\\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\\nSeeing 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\\nOver 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\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
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\nDr. 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\nSeeing 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\nOver 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\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
\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:"709",leadTitle:null,fullTitle:"Inflammatory Bowel Disease - Advances in Pathogenesis and Management",title:"Inflammatory Bowel Disease",subtitle:"Advances in Pathogenesis and Management",reviewType:"peer-reviewed",abstract:"This book is dedicated to inflammatory bowel disease, and the authors discuss the advances in the pathogenesis of inflammatory bowel disease, as well as several new parameters involved in the etiopathogeny of Crohn's disease and ulcerative colitis, such as intestinal barrier dysfunction and the roles of TH 17 cells and IL 17 in the immune response in inflammatory bowel disease. 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\r\n\tIn the last years, blockchain and distributed ledger technologies (DLTs) have evolved significantly with the objective of providing secure communications, data privacy, cyber-attack resilience and easy deployment/maintenance in multiple fields. Such an evolution, together with the advances in smart contracts, can play a relevant role in the future of decentralized applications. Moreover, Artificial Intelligence (AI) and its different sub-disciplines (e.g., Machine Learning, Deep Learning, Bayesian networks) can enhance blockchains and DLTs in order to provide advanced features like autonomous decision-support systems or intelligent blockchain-enabled services. Furthermore, AI-based applications can benefit from blockchains and DLTs thanks to their ability to allow for accessing trustworthy shared data in insecure environments like the Internet. In this complex scenario, this book looks for shedding light on the potential of the joint use of blockchain and AI, both from a theoretical and a practical point of view, in order to guide the next generation of researchers and developers of AI-enabled blockchain/DLT-based applications.
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Fernández-Caramés works since 2016 as an Assistant Professor in the area of Electronic Technology at the University of A Coruña (UDC) (Spain), he has contributed to more than 40 papers for conferences, to 40 articles for JCR-indexed journals, and to two book chapters, within his current research fields.",coeditorOneBiosketch:"Dr. Fraga-Lamas has over 60 contributions in indexed international journals, conferences, and book chapters, and 4 patents, she has also been participating in over 30 research projects funded by the regional and national government as well as R&D contracts with private companies.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"186818",title:"Dr.",name:"Tiago M.",middleName:null,surname:"Fernández-Caramés",slug:"tiago-m.-fernandez-carames",fullName:"Tiago M. Fernández-Caramés",profilePictureURL:"https://mts.intechopen.com/storage/users/186818/images/system/186818.jpg",biography:"Tiago M. Fernández-Caramés (Senior Member, IEEE) has\nworked since 2016 as an Assistant Professor in the area of\nElectronic Technology at the University of A Coruña (UDC)\n(Spain), where he obtained his MSc degree and PhD degrees in\nComputer Science in 2005 and 2011. Since 2005 he has worked\nin the Department of Computer Engineering at UDC: from 2005\nto 2009 through different predoctoral scholarships and between\n2007 and 2016 as Interim Professor. His current research interests include IoT/IIoT\nsystems, RFID, wireless sensor networks, augmented reality, embedded systems\nand blockchain, as well as the different technologies involved in the Industry 4.0\nparadigm. In such fields, he has contributed to 40 papers for conferences, to 35\narticles for JCR-indexed journals and to two book chapters. Due to his expertise in\nthe previously mentioned fields, he has acted as peer-reviewer and guest editor for\ndifferent top-rank journals, and as project reviewer for national research bodies\nfrom Austria, Croatia, Latvia and Argentina.",institutionString:"University of A Coruña",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of A Coruña",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:{id:"193724",title:"Dr.",name:"Paula",middleName:null,surname:"Fraga-Lamas",slug:"paula-fraga-lamas",fullName:"Paula Fraga-Lamas",profilePictureURL:"https://mts.intechopen.com/storage/users/193724/images/system/193724.jpg",biography:"Paula Fraga-Lamas (Senior Member, IEEE) received her MSc\ndegree in computer engineering from the University of A\nCoruña (UDC) in 2009, and her MSc and PhD degrees in the\njoint program Mobile Network Information and Communication\nTechnologies from five Spanish universities: University of the\nBasque Country, University of Cantabria, University of Zaragoza, University of Oviedo, and University of A Coruña, in 2011\nand 2017, respectively. She holds an MBA and postgraduate studies in business\ninnovation management (Jean Monnet Chair in European Industrial Economics,\nUDC), Corporate Social Responsibility (CSR) and social innovation (Inditex-UDC\nChair of Sustainability). Since 2009, she has been with the Group of Electronic \nTechnology and Communications (GTEC), Department of Computer Engineering\n(UDC). She has over 70 contributions in indexed international journals, conferences and book chapters, and holds four patents. Her current research interests\ninclude Internet of Things (IoT), cyber-physical systems (CPS), augmented/mixed\nreality (AR/MR), fog and edge computing, blockchain and distributed ledger\ntechnology (DLT), cybersecurity, as well as the different technologies involved\nin mission-critical scenarios under the Industry 4.0 paradigm. She has also been\nparticipating in over 30 research projects funded by regional and national government as well as research and development contracts with private companies. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Engineered nanomaterials (ENMs) already became part of our daily life as food packaging agents, drug delivery systems, therapeutics, biosensors, etc. In 2011, according to the Woodrow Wilson Nanotechnology Consumer Products Inventory, Ag nanoparticles (Ag-NPs) were the most commonly consumed ENMs, followed by TiO2, SiO2, ZnO, Au, Pt, etc (http://www.nanotechproject.org). By the most recent definition of European Parliament and Council [1] ‘nanomaterial’ (NM) is any material that is characterized to have at least one dimension ≤ 100 nm, or that comprises of separate functional parts either internal or on the surface, which have one or more dimensions ≤ 100 nm, including structures, e.g. agglomerates or aggregates, which may be larger than 100 nm, but which retain the typical properties of nanoscale.
In many countries ENMs are already used as food supplements and in food packaging: (i) nanoclays as diffusion barriers [2]; (ii) Ag-NPs as antimicrobial agent [3,4]; (iii) silicates and aluminosilicates (E554, E556, E559) as anti-caking and anti-clumping agents and in toothpastes, cheeses, sugars, powdered milks, etc [5]; (iv) TiO2 (E171) for whitening and brightening, e.g. in sauces and dressings, in certain powdered foods [6], etc. According to FAO/WHO report [7] the ENMs have several current or projected applications in the agrofood sector: nanostructured food ingredients; nanodelivery systems; organic and inorganic nanosized additives; nanocoatings on food contact surfaces; surface functionnalized NMs; nanofiltration; nanosized agrochemicals; nanosensors; water decontamination, …
With an increasing number of ENMs present in consumer and industrial products, the risk of human exposure increases and this may become a threat to human health and the environment [8]. Individual ENMs may lead to one or more endpoints, which are not unique to NMs, but which need to be taken into account, e.g. cytotoxicity, stimulation of an inflammatory response, generation of reactive oxygen species (ROS) and/or genotoxicity. Although the exact mechanism underlying NPs toxicity is yet to be elucidated, studies have suggested that oxidative stress and lipid peroxidation regulate the NP-induced DNA damage, cell membrane disruption and cell death [9-12]. It has been suggested that ROS, in turn, modulate intracellular calcium concentrations, activate transcription factors, induce cytokine production [13], as well as lead to increased inflammation [14,15]. Small sized metallic NPs, e.g. Ag-NPs, TiO2, Co-NPs may also cause DNA damage [16-20]. In vitro studies with different types of NPs (metal/metal oxide, TiO2, carbon nanotubes, silica) on various cell lines have demonstrated oxidative stress-related inflammatory reactions. It is believed that this response is largely driven by the specific surface area of the NPs and/or their chemical composition [21-25]. Typically, the biological activity of particles increases with the particle size decrease [26-29]. Moreover, depending on their chemistry, NPs show different cellular uptake, subcellular localization and ability to induce the ROS production [30]. On the contrary, there are also cases reported of NPs having anti-inflammatory properties, such as certain Ce oxide [31] and Ag-NPs [32]. Nanocrystalline Ag has been demonstrated to have antimicrobial and anti-inflammatory properties and was found to reduce colonic inflammation following oral administration in a rat model of ulcerative colitis, suggesting that nano-silver may have therapeutic potential for treatment of this condition [32].
To sum up, based on the information currently available, no generic assumptions can be made regarding the toxicity upon exposure to NMs, their endpoints and the implications of different organs and tissues.
The gastrointestinal tract (GIT) is a complex barrier-exchange system and is one of the most important routes for macromolecules to enter the body, as well as a key actor of the immune system. The epithelium of the small and large intestines is in close contact with ingested materials, which are absorbed by the villi. To date, studies on exposure, absorption and bioavailability are mainly focused on the inhalation and dermal routes, and little is known about the toxicokinetic and toxicodynamic processes following oral exposure, particularly in relation to ingestion of ENMs that are present in food.
ENMs can reach the GIT either after mucociliary clearance from the respiratory tract after being inhaled [33], or can be ingested directly in food, water, drugs, drug delivery devices, etc [8,34]. The dietary consumption of NPs in developed countries is estimated around 1012 particles/person per day, consisting mainly of TiO2 and mixed silicates [35]. It has been shown that several characteristics, such as (i) the particle size [36], (ii) surface charge [37], (iii) attachment of ligands [38,39], (iv) coating with surfactants [40], as well as (v) the administration time and dose [41] affect the fate and extent of ENMs absorption in GIT. The published literature on the safety of oral exposure to food-related ENMs currently provides insufficient reliable data to allow a clear safety assessment of ENMs [42] that is connected primarily with inadequate characterization of ENMs [43]. For instance, it has been demonstrated that smaller particles cross the colonic mucus layer faster than larger ones [37]. The NPs kinetics in the GIT also depends strongly on their charge, i.e. positively charged latex particles remain trapped in the negatively charged mucus, while negatively charged ones diffuse across the mucus layer and their interaction with epithelial cells becomes possible [41].
NPs that pass the mucus barrier may be translocated through the intestinal epithelium, which will depend not only on physicochemical characteristics of NPs [36-41], but also on the physiological state of the GIT [44]. The translocation of NPs potentially used as food components through the GIТ remains to be explored [45]. Much of the current knowledge concerning the potential toxicity of NPs has been gained from in vitro or in silico test systems. Following ingestion, translocation of particles across the GIT can occur via different pathways:
Endocytosis through ‘regular’ epithelial cells (NPs < 50 - 100 nm) [46].
Transcytosis via microfold (M) cell uptake at the surface of intestinal lymphoid tissue (NPs of 20 - 100 nm and small microparticles i.e. 100 - 500 nm) [47]. M cells are specialized phagocytic enterocytes that are localized in intestinal lymphatic tissue – Peyer’s Patches (PP). This transcytotic pathway occurs via vesicle formation at the apical (i.e. luminal) cell membrane that engulfs some extracellular material, which then moves across the cell, escaping therefore to fusion with lysosomes, fuses with the basolateral membrane (i.e. serosal) and releases the material at the opposite side of the intestinal barrier. The mechanism is size-dependent - the smaller the particle, the easier is the passage through the epithelium [48-50].
Persorption, where ‘old’ enterocytes are extruded from the villus into the gut lumen, leaving ‘holes’ in the epithelium, which allow translocation of even large particles, such as starch and pollen [51-53].
Another possible route by which NPs can gain access to the gastrointestinal tissue is the paracellular route across tight junctions (TJs) of the epithelial cell layer. TJs are remarkably efficient at preventing paracellular permeation, although their integrity can be affected by diseases, e.g. inflammation, and/or by metabolites (e.g. glucose), calcium chelators (e.g. citrate) [54] and even particle endocytosis [55].
All above-mentioned routes could be involved in NPs translocation. There are a number of published reports stating the involvement of different types of endocytosis in the process of NPs internalization: clathrin-mediated pathway, caveolin-mediated endocytosis and macropinocytosis for TiO2 [56], size-dependent endocytosis for Au-NPs [57]; endocytotic pathways were described for SiO2 [58,59] and Ag-NPs [60], etc.
Several studies demonstrated that the phenomenon of persorption is also true for NPs, e.g. in the case of colloidal Au-NPs [36]. Small and large NPs gain potentially access to this route, nevertheless its quantitative relevance remains low, as it seems to be very inefficient compared to the active uptake of particles by M-cells. For instance, it was indicated that one lymphoid follicle dome of the rabbit PP could transport about 105 microparticles of 460 nm diameter in 45 min [61]. It could be assumed that for smaller particles this would be even more efficient.
Particulate uptake may occur not only via the M-cells of the lymphoid follicle-associated epithelium (FAE) in PP [49,62], but also via the normal intestinal enterocytes [46]. A number of reports on intestinal uptake of micro- and nanoparticles state that the uptake of inert particles occurs trans-cellularly through normal enterocytes and via M-cells [61,63-65], as well as, to a lesser extent, through paracellular pathway [66].
There are several recognized parameters currently used for in vitro cytotoxicity assessment of ENMs, such as cell viability, stress and inflammatory responses, genotoxicity, etc [67]. However, it should be noted that due to specific physicochemical properties of ENMs, currently existing in vitro toxicity assays may have limited use and the methods should be carefully designed in order to discard the influence of nano-sized materials on the assay itself [28]. The risk assessment is further impaired by the lack of standardized test systems that fulfil these criteria. According to the new European Chemicals Legislation (REACH), new test systems for toxicity screening of ENMs should be developed, e.g. cell culture systems that will better reflect in vivo toxicity parameters [68].
Human colon adenocarcinoma (Caco-2) cells reproducibly display a number of properties characteristic to differentiated enterocytes and are the most popular cell culture system for studying intestinal passage and transport [69,70]. Cultured Caco-2 cells differentiate spontaneously into polarized monolayers [71] that possess an apical brush border and express functional TJs, biotransformation enzymes and efflux pumps [72]. Caco-2 cells grow as a monolayer and fully differentiate also on semi-permeable membranes of bicameral inserts. This permits to separate the apical (AP) compartment from the basolateral (BL) one, reflecting the intestinal lumen and the serosal side, respectively [65]. Transport of molecules and ions from the AP to the BL side and vice versa requires the passage either through the cells (transcellular route) or between the cells through TJs (paracellular route).
The gut lining epithelium is for the most part impermeable to microorganisms and microparticles, except for the lymphoid FAE found in PP [49,73,74]. M cells are responsible for transport of antigens, bacteria, viruses, as well as micro- and NPs to the antigen presenting cells within and under the epithelial barrier as the first step in developing immune responses [75]. There is only an incomplete and inadequate understanding of the development and function of FAE, as well as of the genes and proteins responsible for their specialized functions. One potential approach to study such complex and specialized tissues is to use cell culture systems more precisely reproducing the features of the in vivo tissue. Kernéis et al. [76] demonstrated that co-culturing of Caco-2 cells with murine PP lymphocytes appears to convert Caco-2 cells into M-like cells, including enhanced transport of particles across the epithelium monolayer. The induction of this phenotype did not require direct cell contact, as it was also achieved via physically separated co-culturing of Caco-2 and human Burkitt\'s lymphoma (Raji B) cells in bicameral culture inserts [77]. Although it is not clear whether this model faithfully reproduces all of the features of in vivo M cell function, nevertheless studies have confirmed that Caco-2 cells co-cultivated with Raji B cells in vitro express several genes specifically expressed in FAE in vivo [78].
In an improved in vitro co-culture model in bicameral system Caco-2 cells were exposed to lymphocytes from the BL chamber. In a so-called ‘inverted’ model (Figure 1) the lymphocytes were shown to migrate into the monolayer and induce the conversion of the enterocyte phenotype into the M-cells one [76,79]. Recently, des Rieux et al. [65] characterized the inverted model and compared it with previously developed one [77]. According to these results, in the inverted model, the M cell conversion rate was estimated to range between 15 - 30% (for comparison it was <10% in the human FAE [80]). The comparison of the in vitro models revealed that the inverted model appears to be physiologically and functionally more reproducible and efficient than the normally oriented one [65]. Thus this improved model could be used to better characterize and understand the biological effects, absorption and transportation mechanisms of NPs in intestinal cells.
Co-culture model of Caco-2 and Raji B cells [63].
During their differentiation epithelial cells develop junctional structures between the neighboring cells and form a tight protective barrier that restricts the absorption to some nutrients and substances while, in the meantime, provides a physical barrier impairing the permeation of pro-inflammatory molecules, e.g. pathogens, toxins, antigens and xenobiotics from the luminal environment into the mucosal tissues and circulatory system. This barrier comprises several structures [81], where the TJs are the most apical components of the junctional complex and are the main gatekeepers of the epithelial paracellular passage. TJ barrier disruption and increased paracellular permeability, followed by permeation of luminal pro-inflammatory molecules can activate the mucosal immune system, resulting in chronic inflammation and tissue damage [75]. Intestinal TJ barrier is evidenced to have a critical role in the pathogenesis of intestinal and systemic diseases [82-84]. Under physio-pathological conditions, pro-inflammatory cytokines, antigens and pathogens contribute to barrier impairment [85,86]. Considering the TJs integrity impairments under inflamed conditions, it could be assumed that NPs that lead to stress and/or inflammatory responses could also influence the TJs integrity.
Several methodological approaches allow measuring the barrier function in cell cultures, e.g. the evaluation of the transepithelial electrical resistance (TEER) and the passage of marker molecules, such as Lucifer Yellow (LY) [87]. Our results revealed that under the influence of Ag-NPs < 20 nm, а disruption of the barrier integrity occurs. In figure 2A the TEER values of both mono- and co-cultures of Caco-2 cells after 3h of incubation with different concentrations of Ag-NPs are shown. TEER values decreased as Ag-NPs concentration increased, even though the reduction was less obvious in co-culture conditions – a model that is closer to the physiological conditions of FAE.
TEER values (A) and LY passage (B) of mono- and co-cultures of Caco-2 cells upon incubation with Ag-NPs (NM-300K, JRC repository, Ispra, IT) at 15 – 90 µg/ml. Experiments were conducted on mono- and co-cultures (i.e. Caco-2 cells with Raji B lymphocytes) cultivated for 21 days in polycarbonate bicameral inserts with 3 µm pore size (TranswellTM, Corning Costar, NY) to reach a full differentiation and, for co-cultures, partial conversion into M like cells. TEER values were measured via Millicell-ERS volt-ohm meter (World Precision Instruments, Sarasota, FL) at the beginning and after 3h incubation period with Ag-NPs. The transport of LY was observed during 3h period with a 30 min sampling time from the BL compartment. Both the changes in TEER values (P<0.0001) and the LY passage (P<0.003) were calculated as a percentage from the initial value. Data represent the means ± SEM of 4 independent experiments. *Samples significantly different from the control (results were considered significant at P<0,05).
The passage of LY was evaluated by the amount of LY that passed from AP to BL compartment (Figure 2B). The presence of Ag-NPs increased the level of LY in the BL compartment that was dependent on the NP concentration. These results are in correlation with the NP-induced reduction of TEER values. Interestingly, in contrast to TEER results, the co-cultures had more elevated rate of LY passage than the corresponding mono-cultures.
To have an idea about the molecular mechanisms of the Ag-NPs-induced barrier integrity disruption, an immunostaining with confocal microscopy analysis of two TJs proteins occludin and ZO-1 was realized. As illustrated on Figure 3, in Ag-NP-treated cells the continuity of both occludin and ZO-1 was disrupted with the control comparison and the aggregation of both proteins was observed. It should further be noted that mono-cultures were more susceptible to the influence of Ag-NPs than co-cultures and the alterations in proteins distributions were more visible in mono-cultures. The immunostaining results in turn confirmed the TEER data, where a more obvious reduction was estimated in the case of mono-cultures (Figure 2).
Subcellular localization of the occludin and ZO-1 TJs scaffolding proteins. Mono- and co-cultures of Caco-2 cells grown on bicameral inserts were treated with Ag-NPs (45 µg/ml) for 3h and then processed for immunostaining (B and D). Untreated cells were used as controls (A and C). In order to visualize the occludin and ZO-1 mouse anti-Occludin and mouse anti-ZO-1 (both from Invitrogen) were used as primary antibodies, as well as Alexa Fluor 488 goat anti-mouse (Invitrogen) as the secondary antibody. Images were collected by confocal laser scanning microscope; scale bars are 15 and 25 µm for occludin and ZO-1 staining, respectively.
The observed changes were reversible at low Ag-NPs concentrations (up to 30 µg/ml): the TEER values and TJs proteins distributions were recovered until the control level. Other NPs were also reported to possess the ability to open the TJs. For instance, the chitosan NPs were capable to open transiently and reversibly the epithelial TJs [88].
In contrast to Ag-NPs, we observed no change neither in TEER value and LY passage rate, nor TJs proteins distributions upon incubation of cell mono- and co-cultures with amorphous SiO2 < 25 nm (NM-200, JRC repository, Ispra, IT) (results not shown). These findings provide additional evidence that the major input in the NPs-mediated barrier integrity disruption seems to belong to the charge of the NPs. Particularly, it has been previously reported that neutral and low concentrations of anionic NPs have no effect on blood-brain barrier integrity, in contrast to anionic NPs at high concentrations and cationic NPs [89]. A number of recent in vitro and in vivo studies highlight the importance of NPs surface charge for cellular uptake and biodistribution [90-92], indicating that for the majority of NPs the positive surface charge enhances cellular internalization [92-94]. The latter is likely linked to the adsorption of different bio-molecules at the surface of NPs, dependent on surface charge, as well as on chemical characteristics of NPs [95].
Another underlying condition in the TJs disruption is likely to be the cellular oxidative stress possibly induced by NPs [96]. Our results have shown that the fluorescence intensity of an oxidative stress indicator dichlorofluorescein was increased upon exposure of cells to Ag-NPs within a 3h time period (Figure 4). The ROS generation induction was dependent on NPs concentration reaching from about 1,5 to 3-fold increase, as compared with the untreated cells. Thus one mechanism of toxicity of Ag-NPs could likely be mediated by oxidative stress, already reported to be involved in the modulation of TJs integrity [97].
Effect of Ag-NPs (5 – 90 µg/ml) on intracellular ROS generation in Caco-2 cells. The ROS generation was investigated using the dichlorofluorescein (DCFH) assay. After being oxidized by intracellular oxidants, DCFH becomes DCF and emits fluorescence, quantification of which is a reliable estimation of overall oxygen species generation. The intracellular ROS level is presented as a percentage of the corresponding initial value after incubation together with NPs during 3h at 370C. Data represent means ± SEM of 3 experiments with 3 different samples per condition, P<0.0001.
Altogether, the results reveal that some NPs, e.g. chitosan or Ag-NPs may enhance the epithelial barrier permeability and could therefore serve as an effective carrier for oral drug delivery [44]. However, it should be noted that the epithelial permeability increase in turn might favor the systemic absorption of ENMs, toxins and other xenobiotics, and would likely cause immune activation.
It has been reported that the exposure to some NPs is associated with the occurrence of autoimmune diseases, such as systemic lupus erythematosus, scleroderma, and rheumatoid arthritis [35]. Diseases, such as diabetes, may also lead to an increased absorption of particles in the GIT [41]. Furthermore, inflammation may lead to the uptake and translocation of particles of up to 20 nm [98]. Thus, an issue to be considered in relation to ENMs ingestion is a possible increase in their intestinal absorption in the case of systemic exposures, such as in Inflammatory Bowel Disease (IBD) and/or Crohn\'s disease (CD), which represent chronic disorders characterized by recurrent and serious inflammation of the GIT [99]. Crohn’s disease affects primarily people in developed countries, where the highest incidence rates and prevalence for CD and ulcerative colitis (UC) have been reported from northern Europe, the United Kingdom and North America [100] with a frequency of 1 in 1,000 people in the Western world [5]. However, reports of increasing incidence and prevalence from other areas of the world, e.g. southern or central Europe, Asia, Africa, and Latin America state the progressive nature and worldwide rise of these diseases [100].
An abnormal intestinal barrier function plays a pivotal role in IBD [101]. Increased intestinal permeability has been reproducibly described in patients with CD, which is likely a predisposing factor to the pathogenesis and impaired epithelial resistance [102,103]. A barrier dysfunction has been reported in the colonic mucosa of patients with Irritable Bowel Syndrome (IBS), which results from increased paracellular permeability, presumably by an altered expression of ZO-1 [104]. Moreover, stress is believed to contribute to induction of IBS and recurrence of intestinal inflammation and can increase the paracellular permeability [105]. It should be noted that mediators of inflammation, such as ROS, endotoxins (lipopolysaccharides) and cytokines are able to provoke the disruption of TJs and thereby increase the paracellular permeability [97]. Significant changes in epithelial TJs structure and function were also observed in UC [106,107]. Thus the altered intestinal permeability could certainly be a result of disease progression, but there is evidence that it might also be the primary causative event.
Recently it was suggested that there could be an association between high levels of dietary NPs uptake and CD. Experimental results indicate that the accumulation of insoluble NPs in humans may be responsible for the compromised gastrointestinal functioning, as described in the case of CD and UC [5]. Microscopy studies have also shown that macrophages located in lymphoid tissue can uptake NPs, e.g. spherical anatase (TiO2) with size of 100-200 nm from food additives, aluminosilicates of 100-400 nm typical of natural clay, and environmental silicates of 100-700 nm [108]. According to another study, some insoluble NPs, such as TiO2, ZnO and SiO2, upon their absorption and passage across the GIT, come into contact with and adsorb calcium ions and lipopolysaccharides. The resulting NPs–calcium–lipopolysaccharide conjugates activate both peripheral blood mononuclear cells and intestinal phagocytes, which are usually resistant to stimulation [109].
Despite the insufficiency of data linking the NPs consumption to the initiation of CD and UC, it seems that particles of 0.1 – 1.0 µm may be adjuvant triggers for the exacerbation of these diseases [110]. Micro and NPs have been constantly found in organs, e.g. in colon tissue and blood of patients affected by cancer, CD, and UC, while in healthy subjects NPs were absent [111]. Some evidence suggests that dietary NPs may exacerbate inflammation in CD [6]. More precisely, some members of the population may have a genetic predisposition where they are more affected by the intake of NPs, and therefore develop CD [9]. It has been also reported that micro- and NPs in colon tissues may lead to cancer and CD progression [111]. By contrast, a diet low in calcium and exogenous micro- and NPs has been shown to alleviate the symptoms of CD [5]. This analysis is still controversial, with some proposing that an abnormal response to dietary NPs may be the cause of this disease, and not an excess intake [6].
Although there is a clear association between particle exposure/uptake and CD, little is known of the exact role of the phagocytosing cells in the intestinal epithelium and particularly of the pathophysiological role of M cells. It has been shown that M cells are lost from the epithelium in the case of CD. Other studies found that endocytotic capacity of M cells is induced under various immunological conditions, e.g. a greater uptake of particles of 0.1 – 10 µm has been demonstrated in the inflamed colonic mucosa of rats compared to non-ulcerated tissue [109,112].
Thus more vulnerable members of the population, i.e. those with pre-existing digestive disorders, may potentially be more affected by the presence of ENMs, although, in contrast, ENMs may offer many potential routes to therapies for the same diseases. The diseases associated with gastrointestinal uptake of NPs, such as CD and UC have no cure and often require surgical intervention. Treatments are aimed at maintaining the disease in remission and mainly consist of anti-inflammatory drugs and specially formulated liquid meals [5]. If dietary NPs are conclusively shown to cause these chronic diseases, their use in food should be avoided or strictly regulated.
The absorption, distribution, metabolism and excretion (ADME) parameters are likely to be influenced by the aggregation, agglomeration, dispersability, size, solubility, and surface area, charge and physico-chemistry of NPs [113]. Amongst these parameters the size, chemical composition and surface treatment appear to be the most critical ones for nanotoxicity issues [114]. Chemical composition, beside the chemical nature of the NP itself, also includes the surface coating of the NPs [115]. Coatings can be used to stabilize the NPs in solution, to prevent clustering or to add functionality to the NPs, depending on its intended use. Surface coatings can influence the reactivity of the NPs in various media, including water, biological fluids and laboratory test media [116,117]. From this point of view the interaction of NPs with food components is another aspect that may need consideration and about which little information is currently available. The possible interaction of food components may alter the physicochemical properties of ENMs that in turn may influence their passage through the GIT and their ADME properties.
ENMs, with their very large surface areas, may adsorb bio-molecules on their surface upon contact with food and/or biological fluids to form a bio-molecular “corona” [96,118]. Depending on the nature of the corona, the behavior of the NPs may differ, and there could be the potential for novel toxicities non-characteristic neither for the non-coated NPs, nor for the adsorbed biological material. These bio-molecules include proteins, lipids, sugars, different secondary metabolites and it is those interactions that may actually determine how ENMs will interact with living systems. Thus, the foregoing information on the food should be considered carefully, taking into account its major ingredients or components, which have physiological properties likely to influence the absorption/translocation of ENMs in the GIT.
Several studies have demonstrated that various food components provide beneficial anti-inflammatory and anti-mutagenic effects in the GIT. Although the information regarding these effects on intestinal TJ barrier integrity is limited, some results are available e.g. for glutamine [119,120] and fatty acids [121-123]. A growing number of data suggest the potential protective effect of phenolic compounds on the epithelial barrier function and their anti-inflammatory properties [124,125]. In particular, certain flavonoids that represent a part of human daily nutrition, e.g. epigallocatechin gallate, genistein, myricetin, quercetin and kaempferol are reported to exhibit promotive and protective effects on intestinal TJ barrier [124,126].
We have observed (unshown results) that quercetin attenuates the cytotoxic effect of Ag-NPs on Caco-2 cells, as well as allows recovering of the epithelial barrier function, which was evidenced by the recovery up to the initial value of the TEER and the LY passage rate in both mono- and co-cultures. The immunostaining analysis of occludin and ZO-1 also revealed the recovery of the protein distributions in the presence of quercetin, which additionally suggests the protective effect of the latter upon the harmful effects of Ag-NPs. In a similar study it was reported that positively charged Ni-NPs can efficiently enhance the permeation and uptake of quercetin into cancer cells, which can have important biomedical and chemotherapeutic applications [127].
A number of published reports indicate the potential application of antioxidants [10,128-130] and anti-inflammatory drugs [6,131] that are able to treat the adverse health effects caused by NPs. For instance, berberine, an alkaloid with a potential biomedical application, has been shown to attenuate TJ barrier defects induced by TNF-α, known to disrupt TJ integrity in IBD [132]. It has been reported that rats that underwent instillation of NPs into the lungs together with an antioxidant, i.e. nacystelin, showed an inflammation decrease up to 60% in comparison to those exposed to NPs alone [10].
To have an idea about the state of Ag-NPs in the presence of quercetin, NPs were characterized by transmission electron microscopy (TEM) (Figure 5). It could be seen that in the presence of quercetin a “capping” of Ag-NPs occurs, which confirms already existing data on Ag-NPs stabilization with reducing agents. Surface-active molecules, such as terpenoids and/or reducing sugars are believed to stabilize the NPs in the solutions, i.e. they are believed to react with the silver ions (Ag+) and stabilize the Ag-NPs [133,134]. Flavonoids have been suggested to be responsible for the reduction of Ag+ to Ag-NPs [135]. Fatty acids such as stearic, palmitic and lauric acids are used as agents for the formation and stabilization of Ag-NPs [136].
TEM analysis of Ag-NPs < 20 nm (NM-300K) alone (A) and in the presence of quercetin (B). The average size of Ag-NPs was about 20 nm, scale bar: 100 nm. NPs were characterized by transmission electron miscroscopy (TEM) (Technai Spirit TEM, FEI Company, Eindhoven, NL) by Dr. J. Mast at the Electron Microscopy Unit of the Veterinary and Agrochemical Research Centre VAR-CODA-CERVA, Uccle, BE.
Another major phenolic compound present in human diet is resveratrol, which possesses many beneficial health effects [137-141]. Considering abundance and health-promoting effects of resveratrol, we have also investigated its potential protective activity against the Ag-NP-induced cytotoxicity. The results indicated no protective effect of resveratrol and moreover, at a concentration of 100 μM, non-toxic by itself, it increased the toxic effect of Ag-NPs, illustrating a synergistic effect.
To conclude, it could be assumed that phenolic compounds, depending on the nature and concentration, may exhibit different effects on cells in the presence on NPs. This is not surprising, as it is known that these substances, depending on concentration, may exhibit both beneficial and toxic effects [141].
Nanotechnology offers a wide range of opportunities for the development of innovative products and applications in agriculture, food production, processing, preservation and packaging. However, the present state of knowledge still contains many gaps preventing risk assessors from establishing the safety for many of the possible food related applications of nanotechnology [142]. Currently the routine assessment of ENMs in situ in the food or feed matrix is not possible, as well as equally impossible to determine physicochemical state of ENMs, which increases the uncertainty in the exposure assessment. Complex matrices present in the food complicate the detection and characterization of ENMs in final food/feed products, which itself contain a wide range of natural structures in the nano-size scale. The information on the potential of ENMs to cross the epithelial barriers, such as the GIT, blood-brain, placenta and blood-milk barriers are also important for hazard identification. It is also clear that the evaluation of the pro-inflammatory potential of ENMs is another issue of current importance, as the inflammation itself is associated with a number of high frequency diseases, e.g. cancer, diabetes, bowel diseases, etc.
From the above discussion and the research presented in this review, the need for more toxicology research on manufactured ENMs is clear. In addition to standard tests, there is a need to develop appropriate and rapid screening methods to be able to control the exposure level, as well as improved models that will permit to assess the toxicity and allow better understanding of the mechanisms that are involved. Employment of developed and well characterized in vitro cell culture systems may be relevant for evaluation of gut and immune responses to ENMs and to adapt conditions to specific health conditions or to consumer groups with special needs, such as in the case of bowel diseases. Further studies are necessary to assess whether the characteristic daily intake of ENMs may exacerbate or trigger disease symptoms in subjects with increased susceptibility, such as inflamed state of the GIT in the case of IBD, CD, UC, or even be its cause.
Another aspect deserving thorough investigation is the possible interaction of ENMs with food/feed components, which in turn could influence the overall behavior and effect of not only ENMs, but also the bioavailability of food components.
Authors thank to Dr. Jan Mast, head of the Electron Microscopy Unit in VAR-CODA-CER VA, Uccle, Belgium for scientific and technical support in the realization of Transmission Electron Microscopy analysis, as well as to the Biological Imaging Platform (IMAB) of the Université Catholique de Louvain (Louvain-la-Neuve, Belgium) for the realization of the confocal microscopy. This study was funded by the Belgian Federal Public Service and Belgian Federal Science Policy (BELSPO).
Primary bone tumors are rare in occurrence accounting for approximately 0.2% of all the tumors. Generally, primary tumors are localized, intra-compartmental, or extended, extra-compartmental [1]. Most benign tumors that have not spread to lymph nodes or other organs remain asymptomatic until their presence is indicated by a trivial insult [1, 2]. Therefore, it becomes important to categorize bone lesions in the early stages of their development for prognosis and diagnosis [2]. On the other hand, skeletal metastases are frequent in patients with breast, prostate, and lung cancer and also occur in other tumors such as myeloma, thyroid and renal cancer, lymphoma, and Ewing’s sarcoma [3]. The bone becomes the most common site of metastases in humans due to its highly vascular nature, and this results in pain, pathologic fracture, and decreased quality of life [3].
Bone metastases are either osteolytic or osteoblastic, depending on the dominance of osteoclastic activity or osteoblasts, respectively [3]. As a result the radiological appearance of bone metastasis is lytic, sclerotic, or mixed [4]. General pathogenesis of bone tumors sequentially involves proliferation of primary neoplasm, local tissue invasion, intravasation into blood vessels, extravasation into bone marrow, tumor cell dormancy, proliferation in bone, and modification of bone microenvironment [3]. The site of metastases is governed by the “seed and soil” hypothesis by Paget which states that neoplastic cells grow or proliferate only in a suitable environment [3]. Tumor cells therefore migrate to the heavily vascularized areas of the skeleton, particularly the red bone marrow of the axial skeleton and the proximal ends of the long bones, the ribs, and the vertebral column [5]. Chemotactic factors such as CXCL10 (CXC motif ligand [CXCL]), CXCL12, and osteopontin have been reported to play a major role in tumor migration [6].
Tumors can be classified into low-grade (Grade I), intermediate-grade (Grade II), and high-grade (Grade III) tumors [1]. Grading of bone tumors is roughly based on the cellularity of the lesions compared to the extracellular matrix, nuclear features, the presence of mitotic figures, and necrosis [7]. Grade II tumors are more cellular, with a greater degree of nuclear atypia, hyperchromasia, and nuclear size. Grade III tumors have significant areas of marked pleomorphism, large cells with more hyperchromatic nuclei than Grade II tumors, occasional giant cells, and abundant necrosis [1]. High-grade bone tumors are the fastest growing and most aggressive group of classic osteoblastic subtype. On the basis of histological appearance, bone tumors are classified as parosteal and periosteal. Parosteal tumors belong to low-grade subtype of osteosarcoma, whereas periosteal belongs to the intermediate-grade subtype. Parosteal tumors have fibroblast appearance and are limited to bone surface, but periosteal tumors appear chondroblastic upon histology.
This tumor accounts for 5% of all primary and 20% of the benign skeletal tumors [8]. GCT is an aggressive osteolytic benign bone tumor developing in the long bones, which is characterized by giant, multinucleated osteoclast-like cells, recruited by stromal cells such as osteoblasts [8, 9]. The stromal cells of GCT highly express parathyroid hormone-related peptide (PTHrP) and thus increase the bone tumor cell local invasiveness and migration [9].
Distal femur, proximal tibia, and distal radius are the most common locations for the occurrence of GCT, but due to its association with Paget’s disease, it may also occur in the skull, pelvis, facial bones, and spine. It has been reported to rarely affect greater trochanter of the femur. Though some of the reports claim an equal rate of occurrence in both the genders, some reports show an increased prevalence in females [8].
These tumors have been associated with reduction in length of telomeres [7]. Radiological examination in patients with closed physes displays lytic lesions with well-defined, non-sclerotic margins that are eccentric in location and extend near the articular surface. Thus GCT involves cortical expansion or destruction [8].
Chondrosarcomas majorly involve tumorous growth of chondrocytes, which are mostly found in bones that elongate due to endochondral ossification and involve differentiation in the epiphyseal growth plates of long bones. For example, hypertrophic chondrocytes are found in clear cell chondrosarcoma. The most common sites include proximal femur, proximal humerus, distal femur, and ribs. Sex hormones such as estrogen play a major role in governing the nuclear signaling pathways involved in this process of ossification [1].
There are different histologic variants of chondrosarcoma.
Mesenchymal chondrosarcomas are highly aggressive tumors, composed of resting chondrocytes, and are radiographically and histologically similar to Ewing’s sarcoma [1, 10]. Such sarcomas frequently occur in the pelvic bones, femur, and humerus and less commonly in the head, spine, breast, and prostate [1]. These have high risk of local recurrence and distant metastasis [10].
Dedifferentiated chondrosarcomas are aggressive neoplasms and have poor prognosis [10].
Clear cell chondrosarcomas are low-grade tumors and involve the epiphyseal end of the long bone. The radiographs show a lytic defect at the epiphyseal end of long bones, sharply demarcated with sclerotic margins [10].
Extraskeletal myxoid chondrosarcomas are slow-growing tumors, characterized histologically by prominent myxoid degeneration, and are considered as differentiated tumors [10].
Juxtacortical chondrosarcoma arises on the surface of the bone and is histologically identical to conventional intramedullary chondrosarcoma [1].
Ewing’s sarcoma is an exception to all the bone tumors, because bone tumors are mostly mesenchymal in origin, but Ewing’s sarcoma is reported to have neuroectodermal precursor cells [7]. It has been found to be associated with neuroblastomas in patients younger than 5 years, whereas in patients above 30 years, it is associated with small round cell tumors (e.g., small-cell carcinoma) and large-cell lymphoma [1]. Ewing’s sarcoma is most likely to occur in younger individuals and most commonly in males [11].
Ewing’s sarcoma is characterized by small round cell bone tumor and involves pain at the site of tumor and soft tissue swelling around it [1]. Unlike other primary tumors of the bone, Ewing’s sarcoma is associated with a characteristic translocation in the 11th and 22nd chromosomes. This translocation results in production of an aberrant transcription factor EWS/FLI1 that forms a complex with RNA helicase A and drives the pathogenesis of Ewing’s sarcoma [7, 11]. Its metastasis involves certain non-specific signs of inflammation, anorexia, fever, malaise, fatigue, and weight loss [1].
Osteosarcoma is an osteoid-producing malignancy of mesenchymal origin [12]. It is the third most frequent type of cancer in adolescence and represents more than 56% of all bone tumors [13]. It is the most common bone sarcoma and affects 60% of the patients below 25 years of age and 30% of the patients above 40 years [14, 15]. It is associated with extensive genomic disruptions and propensity of metastatic spread. Seventy-six percent of the osteosarcomas have been found to be associated with reduced expression of HACE1 gene localized to human chromosome 6q21, thus resulting in poor survival [14]. Approximately, 30–40% children with pediatric osteosarcoma die due to metastasis to lungs [1, 16].
Environmental factors such as exposure to radiation, teriparatide (parathyroid hormone 1–34) usage, and consumption of fluorinated drinking water during childhood increase the risk of osteosarcoma [12]. Its localization in regions that are largely cut off from the vasculature reduces the effectiveness of systemically administered chemotherapeutics [17]. The subtypes of osteosarcoma include osteoblastic, chondroblastic, fibroblastic, small cell, telangiectatic, high-grade surface, extraskeletal, and other lower-grade forms of tumors including parosteal and periosteal [12].
Osteosarcomas are one of the widely studied sarcomas of the skeletal system. Several investigations have reported the association of germline mutation disorders such as hereditary retinoblastoma, Rothmund-Thomson syndrome, Li-Fraumeni syndrome, and Bloom syndrome, with increased risk of osteosarcoma [12]. Various other pathways discussed below have been reported to be responsible for supporting growth and metastasis of osteosarcoma.
Constitutively active signal transducers and activators of transcription 3 (STAT3) signaling have been found to be necessary for osteosarcoma survival and migration in vitro and tumor growth in vivo. STAT3 is a proto-oncogene that stimulates self-proliferation (due to expression of cyclin D1), mediates immune evasion, promotes angiogenesis, and confers apoptosis resistance (induced by conventional therapies, due to expression of BCL2) [18]. Similarly an upregulation in the expression of survivin (an oncogenic protein) has also been observed in osteosarcoma (Figure 1) [19].
Attenuation of cell cycle arrest by p53 has been found to affect the upstream p53 signaling pathways [20]. Approximately 26.5% of non-hereditary osteosarcomas have been reported to be associated with somatic loss of p53, out of which 60% are high-grade osteosarcomas, whereas 1% are low-grade osteosarcomas [14]. Tumor suppressor genes such as p15 and p27 have been commonly found to be silenced due to methylation of promoter by DNA methyl transferase that adds methyl group to the fifth carbon position of cytosine ring in CpG islands, leading to heterochromatin and inhibition of gene expression (Figure 1) [21].
Sex steroid hormones have been found to play an important role in development and progression of bone tumors. Previous investigations have revealed the role of aromatase and sulfatase pathways in the in situ formation of active estrogen. Aromatase pathway involves aromatization of androgens to produce estrogen. In sulfatase pathway, estrone 3-sulfate is taken up by the cells and is activated by the removal of sulfate by steroid sulfatase, thus converting inactive estrogen to unconjugated and bioactive estrogen. Both these pathways allow generation of estrogen and androgen by the bone cells in the bone microenvironment (Figure 2) [24].
Growth factors such as transforming growth factor (TGF)-β, insulin-like growth factors (IGFs), bone morphogenetic proteins (BMPs), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) released from degraded bone matrices also promote tumor cell proliferation by production of PTHrP that interacts with parathyroid hormone (PTH)/PTHrP receptors in the bone and kidney to cause hypercalcemia, osteoclast-mediated bone resorption, increased nephrogenous cyclic AMP, and phosphate excretion [4, 5, 6, 25]. PTH is known to regulate osteosarcoma cells, by inducing transcription of c-Fos that in turn targets calcium/cAMP-response element (CRE) through activation of protein kinase A (PKA) [26]. c-Fos is a member of activator protein-1 (AP-1) family of transcription factors containing c-Fos (FosB, Fra-1, Fra-2) (Figure 1) [27].
Additionally, FGF also regulates multiple signaling cascades in both autocrine and paracrine manner [4]. FGF receptor 1 was identified as a c-Fos-regulated gene playing an important role in lung metastases of osteosarcoma. The FGF receptors 1–4 belong to a family of receptor tyrosine kinase (RTK) that triggers intracellular signaling cascades through mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), STAT pathways, and signal transducers phospholipase Cγ (PLCγ) and casitas B-lineage lymphoma (CBL) (Figure 1) [27].
Majority of the osteosarcomas develop as a result of metastases of breast, prostate, or lung tumors into the bone. Breast cancer cells metastasize to the bone and secrete various factors in the bone microenvironment that enhance osteoclastogenesis and inhibit osteoblastogenesis, thus developing several skeletal-related events (SREs) such as pathological fracture, spinal cord compression, bone pain, and hypercalcemia [28]. Similarly, androgen signaling components such as androgen receptor, ARV7, v-ets avian erythroblastosis virus E26 oncogene homolog (ERG), cytochrome P450, and family 17 subfamily A polypeptide 1 (CYP17) and molecules such as phospho-Met, phospho-Src, glucocorticoid receptor, and Ki67 have been implicated to play a major role in the metastasis of castration-resistant prostate cancer (CRPC) [29].
Some of the reports associate migration and invasion of breast cancer cells to the upregulation of micro RNAs, miR-10b, miR-373, and miR-520c. Out of these, miR-373 and miR-520c have been found to silence CD44 gene that codes for hyaluronan receptor (plays an important in cellular adhesion). Similarly, miR-218 that is involved in osteoblast differentiation promotes breast cancer cell osteomimicry (ability to acquire bone cell phenotype for immune escape). miR-154 and miR-379 overexpression in bone metastatic cells was associated with mesenchymal properties and enhanced invasive potential [30].
Cross talk of various signaling pathways in osteosarcoma. (i) JAK–STAT pathway confers apoptosis resistance, thus enhancing tumor cell survival. (ii) Inactivation of p53 favors cell cycle progression in cells with DNA damage and promotes tumorigenesis. (iii) Cross talk between GPCR-regulated PTHrP signaling and RTK-mediated survival/growth factors. (iv) Role of RTK in supporting tumor cell survival and proliferation as a response to various growth factors. (v) Wnt signaling mechanism plays a major role in tumors associated with bone tissue.
(A) Percentage of primary bone cancers in adult human population [22]. (B) Osteosarcoma cases per 100,000 population per year [23]. (C) Percentage of males and females diagnosed with primary bone tumor in the United States in the year 2017 [22].
General pathogenesis of bone tumors sequentially involves proliferation of primary neoplasm, local tissue invasion, intravasation into blood vessels, extravasation into bone marrow, tumor cell dormancy, proliferation in the bone, and modification of bone microenvironment. The site of metastases is governed by the “seed and soil” hypothesis by Paget which states that neoplastic cells grow or proliferate only in a suitable environment [3].
The initial step in metastasis involves escape of cancer cells from primary tumor into the systemic circulation, through epithelial–mesenchymal transition (EMT). EMT involves loss of cell surface intercellular adhesion proteins and epithelial polarization. EMT is followed by dissolution of the extracellular matrix by secreting certain proteolytic enzymes and migration into surrounding tissue to enter systemic circulation through intravasation. Such circulating tumor cells (CTCs) escape anoikis (cell apoptosis due to loss of cell-matrix or cell-cell interactions, preferably through overexpression of tyrosine kinase receptor, TrkB) resulting in activation of PI3K-AKT pro-survival pathways. These tumor cells also upregulate certain proteins on their surface (e.g., CD47) to escape destruction by macrophages [4]. The two major factors that govern the localization of CTCs are blood flow and molecular signaling. For example, the metastasis of breast cancer to thoracic spine is due to the venous drainage of the breast to thoracic region, whereas lung cancer shows general skeletal distribution due to the drainage of pulmonary veins into the left side of the heart, followed by eventual entry into systemic circulation. Alternatively, prostate cancer majorly displays metastasis to the axial skeletal in the lumbar spine, sacrum, and pelvis due to their drainage through pelvic plexus. As far as the signaling pathways are concerned, CXCL12-CXCR4 (CXC motif ligand [CXCL], CXC chemokine receptor [CXCR]) axis has been found to regulate CTC homing to the bone. CXCL12, also called as stromal cell-derived factor 1 (SDF1), is a chemokine factor secreted by bone marrow MSCs, endothelial cells, and osteoblast and primarily binds to G protein-coupled receptor, CXCR4, thus activating cell survival, chemotaxis, and expression of integrin αvβ3 on the surface of CTCs [4]. Another receptor involved in osteotropism is the calcium-sensing receptor (CaSR), expressed by advanced primary breast tumors that causes enhanced calcium-induced migration to the bone [30]. In addition to CXCL12-CXCR4 axis, non-receptor cytoplasmic tyrosine kinase, Src, has also been shown to mediate improved survival of breast cancer cells in the bone marrow by increasing the resistance to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and activation of AKT signaling [4].
After tumor cells colonize the bone, they induce the expression of receptor activator of nuclear factor-κB ligand (RANKL) via production of PTHrP, prostaglandin E2 (PGE2), interleukin 6 (IL-6), IL-1β, TNF, and epidermal growth factor (EGF), which promote osteoclast differentiation and activation. RANKL induces osteoclastic bone resorption resulting in growth of osteolytic tumor that causes hypercalcemia, and it also acts as a chemoattractant to the bone for tumor cells [6]. In relation to this, hypoxia-inducible factor (HIF)-1α has been reported to act as an upstream master switch to many of the osteolytic factors such as IL-11 and IL-8 and angiogenic factors such as PDGF and vascular endothelial growth factor (VEGF) [4, 31]. TGF-β plays a central role in the pathogenesis of osteolytic bone metastasis from breast carcinoma via potentiation of estrogen receptor (ER)-α-mediated transcription induced by constitutively active ERα [25]. A higher expression of ERα in the cortical bone suggests its role in bone formation, whereas trabecular bone cells show a higher expression of ERβ [32].
Osteolytic bone metastases are most often caused by breast cancer and multiple myeloma [6, 33], whereas osteoblastic metastases are mostly observed in bone metastasis of prostate cancer, which is due to osteoblast stimulation by cancer cells [6, 34]. Factors that are locally produced by cancer cells, such as bone BMP, IGF, FGF, TGF-β, and endothelin-1, also promote osteoblast proliferation and bone formation [6].
Another important cellular component of bone microenvironment that is involved in tumor metastases is osteocytes. Osteocytes present in the bone regulate osteoclast development through expression of RANKL, macrophage colony-stimulating factor (M-CSF), and osteoprotegerin (OPG) and inhibit osteoblast differentiation by the expression of sclerostin. Osteocytes have an interesting ability to respond to mechanical stress and pressure. An increase in pressure due to prostate cancer metastasis thus results in upregulation of matrix metalloproteinases (MMPs) and chemokine (C-C motif) ligand 5 (CCL-5). Additionally, apoptotic osteocytes have been shown to release IL-11 that enhances osteoclast differentiation. Endothelial cells are yet another important component of the bone marrow that contributes to the bone metastatic process. Endothelial cells in the metaphysis of the long bone aid CTC adhesion due to constitutive expression of P-selectin, E-selectin, vascular cell adhesion molecule 1 (VCAM1), and intercellular adhesion molecule A (ICAM-1). Decrease in shear forces due to reduced blood flow velocity in the large volume of sinusoids also favors CTC attachment [4].
The bone marrow is also a major reservoir for dendritic cells, macrophages, myeloid-derived cells, and different subsets of T cells. T and B cells are known to produce RANKL and impact osteoclastogenesis, whereas production of IL-6, IL-23, and IL-1 by dendritic cells in the bone microenvironment of multiple myeloma patients causes an increase in Th17 cells that in turn increase IL-17. IL-17 is an important cytokine that promotes osteoclast and myeloma proliferation and also mediates interactions between T cells and bone metastatic environment. Additionally, myeloid-derived suppressor cells from the bone marrow suppress innate and adaptive immune responses by impairing T-cell antigen recognition and promotion of regulatory T cells [4].
However, as an individual ages, the hematopoietic red bone marrow gets converted to adipose tissue-rich yellow bone marrow that has a significant impact on the development of bone metastasis. These bone marrow adipocytes not only serve as an energy source but also secrete several pro-inflammatory mediators such as IL-1β, IL-6, leptin, adiponectin, VCAM-1, TNF-α, and CXCL12 that increase cancer cell survival and proliferation [4].
Histological examination of tissue biopsy has been the most commonly used procedure for the diagnosis of bone tumors. Clinical and radiological observations also aid in diagnosis and provide a complete staging of bone cancers. But molecular and genetic markers increase the accuracy of diagnosis, assist in subtyping bone tumors, and also provide an overview of target molecules for designing therapeutic approaches. The biomarkers can be specific or non-specific; diagnostic, prognostic, or therapeutic; and serological, genetic, or histological. The clinical presentation of bone tumors is non-specific, and the most common symptoms include pain and swelling. The clinical features involve limited movement, skin hyperthermia, weight loss, and the presence of a visible mass in the anatomical profile [10].
The serological markers are generally a reflection of osteoblastic and osteoclastic activities in the bone [10]. As mentioned in the earlier sections, breast cancer metastases are mostly osteolytic, whereas metastases of prostate cancer are generally osteoblastic. Therefore, elevated levels of urinary N-terminal cross-linked telopeptide (NTx of type I collagen) and serum carboxyterminal cross-linked telopeptide (ICTP of type I collagen) in solid tumor patients and serum tartrate-resistant acid phosphatase type 5b (TRAcP-5b) in patients with breast tumor metastasis can be used for diagnosis. On the other hand, serum levels of bone-specific alkaline phosphatase (BSAP), procollagen type I N-terminal propeptide (PINP), and OPG serve as the biomarkers for prostate cancer metastasis [10, 30].
With reference to the genetic changes, sarcomas can be divided into three categories: sarcomas with specific translocations (e.g., Ewing’s sarcoma, aneurysmal bone cyst), tumors with gene mutations or amplifications (e.g., chondrosarcomas, fibrous dysplasia), and sarcomas with genetic instability. These cytogenetic changes can be detected using banding and multicolor fluorescence in situ hybridization (FISH), array comparative genomic hybridization (array CGH), targeted detection techniques such as qPCR, and techniques to detect mutation [10].
There are several markers that are used for prognosis or diagnosis of different types of tumors that are discussed below:
Degradation of collagen and the ground substance in the bone (due to prolonged exposure to fluoride) results in increased concentration of serum sialic acid that can be used as a serum biomarker for osteosarcoma [10].
Expression of heat shock protein (HSP gp96), in the cytoplasm of osteoblastic sarcoma, has been found to be associated with pathogenesis of bone tumors. But it does not provide any idea regarding the degree of malignancy [10].
The osteosarcoma patients displayed increased levels of endostatin, placental growth factor (PlGF), and FGF-1 and FGF-2 in serum [10].
Gas chromatography–mass spectrometry profiles of small-molecule metabolites in urine and serum samples of osteosarcoma patients displayed a disrupted energy metabolism, downregulated amino acid metabolism, and increase in glutathione metabolism and polyamine metabolism [10].
qPCR and western blot analysis for detection of IGF-1 receptor showed its increased expression in osteosarcoma tissues, suggesting it as a prognostic marker. Western blotting and enzyme-linked immunosorbent assay (ELISA) confirmed a decrease in serum levels of gelsolin in the osteosarcoma samples [10].
The presence of FGF-2 or leukemia inhibitory factor (Lif) serves as a biomarker, suggesting reduction of osteogenesis on osteosarcoma cells. Elevated serum levels of CXCL4 and CXCL in osteosarcoma patients affirmed the role of these markers in clinical manifestation. In addition to this, biomarker Snail2 is also useful in prognosis of bone tumors [10].
Metastatic prostate cancers have been found to express the well-known markers of aggressiveness, namely, prostatic-specific antigen (PSA) [30].
Increase in erythrocyte sedimentation rate (ESR), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) are indicators of osteosarcoma [1, 12].
Immunohistochemistry of primary osteosarcomas showed expression of mitotic arrest defective protein 2 (MAD2). Immunohistochemical analysis of osteosarcoma biopsies indicated reduced expression of cysteine-rich protein with Kazal motifs (RECK). Immunohistochemistry analysis also showed expression of WNT-5a and ROR2 in patients with advanced stages of osteosarcoma [10].
Assessment of CCN3 expression levels at diagnosis may represent a useful molecular tool for early identification of patients with osteosarcoma. Gene alteration of c-kit protein also serves as a prognostic marker for osteosarcoma. The transcriptional regulator, Oct-4, has been found to play a marked role in proliferation and spread of cancer. A reduced expression and inactivation of miR-34 gene have been reported to be associated with osteosarcomas. The action of miR-34 is p53 dependent. A dominant polymorphic variant of TGFβ receptor 1 (TGFBR1), TGFBR1*6A, is found to be associated with increased susceptibility of osteosarcoma for metastasis. Bcl-xL, a member of Bcl-2 (B-cell lymphoma (BCL)) protein family, has been investigated to function as a dominant regulator of apoptotic cell death and plays an important role in malignant transformation. Cytotoxic T-lymphocyte antigen-4 (CTLA-4), a molecule that decreases immune response mediated by T cells, promotes development of osteosarcoma. Overexpressions of Cortactin (CTTN) gene, present in 11q13 amplicon, serve as a valid biomarker for osteosarcoma [10].
Ewing’s sarcomas are associated with rearrangement of the EWS gene on chromosome 22q12 with an erythroblast transformation-specific (ETS) gene family member, resulting in formation of EWS-ETS fusion protein (EWS-FLI). FLI1 has been suggested as a useful marker particularly when hematolymphoid markers are negative. This translocation defines Ewing’s sarcoma family of tumors (ESFT) and provides a major tool for their accurate diagnosis. The translocation results in different types of genetic abnormalities, e.g., five forms of EWSR1-FLI1, three forms of EWSR1-ERG, and one form of EWSR1-FEV. A high expression of BMI-1 in ESFT cells was found to significantly affect survival and proliferation. Expression of CXCR4 has been reported to increase the risk of tumor metastases, whereas CXCR7 expression is associated with shorter survival [10].
Ewing’s sarcoma has been reported to be associated with modulation of RANKL by VEGF-165, thus resulting in activation of osteoclast-mediated bone destruction [10].
On the basis of histological observations, chondrosarcomas are classified into three categories:
Grade I (low grade)—cytology similar to enchondroma and hyperchromatic plump nuclei of uniform size [10].
Grade II (intermediate grade)—increased cellularity, hyperchromasia, distinct nucleoli, and foci of myxoid alteration [10].
Grade III (high grade)—increased cellularity and nuclear atypia, occasional giant cells, abundant necrosis, and presence of mitosis [10].
Deletions in the loci of CDKN2A, EXT1, and EXT2 genes, p53 mutation as late event in tumor progression, and amplification of 12q13 and loss of 9p21 are genetic aberrations found in conventional chondrosarcomas [10].
Higher expression of PTHR1 and Bcl-2 was found to be associated with increasing histological grade in chondrosarcoma, suggesting its involvement in tumor progression. A higher expression of Aurora kinases A and B was relevant as prognosis marker for chondrosarcoma. Somatic heterozygous isocitrate dehydrogenase 1 (IDH1) hot spots (R132C and R132H) or IDH2 (R172S) mutations are specifically found in cartilaginous tumors [10].
qPCR analysis showed a high expression of COX-2 protein in solitary peripheral chondrosarcoma. Some of the studies reported a significant role of nitrotyrosine, COX-2, CD34, and lymphatic marker podoplanin with histological grades of chondrosarcoma. Molecules such as integrin-linked kinase α and β-parvin and Mig-2 allow attachment of cells to matrix and govern cell motility and growth, thus playing an important role in progression and prognosis of chondrosarcomas [10].
Significantly high serum levels of receptor activator of nuclear factor-κB (RANK), OPG, IL-8, IL-6, and OPG/soluble RANKL ratio have been used to detect bone tumors. Osteosarcoma patients display a higher serum concentration of IL-16 as compared to chondrosarcoma patients [35].
Radiographic diagnosis: Plain radiographs, computed tomography (CT) scans, and magnetic resonance imaging (MRI) are used to investigate the extent of tumors and to study the surrounding structure such as blood vessels, nerves, and soft tissues [1, 12].
Positron emission tomography (PET)-CT: [F-18]-Fluorodeoxy-D-glucose (FDG)-PET is a noninvasive imaging tool used for accurate discrimination between responding and nonresponding osseous tumors [1, 12].
Bone scintigraphy: This method involves total body scan and identifies axial and appendicular skeletal metastasis. It helps in determining intraosseous extension of tumors and sites of metastasis [1, 12].
Thallium scintigraphy: This method is used for determining tumor response to neoadjuvant (preoperative) chemotherapy when MRI is not helpful and also for detection of local recurrence [1].
Incisional or core needle biopsy is the final step in the diagnostic process. The tumor is staged using the Musculoskeletal Tumor Society staging scheme or the American Joint Commission on Cancer (AJCC) system [12].
Increased uptake of technetium diphosphonate in the clinical bone scans of osteolytic lesions in cancer patients also provides a diagnostic tool to identify increased cellular activity and metastasis [36].
Bone scans, X-rays, and histologic evaluation of autopsy specimens are commonly used for radiologic and histologic assessment of tumor sites [5].
Osteosarcoma is typically treated with surgery and adjuvant chemotherapy that usually includes a combination of methotrexate, doxorubicin, and cisplatin [37]. Once the cancer has spread to the bones, it can rarely be cured, but often it can be treated to slow down its growth [38]. The therapeutic strategies for bone tumors should involve the following:
Treatment of cancer cells: This involves inhibition of tumor cell proliferation or killing of cancer cells to extend the patient’s survival time. This could be achieved by usage of cytotoxic drugs, hormonal deprivation, or inhibition of specific signaling pathways by targeted agents [4].
Disruption of the vicious cycle created due to complex biological signaling between cancer cells and bone resident cells [4].
Palliative therapies to reduce the extremely debilitating and painful symptom of bone metastasis and improve the quality of life for cancer patients [4].
As discussed in the previous sections, various signaling pathway are involved in the proliferation and migration of tumor cells. Targeting these signaling pathways by use of different inhibitors could hamper the survival of tumor cells. However, it has already been known that the sex hormones play a major role in tumor cell survival and metastases. Thus, hormone therapy for curing tumors would basically involve hormone deprivation approaches. These strategies might inhibit the action of hormones responsible to bone metastases, resulting in osteolytic or osteoblastic tumors.
Ubiquitous and extensive expression of androgen receptor in the bone marrow of both males and females of all ages provides a direct evidence of action of androgen on the bone marrow and offers clues to clinicopathological correlates [39]. Most prostate cancers and their stages depend upon androgen and androgen receptor (AR) for their growth and survival. Androgen receptor is a transcription factor that regulates the expression of several genes in response to binding of androgen (such as testosterone and dihydrotestosterone) and thus regulates the process of proliferation and survival. As mentioned earlier, bone metastasis of prostate cancers majorly results in osteoblastic bone tumors [40]. Therefore, systemic treatment for advanced prostate cancer involves androgen deprivation therapy (ADT) that includes the following approaches:
To reduce the levels of circulating androgen by surgical or chemical castration. Surgical castration results in reduction of circulating androgen levels by >90% within 24 hours, whereas chemical castration is achieved by application of analogs of luteinizing hormone-releasing hormone (LH-RH) and results in reduction of circulating levels of testosterone [40].
LH-RH is a neurohormone, secreted by the hypothalamus, and regulates the secretion of gonadotropin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) from the pituitary. LH-RH acts via binding to its receptor, LH-RHR. These receptors have also been found in the cytoplasm of many tumor cells that involve both reproductive and nonreproductive tissues. LH-RH agonists and antagonists have been found to downregulate these receptors and thus inhibit tumor growth [41]. Leuprolide acetate (Lupron, Eligard), goserelin acetate (Zoladex), triptorelin (Trelstar), and histrelin (Vantas) are some of the LH-RH agonists, whereas degarelix is an antagonist [4, 40]. LH-RHR can also be targeted specifically by peptides conjugated to anticancer drugs, thus developing cytotoxic analogs [41]. AN-152, commercially designated as AEZS-108, has been developed by conjugating 14-OH group of doxorubicin (DOX) to epsilon-amino group of D-Lys side chain of carrier peptide, through a glutaric acid spacer. The drug is endocytosed by cells through receptor-mediated endocytosis and thus selectively acts on cells that express its receptor. After internalization the drug is cleaved from the LH-RH moiety and accumulates in the nucleus. Because of receptor-mediated entry, the drug shows lesser side effects and also overcomes the resistance [41].
Administration of LH-RH agonist or antagonist for ADT not only results in suppression of testosterone to castration levels but also depletes estradiol, because it is derived by aromatization of testosterone [42]. Estradiol deficiency negatively impacts the bone health resulting in decline of bone mineral density (BMD) and increased risk of fractures [42]. This decrease in bone density also results in development of renal stones leading to risk of urinary calculi [43]. Recently parenteral (e.g., intravenous, intramuscular, or transdermal) administration of estradiol has been investigated to suppress androgen production through negative feedback loop involving hypothalamic–pituitary axis and avoids fall in endogenous estradiol levels. This also eliminates the risk of embolic cardiovascular toxicity that was caused due to oral administration of estradiol [42].
To prevent binding of androgen to AR, by competitive inhibition using antiandrogens. These molecules compete with androgen for the ligand-binding domain of AR [40]. The antiandrogens can be of two categories, steroidal and nonsteroidal. Cyproterone acetate, a derivative of hydroxyprogesterone, is a steroidal antiandrogen and an antigonadotropin, which has a binding affinity for AR. But it has been found that it is not a pure antagonist but rather a partial agonist that adversely affects the survival of prostate cancer patients when combined with castration [40]. Among the nonsteroidal antiandrogens are the first-generation flutamide, nilutamide, and bicalutamide and second-generation enzalutamide and the cytochrome P450 c17 (CYP17, a critical enzyme in testosterone synthesis) inhibitor, abiraterone acetate, which prevents synthesis of androgens. Abiraterone inhibits 17-α-hydroxylase/17,20 lyase, a testosterone synthesis enzyme found in the adrenals, testis, and tumor [40, 44]. All these nonsteroidal antiandrogens are similar in terms of the chemical structure of their moiety that binds to the ligand-binding pocket [40]. It has been found that treatment with abiraterone acetate plus prednisone prolongs survival among patients with metastatic castration-resistant prostate cancer [44], though back pain, nausea, constipation, bone pain, arthralgia, urinary tract infection, edema, cardiac events, and elevation in levels of aminotransferase are some of the side effects associated with administration of abiraterone [44, 45].
Flutamide was the first nonsteroidal antiandrogen drug approved by the US Food and Drug Administration (FDA) for prostate cancer and forms the basis for all other nonsteroidal antiandrogens. The recommended dose of flutamide is 250 mg three times per day, so as to achieve a Cmax and Cmin of approximately 1.7 and 0.8 μg/ml, respectively. It acts via blocking the binding of androgen to the ligand-binding pocket of AR, resulting in inhibition of nuclear translocation of androgen-bound AR. But improvement in disease upon cessation of flutamide treatment has been observed in patients, due to gain-of-function mutation in the ligand-binding domain of AR, T877A. Flutamide gets eliminated through the kidney, and liver toxicity is one of the common adverse effects [40].
Enzalutamide (previously called MDV3100) also acts via inhibiting the binding of androgen to AR, thus blocking its nuclear translocation and interaction with co-activators [4, 29, 40, 46]. Its recommended dose is 160 mg/day [40, 47]. However, clinical resistance due to gain-of-function mutation in AR ligand-binding domain (F876 L) and constitutive expression of active spice variants of AR that lack ligand-binding domain results in poor survival rates. Apalutamide and darolutamide also belong to the second generation of nonsteroidal antiandrogen that blocks the androgen binding to AR [40].
A novel first class of drug, ralaniten, is currently under clinical trials for patients who have previously received abiraterone, enzalutamide, or both. This class of drug binds to the unique region in the N-terminal domain of both full-length and truncated constitutively active splice variant of AR [40].
ADT that effectively reduces the serum testosterone levels has been a core tool for treating metastatic and advanced prostate cancer [48]. However, neoadjuvant ADT has been suggested to have several advantages in prostate cancer patients undergoing transperineal prostate brachytherapy. The agents that are mainly used as adjuvant ADT include estrogens, antiandrogen monotherapy, and combined androgen blockade (CAB) using antiandrogen plus a gonadotropin-releasing hormone receptor (GnRH) agonist. It has been reported that in comparison to GnRH agonist, degarelix, a GnRH receptor antagonist, is more efficient in achieving castration levels of testosterone and PSA, without risk of testosterone flare [48, 49].
ADT is the mainstay of treatment for advanced prostate cancer, but eventual development of castration-resistant prostate cancer (CRPC) reduces the survival rates. One of the main reasons for development of CRPC is the sustained levels of androgen within the tumor due to suboptimal androgen suppression by primary ADT. Moreover, apart from the hormone-independent subsets, the other subsets of CRPC cells adapt themselves to the low testosterone environment induced by ADT and become hypersensitive to even lower concentrations of testosterone and other androgen precursors. Therefore, secondary hormone therapies are proving to be more efficient to achieve maximum suppression of testosterone. GTx-758 (3-fluoro-N-(4-fluorophenyl)-4-hydroxy-N-(4-hydroxyphenyl) benzamide) is an oral nonsteroidal selective estrogen receptor (ERα) agonist that lowers the free testosterone and PSA levels by increasing sex hormone-binding globulin (SHBG). This also helps to avoid side effects related to estrogen deficiency [50].
Finasteride and dutasteride (5α-reductase enzyme inhibitors) are found to inhibit 5α-reductase-mediated conversion of testosterone to the high affinity androgen receptor ligand, 5α-dihydrotestosterone [51].
Estrogen is chemically related compounds derived from androgen precursors but contain a defining aromatic and hydroxyl group at the 17th position. Estrogens comprise the natural ligands for estrogen receptors (ERs), with 17β-estradiol being a potent agonist. 17β-estradiol has been reported to inhibit metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1)-mediated osteosarcoma migration, invasion, metastasis, and induction of cell apoptosis, in an estrogen receptor α (ERα)-independent manner [15]. Earlier it was thought that binding of ER agonists induces a conformational change in the receptors, conferring the ability for co-activators to bind, whereas ER antagonists were thought to compete for binding [52]. But later studies with tamoxifen revealed that the same molecule can behave as an agonist (tamoxifen acts as an estrogen agonist in the uterus, promoting hypertrophy) as well as an antagonist (tamoxifen exhibited estrogenic activity in the bone, thus protecting against bone loss), depending on the tissue context. Recently it has been found that oxysterols such as 27-hydroxycholesterol (27 HC) also modulate the activity of estrogen receptors (ERs) and are therefore classified as endogenous SERMs. 27 HC is derived from cholesterol in the presence of enzyme CYP27A1 (cytochrome P450 enzyme). Breast cancer is the most common cancer in women, and its metastasis is majorly hormone (estrogen receptor) dependent. Some of the reports emphasize on the role of 27 HC in cancer progression and drug resistance, but several other reports also highlight its beneficial role in inhibiting proliferation and invasion of prostate cancer cells by blocking sterol-regulatory element-binding protein 2 (SREBP2). However, their different affinities for the different subtypes of ERs (α and β) and different relative expressions of these subtypes in tissues may explain some the of SERMs’ pharmacology. Recent evidence also suggests that binding of the receptor even by structurally related compounds could result in unique conformational changes, thus allowing recruitment of distinct sets of co-activators and/or corepressors to the receptor [52].
SERMs such as genistein, daidzein, and 4-hydroxytamoxifen have been reported to downregulate the expression of epidermal growth factor (EGFR) in vitro in osteosarcoma cells in an ER-dependent manner. The reduction in EGFR expression resulted in upregulation of markers for osteoblast differentiation, thus resulting in suppression of tumor cell proliferation [53].
Isoflavones such as genistein and daidzein are abundantly found in soybeans and soy-based food products. Isoflavones, coumestans, and lignans belong to a class of phytoestrogens. Phytoestrogens are plant-derived substances that resemble 17β-estradiol and can bind to activate intracellular estrogen receptors. These dietary phytoestrogens have been reported to exhibit bone-protecting effect without the risk of breast cancer [54].
Genistein has also been demonstrated to elicit different cell responses through different signaling mechanisms. A combination of genistein and 17β-estradiol has been shown to significantly increase apoptosis of breast cancer cells by increasing the BAX/BCL-2 (BCL-2-associated X protein (BAX)) ratio and reducing phosphorylation of extracellular signal-regulated kinase (ERK) ½ and AKT [55].
Osteosarcoma is a malignant tumor in the bone that originates from osteoblasts or osteoblast precursors. The reports clarify that normal osteoblasts express ERα, whereas osteosarcomas do not (due to promoter DNA methylation). Thus a treatment strategy that involves induction of ERα expression in osteosarcoma cells in combination with estrogen administration would reduce proliferation of osteosarcoma and increase cell differentiation. In vitro treatment of osteosarcoma cells with decitabine (DAC, 5-Aza-2′-deoxycytidine) has been found to induce the expression of ERα but reduce the expression of metastasis-associated markers such as vimentin, slug, zeb1, and MMP9, with simultaneous decrease in stem cell markers such as SOX2, OCT4, and NANOG. Subsequent treatment with 17β-estradiol synergized with DAC in reducing cell proliferation and inducing differentiation markers such as alkaline phosphatase, osterix, and bone sialoproteins [21].
The bone is the frequent site for metastasis of breast cancer. Estrogen plays a critical role in development and progression of breast cancer by interacting with ERα and ERβ. In postmenopausal women, estrogens (estrone and estradiol) are synthesized from androgens (androstenedione and testosterone) at extragonadal sites, including the breast. Thus the third generation of therapy involves inhibition of these aromatase enzymes, catalyzing the conversion of androgens to estrogens [56]. The aromatase inhibitors fall into two categories: steroidal and nonsteroidal. Letrozole and anastrozole are the third-generation nonsteroidal aromatase inhibitors that block the extragonadal conversion of androgens to estrogens and give rise to an estrogen-depleted environment [51, 56, 57]. This lowers the estrogen in breast tissues and reduces their metastasis to the bone [56]. But in patients with hormone receptor-positive breast cancer, both the disease and its therapeutic treatment with antiestrogenic agents negatively impact the bone and result in decrease in bone mineral density. Therefore anti-hormonal therapy is considered only in cases where cancer cells express the ERα [58]. However, unlike nonsteroidal aromatase inhibitors, a steroidal aromatase inhibitor, e.g., exemestane (probably due to its steroid structure), has been reported to exert beneficial effects on the bone through its primary metabolite 17-hydroexemestane [51, 57].
Fulvestrant, an alkylosulfonian derivative of estradiol, is another category of estrogen inhibitors (estrogen receptor antagonist), which competitively binds to ER with high affinity and downregulates expression of ERβ by functional blockade [59, 60]. Fulvestrant has been reported to induce mitochondrial depolarization at high concentrations that results in release of apoptogenic factors, loss of oxidative phosphorylation, and eventually cell death due to apoptosis [60].
2-Methoxyestradiol (2-ME) belongs to another class of anticancer drugs, which act via induction of neuronal nitric oxide synthase and generation of nitric oxide in the nuclei of cancer cells. However, recently 2-ME has been found to activate epigenetically silenced ERβ, resulting in apoptosis of malignant cancer cells [60].
Furthermore, some of the recent reports emphasize the role of mutant ERα gene (ESR1) in cancer progression and drug resistance. These mutations have been observed to get accumulated in circulating DNA of bone metastasis patients [32].
Zoledronic acid is a known anti-resorptive agent and exhibits antitumor effects in ER-ve breast cancers. Some of the recent studies emphasize that it’s the menopausal status (and not the hormone receptor status) that determines its anticancer efficiency [61]. This differential effect of zoledronic acid in pre- and postmenopausal bone metastasis patients has been suggested to be regulated by bone turnover effect of estrogen. Estrogen inhibits osteoclastogenesis via its direct effect on osteoclast and their precursors. Similarly, zoledronic acid also exhibits pro-apoptotic effects on osteoclasts by inhibiting mevalonate pathway and thus prevents release of growth factors that stimulate tumor growth. But in contrast to estrogen, zoledronic acid also reduces the number and activity of osteoblasts. Therefore, replacement of estrogen with zoledronic acid could be a more effective antitumor therapy in a low-estrogen bone microenvironment. Though administration of zoledronic acid does not alter growth of ER+ve cells at the primary site of tumor, it hampers their dissemination in the bone. As the cells evade the bone microenvironment, zoledronic acid-mediated bone turnover inhibits their proliferation and prevents overt metastases. Thus zoledronic acid could inhibit bone metastases of both ER-ve and ER+ve breast cancer cells [61].
One of the study reports dealing with in vitro microarray data analysis revealed that glucocorticoid was more efficient in controlling osteosarcoma cell growth than 17β estradiol. Glucocorticoid upregulated the expression of tumor suppressor genes resulting in apoptosis and downregulated the oncogenes associated with cell cycle and mitosis, whereas estradiol had an opposite action [62].
Primary bone tumors are a rare occurrence, and most of the bone tumors arise due to metastases of breast, prostate, or lung cancers. The bone is the preferred site for metastases because of its highly vascular nature and extensive molecular signaling. A large number of bone tumor cases have been observed in an adolescent population experiencing a growth spurt and hormonal changes. Therefore, the treatment methodologies for bone tumors rarely involve the use of hormones as drugs but rather deal with hormone deprivation or inhibition. Though therapeutic approaches involving deprivation or replacement of hormones negatively affect bone health, the hormonal therapy alone or in combination with chemotherapeutic drugs offers a promising strategy for inhibition of bone tumors and improving the survival rates.
This article reflects collective intellectual wisdom of the authors. We thank Savitribai Phule Pune University, Pune, India, for providing the necessary infrastructure during the compilation of this chapter. We also thank our colleagues, whose work has been cited in this article, for their inspiration.
The authors declare no conflict of interest with relation to this study.
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