:"Laure Cayrefourcq",slug:"laure-cayrefourcq",email:"l-cayrefourcq@chu-montpellier.fr",position:null,institution:null},{id:"270198",title:"Dr.",name:"Catherine",middleName:null,surname:"Alix-Panabières",fullName:"Catherine Alix-Panabières",slug:"catherine-alix-panabieres",email:"c-panabieres@chu-montpellier.fr",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Technical strategies for enrichment, detection, and characterization of CTCs",level:"1"},{id:"sec_2_2",title:"2.1 Strategies for CTC enrichment",level:"2"},{id:"sec_3_2",title:"2.2 Strategies for CTC detection",level:"2"},{id:"sec_4_2",title:"2.3 Strategies for CTC characterization",level:"2"},{id:"sec_6",title:"3. Biology of CTCs",level:"1"},{id:"sec_6_2",title:"3.1 Epithelial to mesenchymal plasticity",level:"2"},{id:"sec_7_2",title:"3.2 Anoikis resistance",level:"2"},{id:"sec_8_2",title:"3.3 Escape to the immune system",level:"2"},{id:"sec_9_2",title:"3.4 CTC microemboli",level:"2"},{id:"sec_11",title:"4. Clinical relevance of CTCs",level:"1"},{id:"sec_11_2",title:"4.1 Breast",level:"2"},{id:"sec_12_2",title:"4.2 Prostate",level:"2"},{id:"sec_13_2",title:"4.3 Colon",level:"2"},{id:"sec_14_2",title:"4.4 Lung",level:"2"},{id:"sec_16",title:"5. Other circulating biomarkers as liquid biopsy",level:"1"},{id:"sec_16_2",title:"5.1 Circulating tumor DNA",level:"2"},{id:"sec_17_2",title:"5.2 MicroRNAs",level:"2"},{id:"sec_18_2",title:"5.3 Exosomes",level:"2"},{id:"sec_19_2",title:"5.4 Tumor-educated platelets",level:"2"},{id:"sec_21",title:"6. Conclusion",level:"1"},{id:"sec_22",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Pantel K, Alix-Panabieres C. Circulating tumour cells in cancer patients: Challenges and perspectives. Trends in Molecular Medicine. 2010;16(9):398-406\n'},{id:"B2",body:'Cohen SJ et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2008;26(19):3213-3221\n'},{id:"B3",body:'Cristofanilli M et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. 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Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. JNCI Journal of the National Cancer Institute. 2014;106(5):dju066\n'},{id:"B69",body:'Bidard FC et al. Circulating tumor cells in breast cancer patients treated by neoadjuvant chemotherapy: A meta-analysis. Journal of the National Cancer Institute. 2018;110(6):560-567\n'},{id:"B70",body:'Trapp E et al. Presence of circulating tumor cells in high-risk early breast cancer during follow-up and prognosis. Journal of the National Cancer Institute. 11 Oct 2018. DOI: 10.1093/jnci/djy152. [Epub ahead of print]\n'},{id:"B71",body:'Scher HI et al. Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer. Journal of Clinical Oncology. 2015;33(12):1348-1355\n'},{id:"B72",body:'Scher HI et al. Circulating tumor cell number as a prognostic marker in progressive castration-resistant prostate cancer: Use in clinical practice and clinical trials. The Lancet Oncology. 2009;10(3):233-239\n'},{id:"B73",body:'Scher HI et al. Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: A reanalysis of IMMC38 trial data. The Lancet Oncology. 2009;10(3):233-239\n'},{id:"B74",body:'Lorente D et al. Interrogating metastatic prostate cancer treatment switch decisions: A multi-institutional survey. European Urology Focus. 2018;4(2):235-244\n'},{id:"B75",body:'Kuske A et al. Improved detection of circulating tumor cells in non-metastatic high-risk prostate cancer patients. Scientific Reports. 2016;6:39736\n'},{id:"B76",body:'Groot Koerkamp B et al. Circulating tumor cells and prognosis of patients with Resectable colorectal liver metastases or widespread metastatic colorectal cancer: A meta-analysis. Annals of Surgical Oncology. 2013;20(7):2156-2165\n'},{id:"B77",body:'Huang X et al. Meta-analysis of the prognostic value of circulating tumor cells detected with the CellSearch System in colorectal cancer. BMC Cancer. 2015;15:202\n'},{id:"B78",body:'Rahbari NN et al. Meta-analysis shows that detection of circulating tumor cells indicates poor prognosis in patients with colorectal cancer. Gastroenterology. 2010;138(5):1714-1726\n'},{id:"B79",body:'Krebs MG et al. Circulating tumor cell enumeration in a phase II trial of a four-drug regimen in advanced colorectal cancer. Clinical Colorectal Cancer. 2015;14(2):115-122.e1-2\n'},{id:"B80",body:'Lalmahomed ZS et al. Prognostic value of circulating tumour cells for early recurrence after resection of colorectal liver metastases. British Journal of Cancer. 2015;112(3):556-561\n'},{id:"B81",body:'Hirose T et al. 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The New England Journal of Medicine. 2008;359(4):366-377\n'},{id:"B86",body:'Gorges TM et al. Enumeration and molecular characterization of tumor cells in lung cancer patients using a novel in vivo device for capturing circulating tumor cells. Clinical Cancer Research. 2016;22(9):2197-2206\n'},{id:"B87",body:'Leon SA et al. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Research. 1977;37(3):646-650\n'},{id:"B88",body:'Pantel K, Alix-Panabières C. Real-time liquid biopsy in cancer patients: Fact or fiction? Cancer Research. 2013;73(21):6384-6388\n'},{id:"B89",body:'Heitzer E, Ulz P, Geigl JB. Circulating tumor DNA as a liquid biopsy for cancer. Clinical Chemistry. 2015;61(1):112-123\n'},{id:"B90",body:'Douillard JY et al. Gefitinib treatment in EGFR mutated Caucasian NSCLC: Circulating-free tumor DNA as a surrogate for determination of EGFR status. Journal of Thoracic Oncology. 2014;9(9):1345-1353\n'},{id:"B91",body:'Webb S. The cancer bloodhounds. Nature Biotechnology. 2016;34(11):1090-1094\n'},{id:"B92",body:'Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nature Reviews. Genetics. 2009;10(10):704-714\n'},{id:"B93",body:'Armand-Labit V, Pradines A. Circulating cell-free microRNAs as clinical cancer biomarkers. Biomolecular Concepts. 2017;8(2):61-81\n'},{id:"B94",body:'Kalluri R. The biology and function of exosomes in cancer. The Journal of Clinical Investigation. 2016;126(4):1208-1215\n'},{id:"B95",body:'Greening DW et al. A protocol for exosome isolation and characterization: Evaluation of ultracentrifugation, density-gradient separation, and immunoaffinity capture methods. Methods in Molecular Biology. 2015;1295:179-209\n'},{id:"B96",body:'Hoshino A et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527(7578):329-335\n'},{id:"B97",body:'Peinado H et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature Medicine. 2012;18(6):883-891\n'},{id:"B98",body:'Best MG et al. RNA-Seq of tumor-educated platelets enables blood-based Pan-cancer, multiclass, and molecular pathway cancer diagnostics. Cancer Cell. 2015;28(5):666-676\n'},{id:"B99",body:'Stone RL et al. Paraneoplastic thrombocytosis in ovarian cancer. The New England Journal of Medicine. 2012;366(7):610-618\n'},{id:"B100",body:'Diem S et al. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung Cancer. 2017;111:176-181\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Laure Cayrefourcq",address:"l-cayrefourcq@chu-montpellier.fr",affiliation:'
Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre of Montpellier, Montpellier, France
Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre of Montpellier, Montpellier, France
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