Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\n
Seeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\n
Over these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\n
We are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\n
Thank you all for being part of the journey. 5,000 times thank you!
\\n\\n
Now with 5,000 titles available Open Access, which one will you read next?
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n
"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\n
Seeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\n
Over these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\n
We are excited about the present, and we look forward to sharing many more successes in the future.
\n\n
Thank you all for being part of the journey. 5,000 times thank you!
\n\n
Now with 5,000 titles available Open Access, which one will you read next?
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"9030",leadTitle:null,fullTitle:"Perspectives on Economic Development - Public Policy, Culture, and Economic Development",title:"Perspectives on Economic Development",subtitle:"Public Policy, Culture, and Economic Development",reviewType:"peer-reviewed",abstract:"Among the most discussed and contested areas of policy are those that surround economic development. 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She has also written popular science books for the public.\n Orcid: https://orcid.org/0000-0002-2009-4898. \nWebsite https://www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:"University of Nottingham",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}}],coeditorOne:{id:"309529",title:"Dr.",name:"Albert",middleName:null,surname:"Rizvanov",slug:"albert-rizvanov",fullName:"Albert Rizvanov",profilePictureURL:"https://mts.intechopen.com/storage/users/309529/images/9189_n.jpg",biography:'Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence “Regenerative Medicine” and Vice-Director of Strategic Academic Unit \\"Translational 7P Medicine\\". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. 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\n\t\t\t
1. Introduction
\n\t\t\t
The possibility of having experimental models of brain tumors allows for testing therapies applicable to human brain tumors. They can be induced by viruses, chemicals or radiation. Radiation-induced brain tumors have seldom been used, but diverse virus groups have been used to induce brain tumors. Among DNA viruses, both adenoviruses and papovaviruses have been shown to induce brain tumors in animals. The RNA viruses causing experimental brain tumors have consistently belonged to the retrovirus group, and have been generally limited to the murine sarcoma virus, the avian sarcoma virus, and the murine sarcoma virus. In these models, brain tumors are induced in rodents after intracerebral inoculation, with a variable latency, and the induced tumors are generally classified as gliomas, sarcomas, ependymomas or choroid plexus tumors.
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On the other hand, the heterotransplantation of human brain tumors into immunodeprived animals gained great interest after the development of the nude mouse model, a thymus-deficient animal that provided the possibility for the xenografting of human brain tumors. It is known that human meningiomas and glioblastomas can grow after subcutaneous transplantation into the nude mouse, maintaining its original morphology. Nevertheless, at present, diverse chemical agents provide the best models of experimental neurocarcinogenesis.
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2. Viral neurocarcinogenesis
\n\t\t\t
The role of viruses in human oncology is a question that has interested for many years to researchers and clinicians (Bigner and Pegram, 1976). However, despite the intense research that has been developed over the last decades in this field, we still can not establish a clear etiological association between the presence of certain viruses and tumor development in humans, with some exceptions, such as the case of Epstein-Barr virus associated to Burkitt\'s lymphoma, although there has never been any conclusive proof that this virus causes the tumor.
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From an experimental point of view, one of the models used to trigger the development of neural tumors in experimental animals is inoculation by different routes of virus with oncogenic capacity (Bullard and Bigner, 1980). The potential value of virus-induced gliomas has been questioned, however the information obtained from these experimental models has enabled significant progress in the treatment of human cancers. This experimental model of virus-induced neurocarcinogenesis offers the advantage that some of the viruses used will induce the development of tumors in a short period of time, the tumors are specifically located at the Central Nervous System (CNS) or Peripheral Nervous System (PNS), so that we can not rule out the possible viral etiology of certain types of brain tumors in humans. However, at present, numerous studies failed to establish any etiological association between viruses and humans brain tumors (Minn et al, 2002).
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We now know different animal viruses that can act as transforming agents in normal cells, since they are capable of causing malignant transformation of a cell through its ability to integrate genetic information. It is well known that, for example, intracerebral inoculation of retroviruses can induce brain tumors in a wide variety of animals. Viral carcinogenesis allows us to induce experimental tumors with a short latency period and with a more specific location that offers radiation carcinogenesis, location depends on the route of administration, animal age and the amount of virus inoculated. However, it is obvious that experimental models of viral neurocarcinogenesis have the inconvenience and risks involved in the handling of virus particles.
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Numerous studies have shown that RNA viruses (retroviruses) are able to induce the development of tumors in the CNS of experimental animals. Within this group, we highlight the avian sarcoma virus, murine sarcoma virus and simian sarcoma virus, being the most widely used in experimental neuro-oncology. Avian sarcoma virus (ASV) has been one of the most used in the literature to induce experimental brain tumors. The tumors are usually induced in chickens by intracerebral inoculation, and intracerebral tumors originated showed characteristics of sarcomas. There have been studies of ASV inoculation in the brains of monkeys because of their similarity to man, and tumors induced were fibrosarcomas. Interestingly, no author has reported the existence of glial tumors, but it has shown the ability of this virus to infect and replicate in glial cells when they grow in tissue culture.
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Murine sarcoma virus (MSV) with its three strains: Moloney MSV, Kirsten and Harvey, can cause leukemia and sarcomas when inoculated subcutaneously in rodents and also is capable of inducing brain tumors in rats when inoculated intracerebrally. Neoplasms that may result show usually the aspect of glioblastomas, gemistocytic astrocytomas, oligodendrogliomas and hemangioblastomas, depending on the age of the animal and the dose of virus inoculated.
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The simian sarcoma virus (SSV), after intracerebral inoculation in marmosets (Sanguinus nigricolli) induces the development of tumors that are morphologically similar to human glioblastoma multiforme, being able to demonstrate the presence of virus particles within tumor cells.
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Among the known DNA virus, adenovirus and papovavirus have proved very effective in inducing brain tumors after intracerebral inoculation in animals, preferably in neonatal age.
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Intracerebral inoculation of polyoma virus induces a high incidence of intracranial sarcomas in experimental animals, increasing their impact in terms of age of the animal (Rabson and Kirschstein, 1960). However, when inoculated cells transformed in vitro with the same virus, tumors of astrocytic aspect can be seen.
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The SV-40 virus shows no oncogenic effect in monkeys, a species from which it was originally obtained, but it is one of the more capable oncogenic virus in rodents. Intracerebral inoculation in hamsters induces the development of ventricular tumors that were classified as ependymoma, choroid plexus papillomas and meningeal sarcomas. The induction of brain tumors by this type of virus depends very heavily on the dose. The role of SV-40 virus in human tumor development, not only brain tumors but also bone tumors and mesothelioma, has been subject of discussion for decades, but now there is conclusive evidence. Furthermore, human adenoviruses can cause meningeal tumors when inoculated intracerebrally into experimental animals, with tumor development after latent periods of 35 to 40 days.
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While most existing data in the literature refer to the oncogenic virus ASV virus and SV-40, other viruses whose first guest is the man also play an important role in viral neurocarcinogenesis, such as Ad12 virus, BKV and JCV, three DNA viruses that have been widely used in experimental studies designed to establish a possible relationship between virus inoculation and the development of brain tumors. The human adenovirus Ad12 is able to induce brain tumors in rats after intracerebral inoculation, with a greater susceptibility of neonatal animals, where the range of incidence may vary between 8 and 100%. Furthermore, induced tumors develop after periods of latency between 31 and 235 days. The human papovavirus BK is capable of inducing brain tumors with different histological features, when inoculated into experimental animals. This virus is specifically used to induce choroid plexus papillomas and ependymomas after being inoculated intracerebrally.
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The JC virus (JCV), when inoculated subcutaneously or intraperitoneally into young hamsters, induces the development of a variety of tumors, especially mesenchymal neoplasms, and may even induce the development of peripheral neuroblastomas. Moreover, intracerebral inoculation can induce the development of malignant astrocytomas. In human neuro-oncology, this virus has been associated with the development of medulloblastomas and more recently, with recurrence of glioblastomas.
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On the other hand, it is important to note that in recent years, a new focus on the use of viruses has emerged in experimental neuro-oncology, and currently the use of viruses, or parts of them, are used as therapeutic vectors. Although some success has been reached using oncolytic viruses in experimental treatments for malignant gliomas in humans, the fact is that so far the results with these new techniques do not appear to meet the initial expectations (Zemp et al, 2010).
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3. Chemical neurocarcinogenesis
\n\t\t\t
The discovery of chemical carcinogens has stimulated neuro-oncology research because, after systemic application, these compounds induce a high incidence of tumors in the CNS and PNS, such as demonstrated Druckrey et al. in 1969, with the N-methyl-N-nitrosourea (MNU). Subsequently, we have found a greater number of chemical compounds, with equal effectiveness. Some of these compounds only occasionally induce tumors in the CNS of adult animals, but they represent, however, powerful neuro-oncogenic agents when administered transplacentally or during the early stages of postnatal life. Compounds, such as N-propyl-N-nitrosourea, N-butyl-N-nitrosourea, N-dimethyl-N-nitrosourea, and N-Trimethyl-N-nitrosourea, have been used. However, at present, N-ethyl-N-nitrosourea (ENU) is considered the best chemical agent to induce experimental brain tumors, because it is capable of inducing a high incidence of tumors, with known latency and morphology.
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3.1. Mechanism of tumor induction in chemical neurocarcinogenesis
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Most carcinogenic compounds actually represent precarcinogens which are converted in the host. The final product of this transformation is an electrophilic group that is capable of reacting with various cell constituents. It is clear that neuro-oncogenic compounds exhibit biological effects as alkylating metabolites which are formed during processing in vivo. The molecular basis of malignant transformation is not fully clarified, and at present, the cell being the target for the initiation of carcinogenesis has not identified. Most investigations are based on the interaction of carcinogens with nucleic acids and proteins.
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Recent studies suggest the possibility that the induction of neural tumors by nitrosourea compounds may be related to a deficiency in DNA repair mechanisms in the Nervous System. When applied 14C-ENU in neonatal rats, the loss of O6-ethylguanina in liver DNA is very rapid. However, it persists for several days in the cerebral DNA (Goth and Ralewsky, 1974). In the non-target organs for carcinogenic action, the O6-alkylation excision is repaired during replication, or alteration remains in the sequence of DNA bases.
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It is assumed that the inability of the neuro-oncogenic agents to induce neuronal tumors may be because neurons represent a cell population that has no capacity to divide. The permanent genetic alterations are the result of a mutation (transition) and this requires DNA replication. On the other hand, no direct evidence exists to affirm that the alkylation of nucleic acids is the cause that triggers the initiation of malignant tumors development.
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\n\t\t\t\t
3.2. Factors affecting the induction of experimental brain tumors in chemical neurocarcinogenesis
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In chemical neurocarcinogenesis, the incidence, distribution, histology of tumors, and survival time of animals are influenced by the species and age of animals, in addition to dose and mode of application of the carcinogen.
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3.2.1. Species
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The susceptibility of different species to the carcinogenic activity of nitrosoureas has been investigated by several authors. Thus, Druckrey et al. (1970) observed that strains of rats such as Sprague-Dawley and Fischer, Long-Evans and Wistar, were susceptible to the carcinogenic action, producing a high number of tumors in the CNS. However, the response was not uniform, for example, male Sprague-Dawley rats treated with MNU only developed brain tumors, while male Fischer rats showed a high incidence of PNS tumors (Swenberg et al. 1972).
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3.2.2. Age of animals
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There is evidence that the response to neuro-oncogenic agents in fetuses and newborn rats differs significantly from the response in adult animals. The main characteristics of the perinatal induction of tumors in the nervous system by chemical agents can be summarized in the following points:
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In adult animals, repeated doses of the carcinogen is needed to obtain a high incidence of neurogenic tumors. In the perinatal carcinogenesis, however, a single dose is sufficient to induce tumors in the nervous system, approximately in 90-100% of the experimental animals. On the other hand, some compounds such as 1,2-dimethylhydrazine, only induce tumors in fetuses and newborn rats, but never produce neurogenic tumors in adults.
Transplacental induction of neurogenic tumors in rats is possible only after day 11 of gestation. This is not due to lack of penetration of the carcinogen in fetal tissue, because embryotoxic and teratogenic effects occur after treatment, during the early stages of development. Nervous system susceptibility to chemical carcinogens increases sharply after day 11 of gestation and peaks during late intrauterine development period (Druckrey et al. 1969). After the first month of postnatal development, the response to neuro-oncogenic agents is broadly similar to that obtained in adult animals.
In adult animals, the tumors are located mainly in the brain (Denlinger et al, 1973). However, after perinatal application, tumors typically occur at the level of the spinal cord and the PNS. Trigeminal nerve tumors occur more frequently when the carcinogen is administered at the end of gestation, whereas in this case, the number of brain tumors is less than when the carcinogen is administered on day 15 of intrauterine development (Kahle, 1970).
The prenatal administration of these compounds increases the neurospecific carcinogenic effect. After transplacental administration tumors are located almost exclusively in the CNS. Postnatal application also produces a significant number of extraneural tumors (Schreiber et al, 1972).
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3.2.3. Dosage and application
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The incidence and latency period of experimental tumors is highly influenced by the dose of carcinogen. The number of tumors transplacentally induced by ENU can vary between 100% and 63% when the carcinogen dose is reduced from 80 mg / kg to 5 mg / kg. Moreover, the latency period is increased from 180 days to 500 days, when the dose of ENU administered in neonatal rats is reduced in the same way. The mode of application of the carcinogen plays a key role in the location and type of tumor that will be induced. Thus, local application of nitrosoureas can induce the formation of local tumors, but when these compounds are administered by intravenous injection, they can produce tumors that are spread throughout the body.
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3.2.4. Hormonal and immunological factors
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The possible influence of hormones on chemical carcinogenesis was first indicated by Ivankovic (1969) and Alexandrov (1973). They found that pregnant mice, when injected one or more doses of MNU, developed a high incidence of tumors of the uterus, vagina and breast cancer, however, when similar doses were administered in non-pregnant rats the results were different. Schreiber et al. (1972) found an increase in the number of extraneural tumors induced by MNU in rats to which previously had undergone ovariectomy. However, neither the execution of ovariectomy, or the application of testosterone or other oral contraceptives, have altered the oncogenic results (Schreiber et al. 1972; Thomas et al. 1972).
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Regarding the role of immunological factors in the development of nervous system tumors, there is very little data. Delinger et al. (1973) studied the effect of the suppression of cell-mediated immunity in carcinogenesis with MNU in Fischer rats. They used a treatment with anti-lymphocyte serum and observed no change in the incidence of neurogenic tumors.
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3.3. Morphology and biology of nitrosourea-induced brain tumors
Regardless of the type of carcinogen used, preferably tumors develop in a number of specific regions of the nervous system. For example, in the brain, they are located mainly in the periventricular region, in the subcortical white matter of the cerebral hemispheres, and hippocampus. The periventricular tumors usually develop around the lateral ventricles, including the caudate nucleus and corpus callosum. Tumors rarely appear localized in the cerebellum. In the spinal cord, are normally at cervical and lumbar segments. These tumors are also developed on the cranial nerves, of which the trigeminal nerve is the most frequent location (Mennel and Zulch, 1971; Ivankovic, 1972, Schreiber et al. 1972).
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3.3.2. Morphology
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Tumors induced by chemical carcinogenesis in the nervous system are tumors with similar morphology to that presented gliomas and malignant schwannomas in humans.
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After numerous histological studies on a large number of tumors induced in rats by nitrosoureas (Wechsler et al. 1969, Druckrey et al. 1970), unequivocal neuronal tumors were not found. After studies by light and electron microscopy of neurogenic tumors induced by ENU, Koestner et al. (1971) and Swenberg et al. (1972) established a classification for them that correlated with human tumors, but using different terminology. Thus, these authors classified the experimental brain tumors induced by ENU as:
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Mixed gliomas (oligodendro-astrocytomas).
Anaplastic gliomas, tumors that show great cellular pleomorphism with high mitotic activity and regressive changes.
Glioependymomas, tumors with ependymoma features that contained pleomorphic glial cells.
Gliosarcomas, containing neoplastic glial cells and mesodermal cells.
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In 1973, Jones et al. provide another classification showing distinct groups (in order of frequency of occurrence) of ENU-induced tumors:
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Gliomas of periventricular subependymal plate, they are divided in turn into ependymomas and ependymoma-oligoastrocytomas.
Astrocytic and oligodendrocytic tumors.
Neural tumors of the spinal cord and intracranial nerve ganglia.
Neuronal-like tumors and
Meningeal tumors.
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Gliomas of periventricular subependymal plate are the first tumors are the first tumors that develop, they are identical to the anaplastic glioependymomas, and almost equivalent to the periventricular pleomorphic gliomas originating from the undifferentiated cells of the subependymal plate described by Lantos (1972). The presence of true ependymomas between the ENU-induced tumors is controversial, and generally they have been considered as such, either by their intraventricular location, or due to their histological features, reminiscent of ependymomatous tumors of humans. Unequivocal ependymomas were not seen in series of mice exposed transplacentally to ENU, but according to accepted classifications, approximately 20% of the ENU-induced brain tumors could be diagnosed as ependymomas, anaplastic ependymomas, or mixed glial tumors with ependymoma areas (Mandybur and Alvira, 1982). In many classifications, ependymomatous tumors were termed as "anaplastic glioependymomas" due to the presence of ependymoma-like cells, but these tumor cells coexist with other glial-like cells, pleomorphic cells and generally with rounded cells being very similar to those of human oligodendrogliomas. In any case, the histopathological diagnosis of the ENU-induced ependymomas is based on the existence of tumor cells arranged in rosettes around blood vessels. Ultrastructurally, there are two cell types: a small undifferentiated cell, and a larger type, more differentiated. Transitional forms between these two cell types can be seen. Undifferentiated cells are small, with a relatively large nucleus and little cytoplasm. The more differentiated tumor cells have a pleomorphic nucleus in an eccentric position, surrounded by abundant cytoplasm. Overall neoplastic ependymal cells do not possess cilia or blepharoplasts, and are not equipped with junctional complexes. Studies by Mandybur and Alvira (1982) supported that the named “ENU-induced ependymomas” are not true ependymal tumors and that differ from the human ependymomas, because none of the ultrastructural features of normal or tumoral ependymal cells were present. Therefore these authors suggested that these tumors may actually be regarded as undifferentiated tumors, with some features of ependymomas.
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On the other hand, the histology of tumors induced by ENU and MNU are similar. There are however some differences that were highlighted by Swenberg et al. (1972). These authors found that ENU-induced gliomas are better differentiated than the MNU-induced tumors, and that ENU produces a greater number of anaplastic schwannoma-like tumors. In animals treated with MNU, gliosarcoma can be found in 10% of cases, however, this type of tumor is completely absent in the treatments with ENU, a carcinogen that produced almost exclusively oligodendroglioma-like tumors and malignant schwannoma-like tumors, as was pointed out by Schiffer et al. (1970). This criterion has been confirmed in numerous studies later and most of the reviews about the morphology of the ENU-induced brain tumors reflected the observation that most tumors can be considered as malignant oligodendroglioma-like tumor or malignant schwannoma-like tumors (Vaquero et al, 1994).
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The oligodendroglioma-like tumors are characteristically located at the subcortical white matter of the cerebral hemispheres, showing macroscopic appearance of well-defined tumors, often with hemorrhagic characteristics and foci of necrosis. Sometimes these tumors develop large cystic cavities.
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In light microscopy studies, the oligodendroglioma-like tumors show a fairly uniform cell population. They are composed of small cells, which show a dark and small nucleus, and a clear cytoplasm. Regressive changes are absent and there are small hemorrhagic foci. Outlying areas of these tumors have a cellular isomorphism, which is not appreciated in the central areas, where the existing cell population shows more pleomorphism, containing giant cells, occasionally multinucleated. Ultrastructural studies reveal the presence of neoplastic cells with an elongated or oval dark nucleus, and a small, clear cytoplasm, poor in organelles. However, some neoplastic cells show a dark nucleus and a dense cytoplasm. These findings suggest that these tumors are primitive undifferentiasted tumors with some oligodendroglial features, and their undifferentiated character is supported by immunohistochemical studies. On immunohistochemistry, there is a concordance between our results and those of other authors regarding the expression of the protein S-100, PGA and vimentin (Conley, 1979, Mauro et al. 1983; Mennel and et al. 1990; Raju, 1990; Reifenberg et al. 1989) but importantly we have obtained strong synaptophysin positivity in most of these tumors. Considering that in human pathology, this marker is useful for the recognition of primitive neuroectodermal tumors such as medulloblastoma (Molenaar et al, 1990) and also for the neuronal characterization of brain tumors, it is logical to suppose that the majority of ENU-induced brain tumors can be regarded as undifferentiated neuroectodermal tumors with possible neuronal differentiation, regardless of their morphological appearance. Furthermore, in our studies, most of the ENU-induced oligodendroglioma-like tumors show immunopositivity to the neuroblastic marker NB-84. This finding agrees with some of the previous classifications of these neoplasms, such as that of Jones et al. (1973), who first identified the ENU-induced tumors as neuroblastomas.
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The schwannoma-like tumors generally developed at the skull base, on the zone of the Gasser ganglion. They can be also located in the spinal root, with usually solid and sometimes cystic consistency. In our studies, these malignancies began to show neurological symptoms after a latent period ranging between 3 and 7 months after carcinogen administration. After 8 months of postnatal life, the development of these tumors is more infrequent, and after this time, intracerebral neoplasms, mainly of oligodendroglioma-like type, started to become symptomatic.
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The microscopical study of these tumors with hematoxylin-eosin technique suggests that they can be classified "malignant schwannomas". They generally show a cell population highly isomorphous, consisting of small cells with dark and more or less rounded nucleus, usually in a central position, with the typical appearance of undifferentiated cells. Furthermore, a great number of mitotic figures can be seen. Moreover, in these tumors there is a large blood supply, with hyperplasia of the vessels and the formation of large cystic spaces. Sometimes is possible to find areas of necrosis. Despite the large cellular isomorphism that characterizes these tumors, is possible see compact areas showing cells with fusiform aspect, arranged in palisade, or sometimes areas with looser reticular aspect. When the tumors are located in the region of trigeminal ganglion, is frequent the presence of large neuron-like cells interspersed with the small undifferentiated cells, which supposedly correspond to trigeminal ganglion neurons that are trapped between tumor cells, but the possibility of actually correspond to a gangliocytic differentiation of the tumor can not be ruled out.
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In the ultrastructural study of these tumors, at least two cell types can be found. On the one hand, there was a cell type with dark nucleus, whose chromatin is condensed to form a ring around the nuclear membrane and cytoplasmic features suggesting a neoplastic Schwann-cell. The other cell type shows a small, dark and round nucleus usually with a central position and chromatin that was condensed at the nuclear periphery. These cells showed a dense cytoplasm, with abundant rough endoplasmic reticulum, free ribosomes and polyribosomes, microtubules, primary lysosomes and a large quantity of mitochondria with dense matrix. Some of these cells show cytoplasmic granular vesicles, suggesting neuronal differentiation.
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Figure 1.
Macroscopic appearance of an ENU-induced intraparenchymatous brain tumor
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Finally, interspersed with these two cell types, it is possible to observe the existence of small cells, with scant cytoplasm and much more irregular nuclear configuration, which were interpreted as undifferentiated tumor cells.
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The immunohistochemical study of these tumors shows a clear positivity for S-100 protein and synaptophysin. Furthermore, neuroblastic specific markers, such as NB-84 are positive in all cases. Vimentin is strongly positive in only some cases, and finally, the detection of GFAP is negative in all cases.
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Figure 2.
Microscopic aspects of ENU-induced brain tumors. A: Tumor with oligodendroglial aspect showing abundant mitoses. B: Expression of GFAP in astrocytes trapped in the tumor. C: Expression of synaptophysin in an ENU-induced brain tumor with oligodendroglial appearance. D: Tumor cells showing positivity to the neuroblastic marker NB-84.
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Figure 3.
Macroscopic appearance of ENU-induced tumors at level of trigeminal ganglion (A) and lumbar roots (B).
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Figure 4.
A: Microscopic appearance of an ENU-induced tumor at level of trigeminal ganglion. Mature neurons can be seen, generally interpreted as trapped neurons from trigeminal ganglion. B: Ultrastructural aspect of tumor cells show undifferentiated aspect with dense granules (arrows), suggesting the neuroblastic nature of the tumor cells.
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3.3.3. Development
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The first sequence of the development of brain tumors induced by transplacental administration of ENU in rats was studied by Lantos and Cox in 1976. There is a latency period that it is the time between birth and the first neurological manifestations. This period has generally been estimated between 5 or 6 months. When animals are killed during this period of time, tumor lesions can be observed with different levels of development.
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The different stages of development of tumors induced by administration of ENU transplacentally in rats were also studied by Shiffer in 1991. This author adopted the terms proposed by Koestner et al (1971), and reported various lesions which differed in size and that called as "early neoplastic proliferations" (less than 300 microns), microtumors (between 300 - 500 microns) and "tumors" (greater than 500 microns in diameter). The first "early neoplastic proliferations” appear about two months after birth. These lesions represent early stages of tumor development, and are generally located in the white matter at the level of the lateral ventricles, and the angle of the ventricle, between the caudate nucleus and corpus callosum, or in the subcortical white matter. The tumors that develop from these microtumors retain their morphology, including proliferation centers, but occasionally may have an increased cellular pleomorphism. At four-five months, they show a polymorphic aspect. In many proliferative centers, the cells develop a cytoplasm showing a clear appearance of astrocytes, which subsequently can be gemistocytic. In these neoplasms a central zone showing avascular necrosis, and a peripheral vascular zone can be observed. In most vessels, hyperplasia at level of endothelial cells (Nishio et al. 1983), and an increase in the number of capillaries can be seen.
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3.3.4. Possibility of diagnostic "in vivo"
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In our studies, we have obtained clear evidence that ENU-induced brain tumors in Wistar rats can be detected in vivo using conventional Magnetic Resonance Image (MRI). With this technique, the experimental brain tumors are characteristically hypointense on T1-phase, and hyperintense on T2-phase. They show intense and homogeneous enhancement after paramagnetic contrast administration (gadolinium). It is obvious that using this experimental model, MRI can identify effectiveness of different experimental therapeutic protocols with potential application to human neuro-oncology.
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3.3.5. Transplantation
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Transplantation and culture in vitro of chemically induced brain tumors have provided important information about their biological characteristics. In addition, transplantation on syngeneic newborn animals can get a great number of brain tumor-bearing animals in a short period of time. On the other hand, tumor lines derived from chemically induced brain tumors are often used, especially for studies of drug response, such as the glioma C-6 of rats, the 9L gliosarcoma, the T9 tumor, the RG2 and F98 gliomas, or the RN-2 glioma.
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The C-6 tumor is a glioma induced by methyl nitrosourea in Wistar-Furth rats by Benda et al, in 1968. Usually it shows S-100-positivity. However, this line has the disadvantage of its frequent sarcomatous degeneration, so it is rarely used as a transplantable tumor model, although it has been used occasionally with success in the nude mouse.
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The murine 9L gliosarcoma possibly developed natively in an animal crossing Wistar rats and CD Fischer, through the administration of methyl-nitrosourea. The T9 tumor was induced in F344 rats by methyl-nitrosourea and do not have enough information about its stability in successive passes or transplants.
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Figure 5.
Magnetic Resonance Images showing ENU-induced brain tumors. A, B and D were intraparenchymatous oligodendroglial-like tumors. C and D were extraparenchymatous tumors with features of malignant schwannomas.
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The RG2 and F98 gliomas were both chemically induced by administering ENU to pregnant rats, the progeny of which developed brain tumors that subsequently were propagated in vitro and cloned. They have an invasive pattern of growth and uniform lethality, which make them particularly attractive models to test new therapies.
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The murine glioma RN-2 derived from the induction by ethyl-nitrosourea in F344 rats. It transplanted well and has a stable glial population, many expressing antigenic markers.
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These and other models are commonly used in experimental neuro-oncology, but it is essential to know the limitations of each of the experimental brain tumor models, and depending upon the nature of the study to be conducted, it is important that the appropiate model be selected (Barth and Kaur, 2009). In any case, the achievement of stable tumor cell lines, capable of growing in immunocompetent animals, is of great importance to study the efficacy of new antitumor drugs or biological agents capable of modifying the biological response in presence of a brain tumor.
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3.4. Biological similarities of enu-induced brain tumors with human tumors
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Although the ENU-model of neurocarcinogenesis offers the possibility to study many aspects of the biology of brain tumors, the fact is that there are many differences when establishing morphological similarities between the ENU-induced brain tumors and the different types of brain tumors in man. In human neuropathology it is accepted that certain tumors of neuronal nature, such as the so-called "central neurocytoma" may present an appearance of oligodendroglioma, but immunohistochemical and ultrastructural studies provide the correct classification (Hassoun et al. 1982). It is very similar to what happens in the case of ENU-induced oligodendroglioma-like tumors, and similar considerations can be applied to the ENU-induced malignant schwannomas. In our opinion, the immunostain and ultrastructural pattern of these experimental tumors suggests that, regardless of their histologic appearance with conventional hematoxylin-eosin staining, ENU-induced tumors can be regarded as undifferentiated neuroectodermal tumors with a tendency to neuronal differentiation.
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On the other hand, we consider interesting the discussion about the etiological relationships between human brain tumors and experimental ENU-induced tumors. Although there are no reliable data on the etiological factors that determine the beginning of a human brain tumor, and the possibility of a multifactorial mechanism is considered, is interesting the finding that prenatal exposure to a carcinogen can lead to tumor development several months after birth. Moreover, considering the lifetime of rodents, the age that experimental brain tumors become manifest (mean age of the life of the rat) corresponds to the higher frequency of brain tumor development in humans (adult age). If some types of human brain tumor may be caused by exposure to certain carcinogens in the prenatal period, is an open question (Huncharek, 2010).
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Figure 6.
A: Subcutaneous transplantation of an ENU-induced brain tumor in immunocompetent newborn rat. B: Tumor growth one month later.
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\n\t\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/18135.pdf",chapterXML:"https://mts.intechopen.com/source/xml/18135.xml",downloadPdfUrl:"/chapter/pdf-download/18135",previewPdfUrl:"/chapter/pdf-preview/18135",totalDownloads:2317,totalViews:205,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:"November 6th 2010",dateReviewed:"April 10th 2011",datePrePublished:null,datePublished:"August 23rd 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/18135",risUrl:"/chapter/ris/18135",book:{slug:"brain-tumors-current-and-emerging-therapeutic-strategies"},signatures:"Jesús Vaquero and Mercedes Zurita",authors:[{id:"37487",title:"Prof.",name:"Jesús",middleName:null,surname:"Vaquero",fullName:"Jesús Vaquero",slug:"jesus-vaquero",email:"jvaqueroc@telefonica.net",position:null,institution:null},{id:"37489",title:"Dr.",name:"Mercedes",middleName:null,surname:"Zurita",fullName:"Mercedes Zurita",slug:"mercedes-zurita",email:"mzurita.hpth@salud.madrid.org",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Viral neurocarcinogenesis",level:"1"},{id:"sec_3",title:"3. Chemical neurocarcinogenesis",level:"1"},{id:"sec_3_2",title:"3.1. Mechanism of tumor induction in chemical neurocarcinogenesis",level:"2"},{id:"sec_4_2",title:"3.2. Factors affecting the induction of experimental brain tumors in chemical neurocarcinogenesis ",level:"2"},{id:"sec_4_3",title:"3.2.1. Species ",level:"3"},{id:"sec_5_3",title:"3.2.2. Age of animals ",level:"3"},{id:"sec_6_3",title:"3.2.3. Dosage and application ",level:"3"},{id:"sec_7_3",title:"3.2.4. Hormonal and immunological factors ",level:"3"},{id:"sec_9_2",title:"3.3. Morphology and biology of nitrosourea-induced brain tumors ",level:"2"},{id:"sec_9_3",title:"3.3.1. Tumor location ",level:"3"},{id:"sec_10_3",title:"3.3.2. Morphology",level:"3"},{id:"sec_11_3",title:"3.3.3. Development ",level:"3"},{id:"sec_12_3",title:'3.3.4. Possibility of diagnostic "in vivo" ',level:"3"},{id:"sec_13_3",title:"3.3.5. Transplantation",level:"3"},{id:"sec_15_2",title:"3.4. Biological similarities of enu-induced brain tumors with human tumors",level:"2"}],chapterReferences:[{id:"B1",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlexandrov\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1973In: Transplacental Carcinogenesis. Tomatis L. and Mohr, eds.). IARC Sci. 4\n\t\t\t\t\t112\n\t\t\t\t\t126Lyon\n\t\t\t'},{id:"B2",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarth\n\t\t\t\t\t\t\tR. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKaur\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009Rat brain tumor models in experimental neuro-oncology: the C6, 9L, T9, RG2, F98, BT4C, RT-2 and CNS-1 gliomas. J. Neurooncol.\n\t\t\t\t\t94\n\t\t\t\t\t299\n\t\t\t\t\t312\n\t\t\t\t\n\t\t\t'},{id:"B3",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBigner\n\t\t\t\t\t\t\tD. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPegram\n\t\t\t\t\t\t\tC. 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Acta Neuropathol.,\n\t\t\t\t\t78\n\t\t\t\t\t270\n\t\t\t\t\t282\n\t\t\t\t\n\t\t\t'},{id:"B29",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchiffer\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1991Patterns of tumor growth. In: Neurobiology of brain tumors. Salcman M. ED. Concepts in Neurosurgery, 4Willians and Wilkins, Baltimore. 85\n\t\t\t\t\t210\n\t\t\t\t\n\t\t\t'},{id:"B30",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchiffer\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFabiani\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrossi-Paoletti\n\t\t\t\t\t\t\tPaoletti. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1970Experimental brain tumours induced in rats by nitrosourea derivatives. Part 1. Morphological aspects of methylnitrosourea tumours. J. 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A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKoestner\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWechsler\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDenlinger\n\t\t\t\t\t\t\tR. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1972Quantitative aspects of transplacental tumor induction with ethylnitrosourea in rats. Cancer Res. 32\n\t\t\t\t\t2656\n\t\t\t\t\t2660\n\t\t\t\t\n\t\t\t'},{id:"B33",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThomas\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRogg\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBücheler\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1972The cancer-inducing effect of MNU after administration of hormonal contraceptives. Beitr Pathol. Anat. Allgem Pathol. 146\n\t\t\t\t\t332\n\t\t\t\t\t338\n\t\t\t\t\n\t\t\t'},{id:"B34",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVaquero\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOya\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCoca\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZurita\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1994Experimental induction of primitive neuroectodermal tumours in rats: A re-appraisement of the ENU-model of neurocarcinogenesis. Acta Neurochir. (Wien)\n\t\t\t\t\t131\n\t\t\t\t\t294\n\t\t\t\t\t301\n\t\t\t\t\n\t\t\t'},{id:"B35",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWechsler\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKleihues\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZülch\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIvankovic\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPreussmann\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDruckrey\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1969Pathology of experimental neurogenic tumors chemically induced during prenatal and postnatal life. Ann. N.Y. Acad. Sci., 159\n\t\t\t\t\t360\n\t\t\t\t\t408\n\t\t\t\t\n\t\t\t'},{id:"B36",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZemp\n\t\t\t\t\t\t\tF. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCorredor\n\t\t\t\t\t\t\tJ. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLun\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMuruve\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tForsyth\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010Oncolytic viruses as experimental treatments for malignant gliomas: using a scourge to treat a devil. Cytokine Growth Factor Rev.\n\t\t\t\t\t21\n\t\t\t\t\t103\n\t\t\t\t\t117\n\t\t\t\t\n\t\t\t'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Jesús Vaquero",address:null,affiliation:'
Neuroscience Research Unit, Hospital Puerta de Hierro-Majadahonda, Madrid, Spain
Neuroscience Research Unit, Hospital Puerta de Hierro-Majadahonda, Madrid, Spain
'}],corrections:null},book:{id:"537",title:"Brain Tumors",subtitle:"Current and Emerging Therapeutic Strategies",fullTitle:"Brain Tumors - Current and Emerging Therapeutic Strategies",slug:"brain-tumors-current-and-emerging-therapeutic-strategies",publishedDate:"August 23rd 2011",bookSignature:"Ana L. Abujamra",coverURL:"https://cdn.intechopen.com/books/images_new/537.jpg",licenceType:"CC BY-NC-SA 3.0",editedByType:"Edited by",editors:[{id:"38444",title:"Dr.",name:"Ana Lucia",middleName:null,surname:"Abujamra",slug:"ana-lucia-abujamra",fullName:"Ana Lucia Abujamra"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"18134",title:"Xenograft Model of Human Brain Tumor",slug:"xenograft-model-of-human-brain-tumor",totalDownloads:6229,totalCrossrefCites:1,signatures:"Chen Hua, Dong Jun and Huang Qiang",authors:[{id:"42941",title:"Prof.",name:"Huang",middleName:null,surname:"Qiang",fullName:"Huang Qiang",slug:"huang-qiang"},{id:"53336",title:"Dr.",name:"Chen",middleName:null,surname:"Hua",fullName:"Chen Hua",slug:"chen-hua"}]},{id:"18135",title:"Experimental Brain Tumors: Current Concepts",slug:"experimental-brain-tumors-current-concepts",totalDownloads:2317,totalCrossrefCites:0,signatures:"Jesús Vaquero and Mercedes 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Pannullo, Cecile Yama and A. Gabriella Wernicke",authors:[{id:"52042",title:"Dr.",name:"Susan",middleName:null,surname:"C. Pannullo",fullName:"Susan C. Pannullo",slug:"susan-c.-pannullo"},{id:"58320",title:"Ms.",name:"Cecile",middleName:null,surname:"Yama",fullName:"Cecile Yama",slug:"cecile-yama"},{id:"58321",title:"Prof.",name:"A. Gabriella",middleName:null,surname:"Wernicke",fullName:"A. Gabriella Wernicke",slug:"a.-gabriella-wernicke"}]},{id:"20285",title:"Gamma Knife Radiosurgery After Stereotactic Aspiration for Large Cystic Brain Metastases",slug:"gamma-knife-radiosurgery-after-stereotactic-aspiration-for-large-cystic-brain-metastases",signatures:"Do Hoon Kwon and Won Hyoung Park",authors:[{id:"47632",title:"Prof.",name:"Do Hoon",middleName:null,surname:"Kwon",fullName:"Do Hoon Kwon",slug:"do-hoon-kwon"},{id:"53672",title:"Dr.",name:"Won Hyoung",middleName:null,surname:"Park",fullName:"Won Hyoung Park",slug:"won-hyoung-park"}]},{id:"20286",title:"Management of Brain Tumors in Eloquent Areas",slug:"management-of-brain-tumors-in-eloquent-areas",signatures:"José Manuel González – Darder and Pablo González – López",authors:[{id:"44871",title:"Prof.",name:"José M.",middleName:null,surname:"González-Darder",fullName:"José M. González-Darder",slug:"jose-m.-gonzalez-darder"},{id:"137076",title:"Dr.",name:"Pablo",middleName:null,surname:"González-López",fullName:"Pablo González-López",slug:"pablo-gonzalez-lopez"}]},{id:"20287",title:"Therapeutic Embolization of Cranial Tumors",slug:"therapeutic-embolization-of-cranial-tumors",signatures:"Antonin Krajina, Tomas Cesak, Kamil Zelenak and Svatopluk Rehak",authors:[{id:"35657",title:"Prof.",name:"Antonin",middleName:null,surname:"Krajina",fullName:"Antonin Krajina",slug:"antonin-krajina"},{id:"53229",title:"Dr.",name:"Kamil",middleName:null,surname:"Zeleňák",fullName:"Kamil Zeleňák",slug:"kamil-zelenak"},{id:"53230",title:"Dr.",name:"Tomas",middleName:null,surname:"Cesak",fullName:"Tomas Cesak",slug:"tomas-cesak"},{id:"92163",title:"Prof.",name:"Svatopluk",middleName:null,surname:"Rehak",fullName:"Svatopluk Rehak",slug:"svatopluk-rehak"}]},{id:"20288",title:"Advanced Surgical Management of Gliomas: Technological Requirements, Concept of Information-Guided Resection, and Clinical Results",slug:"advanced-surgical-management-of-gliomas-technological-requirements-concept-of-information-guided-res",signatures:"Yoshihiro Muragaki, Hiroshi Iseki, Takashi Maruyama,\nMikhail Chernov, Takashi Suzuki, Kitaro Yoshimitsu, Manabu Tamura, Soko Ikuta, Masayuki Nitta Taiichi Saito, Jun Okamoto and Kintomo Takakura",authors:[{id:"42507",title:"Dr.",name:"Yoshihiro",middleName:null,surname:"Muragaki",fullName:"Yoshihiro Muragaki",slug:"yoshihiro-muragaki"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"75151",title:"Targeting MYC and HDAC8 with a Combination of siRNAs Inhibits Neuroblastoma Cells Proliferation In Vitro and In Vivo Xenograft Tumor Growth",doi:"10.5772/intechopen.96021",slug:"targeting-myc-and-hdac8-with-a-combination-of-sirnas-inhibits-neuroblastoma-cells-proliferation-in-v",body:'
1. Introduction
Neuroblastoma is the most frequently diagnosed extracranial solid tumor in children. About 90% of cases occur in children less than 5 years old and it is rare in adults. Of cancer deaths in children, about 15% are due to neuroblastoma [1]. Chances of long-term survival, however, are less than 40% despite aggressive treatment [2].
MYC is an oncogenic transcription factor that is overexpressed in many types of cancer. MYC has been shown to directly upregulate a protumorigenic group of miRNAs and represses several suppressor miRNAs, thus contributing to tumorigenesis [3]. For example, MYC overexpression can upregulate the oncogenic miR-17-92 cluster, that are directly activated in lymphoma [4], and can also repress several suppressor miRNAs [3]. The MYC gene is amplified in various human cancers, including in lung carcinoma, breast carcinoma, and colon carcinoma [5].
Histone deacetylases affect gene expression by altering the histone acetylation status, and that as a consequence, HDAC overexpression contribute to tumorigenesis by affecting the expression of key mRNAs and miRNAs. HDACs are overexpressed in most cancers, leading to histone deacetylation, inhibition of growth- suppressive genes, and increased cell proliferation [6]. HDAC8 overexpression correlates with advanced neuroblastoma in patient tumor samples, and HDAC8 inhibition reduced cell proliferation and induced neuroblastoma cell differentiation [7]. HDAC inhibitors reduced the proliferation and induced the apoptosis of neuroblastoma cells in vitro and in vivo in mice [8, 9].
Given that both MYC and HDACs play an important role in the maintenance of the normal cellular physiological functions and that their overexpression is linked to neuroblastoma tumorigenesis, we asked whether the levels of both MYC and HDAC8 should be reduced to obtain significant inhibition of cell proliferation.
Our results demonstrate that miR-665 targets c-MYC and HDAC8 m RNA, miR-665 treatment also increased the percentage of cells in G1 phase and reduced the percentage of cells in S phase of the cell cycle. This is the first report to show that miR-665 is a suppressor miRNA directly targeting the 3’-UTR of c-MYC and HDAC8 in neuroblastoma [10].
We investigated the effects of small interfering RNAs (siRNAs) targeting HDAC8 and MYC in murine neuroblastoma cells. RNA interference is a process of posttranscriptional gene silencing in which a double stranded RNA inhibits gene expression in a sequence-dependent manner via degradation of the corresponding mRNA. siRNAs can be used as potent and specific tools for gene knockdown. Several laboratories have reported siRNA targeting of gene expression in cancer cells and the inhibition of cell proliferation in vitro and tumor growth in vivo [11, 12, 13, 14].
We reported that in vitro, single-agent siRNA HDAC8 or siRNA-MYC inhibited cell proliferation by 40–50%; however, treatment with the combination of siRNA MYC + siRNA-HDAC8 inhibited cell proliferation by 86% [10]. To further confirm these findings in an animal model, we set out to verify if tumor growth can be inhibited in a neuroblastoma xenograft mouse model when tumors are treated with a combination of siRNA-MYC and siRNA HDAC8. Our findings from this study show that the tumor growth was reduced by 80% following intratumoral delivery of a combination of siRNAs targeting both MYC and HDAC8 simultaneously [15].
2. Materials and methods
2.1 Reagents
Cell culture media, DMEM with high glucose (D6429), essential and non-essential amino acids (M5550, m7145), Bt2c AMP (D0627), the colorimetric Caspase 3 kit (Code CASP-3-C), and propidium iodide (P4170) were purchased from Sigma Aldrich, St. Louis. Fetal bovine serum (FBS) was purchased from Phenix Research Products, Candler, NC, USA. BD-Falcon tissue culture 96-well plates (353072) were purchased from BD Biosciences. The RNA extraction miRNeasy kit (Cat No. 217084) was purchased from Qiagen, Germantown, MD, USA. The MTS Cell. Titer 96 Aqueous One Solution (Cat # G3580) cell proliferation assay was purchased from Promega Biotechnology, Madison,WI, USA. The HDAC Kit (#K331–100) was purchased from BioVision, Inc. Co rning. 96-well EIA/RIA plates (CLS3369) were used for ELISA. Antibodies for HDAC 8, H-145 (sc11405), C MYC, C-19 (SC-786), acetylated Histones, Ac- H2B, Lys 5/12/15/20 (SC-8652), Ac-H3, lys9 (sc-8655), Ac-H4, lys16 (sc-8662), and siRNA for c-MYC (pool of 4 different siRNA duplexes, sc-29227) were purchased from Santa Cruz Biotechnology, Dallas, TX, USA. Negative control #2 siRNA (#4390846), siRNA-HDAC 8 (S88696) and Lipofectamine RNAi Max (#13778075) were purchased from Life Technologies/Ambion/ Invitrogen. Negative control miRNA Cel-miR-67 (#CN-001000) sequences based on C. elegans miRNA, mimic hsa-miR-665 (#C 301246–01), and transfection reagent Dharmafect Duo (#T2010–01) were purchased from Dharmacon. Luciferase expression plasmids with the 3’-UTR for HDAC8 (#S804229), C-MYC (#S804638), MYCN (Product No S807230), or empty vector without 3’-UTR (#S890005), and the LightSwitch luciferase assay kit (#32031, LS010) were purchased from Active Motif, CA, USA.
2.2 Cells and cell culture
Mouse neuroblastoma cholinergic clonal cells (S20) were obtained from Dr. Marshall Nirenberg of The US National Institutes of Health (NIH). Cells were grown in monolayers in DMEM supplemented with essential and nonessential amino acids, penicillin/streptomycin, and 10% FBS at 37°C with 5% CO2 and humidity.
Neuroblastoma cells were plated in 96-well plates at 12x103 cells per well and After 48–72 h, cell viability was measured colorimetrically using the MTS Cell Titer 96 Aqueous One Solution. Samples were incubated at 37°C for 3–4 h and samples were read at 490 nm in a plate reader according to the manufacturer’s instructions.
For cell cycle analysis, 1x106 cells were plated in T25 flasks. After 48 h, cells were trypsinized, treated with 75% ethanol and 100ug/ml RNAse A, and then stained with propodium iodide (PI). Untreated and (20,000 cells/ sample) were analyzed for cell cycle distribution via flow cytometry at the Core lab of Children’s Cancer Center Hospital, Houston, TX, USA.
2.3 Transfections
The effects of miR-665 or siRNA on cell proliferation were determined using reverse transfection. First, 100 nM negative control miRNA, miR-665, negative control siRNA, C-MYC siRNA, or HDAC8 siRNA was mixed with Lipofectamine RNAimax. This mixture was added to 12x103 cells, which were then plated in 96-well plates. After 48–72 h, cell viability was measured using MTS Cell Titer 96 Aqueous One Solution and incubated at 37°C for 3–4 h. Samples were read at 490 nm according to manufacturer’s instructions.
miRNA effects on the cell cycle were assessed using reverse transfection of cells with 100 nM negative control miRNA or miR-665 mimic plus Lipofectamine RNAimax. The transfection mixture was added to 1x106 cells, which were then plated in a T25 flask. After 48 h, cells were trypsinized, treated with 75% ethanol and 100ug/ml RNAse A, and then stained with PI. For cell cycle analysis, 20,000 cells/sample were analyzed via flow cytometry in the Core lab of Children’s Cancer Center Hospital, Houston, TX.
2.4 Whole cell extracts
Cell extracts were prepared from untreated,, and miRNA transfected cells for target assays. miRNA-transfected cells were reverse transfected with 100 nM negative control miRNA, miR-665, negative control siRNA, c-MYC siRNA, or HDAC8 siRNA plus Lipofectamine RNAimax. Transfected cells were plated in T25 flasks. After 48–72 h, cell extracts were prepared in assay buffer as described by Khandelia, et al. [16]. Assay buffer consisted of 20 mM Tris–HCL pH 7.5, 150 mM NaCl, 5 mM EDTA, 10% glycerol, 1% Nonidet P40, and protease inhibitor cocktail from Sigma (P8340). Protein concentrations were determined using Pierce’s BCA Assay as per the manufacturer’s instructions.
miR-665 inhibit cell growth compared to untreated cells and cells treated with negative control miRNA. Assays were normalized using equal concentrations of protein (50–100 ug) from untreated, negative control miRNA-, and miR-665- treated cells in assessing total HDAC and Caspase 3 activity, and HDAC8 and c-MYC levels via ELISA.
2.5 Quantitation of miR-665 in transfected cells
Mouse neuroblastoma cells were transfected with 100 nM miR-665 mimic and negative control cel-miR-67. 48 h post-transfection, total RNA was extracted from three biological replicates per treatment using the Qiagen RNEasy mini kit. miR-665 was quantitated via realtime qPCR by Arraystar, Inc. (Rockville, MD, USA).
Real-time PCR was performed for each RNA sample to quantify miR-665 and the housekeeping gene, U6. According to the standard curve, mRNA concentrations in each sample are determined directly using Rotor-Gene Real-Time Analysis software v.6.0 and the 2∆∆Ct method.
2.6 Total HDAC activity
Total HDAC activity was measured in 50–75ug of protein from cell extracts prepared from untreated, or negative control miRNA- or miR 665-transfected cells using the Biovision kit (#K331–100). Acetylated HDAC substrate and other reagents were added according to the manufacturer’s instructions and the final deacetylated product was read at 405 nm in a plate reader.
2.7 HDAC8 and c-MYC protein quantitaion via ELISA
HDAC8 and c-MYC proteins were quantitated using cell extracts prepared from untreated or 1 mM Bt2cAMP treated cells, or negative control miRNA- or miR-665- transfected cells via ELISA. 100ug protein per sample was mixed with 0.02 M carbonate coating buffer (pH 9.5) and added to 96-well BD-Falcon ELISA plates.
Samples were incubated at 4°C for 15 h. Wells were blocked with 10% FBS in PBS, treated with antibodies (diluted 1:30) specific for HDAC8 (SC11405) or c-MYC (SC-798), and incubated at 37°C for 2 h. Samples were washed with PBS + 0.05% Tween, treated with goat anti-rabbit IgG.
HRP secondary antibody (diluted 1:500), and incubated at 37°C for 1 h. Wells were washed and treated with substrate TMB and incubated at room temperature for 30 min, and then the reaction was stopped with 2 N H2SO4. Samples were read at 450 nm in a plate reader.
2.8 Caspase 3 activity
Caspase 3 activity was measured in 50ug protein from untreated, Bt2cAMP-treated, or miR-665-transfected cells using Sigma Aldrich’s colorimeter kit (Code CASP3-C). 50ug protein was mixed with the peptide substrate, Ac-DEVD-pNA (p-nitroanilide), in the presence of 10 mM DTT. Caspase 3 hydrolyzes the substrate, releasing p-nitroaniline, which is read at 405 nm. The specificity of caspase 3 activity was determined in the presence of the inhibitor, Ac-DEVD- CHO.
2.9 Target validation using luciferase expression plasmids
HepG2 cells were used for miR-665 target validation, because miR-665 does not inhibit the growth of these cells. When mouse neuroblastoma cells were used for target validation, the negative control luciferase vector plasmid without any target 3’-UTR showed a 50% decrease in luciferase activity when co-transfected with miR-665 compared to negative control miRNA. This decrease in luciferase activity was non-specific and was caused by cell growth inhibition due to miR-665 transfection.
To validate miR-665 targets, HepG2 cells were grown for 24 h in a 96-well plate. Cells were then co transfected with 100 ng luciferase expression plasmids containing the 3’-UTR for HDAC8, c-MYC, or MYCN, or the empty vector without any target 3’UTR, plus 100 nM negative control miRNA or miR-665 with Dharmafect Duo transfection agent. After 48 h of cotransfection, luciferase activity was measured using the Active Motifs LightSwitch luciferase assay kit. Luminescence was read on a Molecular Devices Soft Max Pro5 luminometer.
2.10 Histone acetylation
Histone acetylation was quantified via ELISA in cell extracts prepared from cells transfected with negative control miRNA, miR-665, negative control siRNA, or HDAC8 siRNA. 100ug protein was mixed with 0.02 M carbonate coating buffer (pH 9.5), added to 96-well BD Falcon ELISA plates, and incubated at 4°C for 15 h. Wells were blocked with 10% FBS in PBS, treated with acetylated antibodies (diluted 1:30) for Ac H2B (Lys 5/12/15/20), Ac-H3 (lys9), or Ac-H4 (lys16), and incubated at 37°C for 2 h. Samples were washed with PBS + 0.05% Tween, treated with an appropriate HRP-conjugated secondary antibody (diluted 1:500), and incubated at 37°C for 1 h. Wells were washed and treated with substrate TMB and incubated at room temperature for 30 min, and then the reaction was stopped using 2 N H2SO4. Samples were read at 450 nm in a plate reader.
2.11 Neuroblastoma tumor model
Mice experiments were performed with the approval of the institutional Animal Care and Use Committee, IACUC at Nanospectra Biosciences Inc. Houston, Texas.
A/J female mice six weeks old were purchased from Jackson Laboratory, Bar Harbor, Maine, USA. Murine neuroblastoma cells, 1x106 cells in DMEM media with 50% matrigel in 100 ul without fetal bovine serum and without antibiotics were subcutaneously injected on the right flanks. After 12 days, tumor growth can be seen and tumors were measured with a caliper.
When tumors reached 100 mm3 in size, mice were divided into two groups with 8–10 mice in each group.
Intratumoral delivery of siRNA.
siRNA-HDAC8 (S88696), Sense Sequence: (5′----3′).
CGACGGAAAUUUGACCGUAtt.
Antisense Sequence:
UACGGUCAAAUUUCCGUCGca.
siRNA-MYC (S70224), Sense Sequence: (5′------3′).
AGGUAGUGAUCCUCAAAAAtt.
Antisense Sequence: UUUUUGAGGAUCACUACCUtg.
Negative control #2 siRNA (#4390846), and Lipofectamine RNAi Max (#13778075) were purchased from Life Technologies/Ambion.
A total of 3 nmol Negative control siRNA or 3 nmol combinations of siRNA-MYC + siRNA-HDAC8 were mixed with Lipofectamine RNAi max (Liposome) in DMEM media without fetal bovine serum and without antibiotic. siRNA complexed with Lipofectamine in a volume of 30 ul was delivered into tumors by intratumoral injection every third day. Tumors were measured every second day with a caliper and mice were weighed every third day. Tumor volume was calculator with a formula, V = Length X width2/2. Experiment was stopped when the control tumors treated with negative control siRNA reached a tumor burden volume of 1200 mm3. Mice were euthanized by CO2 inhalation 2 days after last treatment with siRNA. Tumors were removed and weighed. Tumors were frozen in liquid nitrogen and stored at -80o C freezers until used for preparation of tumor extracts for ELISA.
2.12 Tumor extract preparation
Tumors treated with NC-siRNA or with combined siRNA-HDAC8 + siRNA-MYC were cut into small pieces and homogenized in assay buffer in a glass homogenizer. Assay buffer as described by Khandelia et al. [16], consisted of 20 mM Tris–HCL pH 7.5, 150 mM NaCl, 5 mM EDTA, 10% glycerol, 1% Nonidet P40, and protease inhibitor cocktail from Sigma (P8340). Protein concentrations were determined using Pierce’s BCA Assay as per the manufacturer’s instructions.
2.13 Statistical analysis
Error bars represent standard error of the mean (SEM) from 2 to 3 biological replicates from 3 to 5 independent experiments. P-values were calculated using T.Test (2 tailed, 3 samples, unequal variance) and p < 0.05 was considered statistically significant.
3. Results
3.1 miR-665 inhibits cell proliferation
NB cells transfected with miR-665 show changes in cell morphology, lost the normal spindle shape and cells grew in clumps without processes compared to cells transfected with negative control miRNA (Figure 1A and B). Cell cycle analysis results show that miR-665 treated cells show an increase of 16% of cells in G1 phase of cell cycle and the cell number decreased by 18% in S phase compared to negative control miRNA transfected cells. miR-665 treatment did not affect the cells in G2 phase (Figure 1C). Cell viability decreased proportionally with the increasing concentration of miR-665, represented by black bars (Figure 1D).
Figure 1.
miR-665 effects on cell proliferation (A) cells treated with 100 nM negative control miRNA and miR-665 (B) for 72 hr. were prepared for cell cycle distribution analysis. Propidium iodide stained cells were analyzed by FLOW cytometry (C) Several concentration of miR-665 effect on cell viability (D) STDEV was used for +/− standard error bar; data is from 2 independent experiments with 3 biological replicates for each experiment was used. (figures were printed from published article in “Oncotarget”, N.Prashad Vol 9, 33186–33201, 2018).
3.2 miR-665 targets HDAC 8, c MYC and MYCN
Computational algorithm prediction site TargetScan and miRanda (microRNA.org) predicts mRNA targets for Mirna. miranda predicted hsa-miR-665 targets 3’ UTR of HDAC 8 and the sequence alignment is presented in Figure 2A. miranda, also predicts that hsa-miR-665 targets MYCN 3’ UTR and the sequence alignment is presented in Figure 2B.
Figure 2.
Predicted binding sites for miR-665 in targets HDAC 8, c MYC and MYCN 3’ UTR. Computational prediction site miRanda (microRNA.org) predicted hsa-miR-665 targets 3’ UTR of HDAC 8 and the sequence alignment is presented in (A). miranda, also predicts that hsa-miR-665 targets MYCN 3’ UTR and the sequence alignment is presented in (B). miranda and Targetscan did not include 3’ UTR of C MYC as miR-665 target. Therefore, complimentary sequences between miR-665 and 3’ UTR of C MYC were compared at online pairwise sequence alignment site www.ebi.ac.uk. Sequence alignment is presented in (C). (D) miR-665 targets were validated by co transfection of 100 ng luciferase expression plasmids with 3’-UTR and 100 nM negative control miRNA and miR-665 into HepG2 cells. Empty vector without 3’ UTR was used as a control. After 48 hr., luciferase activity was measured and normalized luciferase activity is presented. Data is presented from 2 independent experiments with 3 biological replicates were used. STDEV was used for +/− standard error bar. (figures were printed from published article in “Oncotarget”, N.Prashad Vol 9, 33186–33201, 2018).
MYC is overexpressed in 30% of all human cancers and frequently predicts for a poor clinical outcome, and deregulated expression of MYC is a hallmark feature of cancer [3] miRanda and Targetscan did not include 3’ UTR of C MYC as miR-665 target. Therefore, Complimentary sequences between miR-665 and 3’ UTR of C MYC were compared at online pairwise sequence alignment site www.ebi.ac.uk. Results show two complementary binding sites for miR-665 in the 3’ UTR of c MYC (Figure 2C).
First we measured total HDAC activity in the cell extracts prepared from negative control miRNA and miR-665 transfected cells in the presence of acetylated HDAC substrate Ac-Lys (Ac)-p NA and deacetylated end product was measured colorimetrically. HDAC 8 and c MYC proteins were measured with antibody in ELISA. The results show that total Pan HDAC activity was decreased by 40%, and HDAC 8 and c MYC proteins were decreased by 40% in miR-665 transfected cells compared to negative control miRNA treated cells (Figure 3A–C).
Figure 3.
miR-665 effect on target HDAC 8, c MYC and MYCN cell extracts from100nM negative control miRNA and miR-665 transfected cells were used for the quantitation of; (A) total HDAC activity, (B) HDAC8 protein by ELISA, (C) c MYC protein by ELISA and (D) caspase 3 activity and specificity of caspase 3 enzyme activity was determined in the presence of inhibitor. Data is presented from 2 independent experiments with 3 biological replicates were used. STDEV was used for +/− standard error bar. (figures were printed from published article in “Oncotarget”, N.Prashad Vol 9, 33186–33201, 2018).
Next, we tested whether HDAC 8, c MYC and MYCN genes are the direct target of miR-665. In these experiments HepG2 cells were used because miR-665 does not affect the growth of these cells (our unpublished results). Luciferase reporter plasmids with 3’ UTR were cotransfected with negative control miRNA and miR-665 in HepG2 cells and after 48 hr. luciferase activity were measured in cell extracts. Results show a 40% decrease in luciferase activity of HDAC 8 3’ UTR, a 51% decrease in luciferase activity of c MYC 3’ UTR and a 50% decrease in luciferase activity of MYCN 3’UTR from the cells co transfected with miR-665 compared to the co transfection with negative control miRNA (Figure 2D). These results validate that m RNAs of HDAC 8, c MYC and MYCN are the direct targets of suppressor miR-665.
3.3 MiR-665 induced activation of caspase 3
HDAC inhibitors induce the caspase 3-dependent apoptosis [8] Suppressor miR-34a increased the activation of caspase 3 and caused caspase dependent apoptosis in neuroblastoma cells [17, 18]. Caspase 3 is a critical part of apoptosis, and is required for the DNA fragmentation and for the typical morphological changes of cells undergoing apoptosis. We investigated the effect of miR-665 on the activation of caspase 3 and activity was measured by the hydrolysis of the peptide substrate attached to p-nitroanilid. Caspase 3 activity was measured in cell extracts prepared from cells transfected with negative control miRNA and miR-665. Results show that caspase 3 activity was increased by 2.5-fold in miR-665 transfected cells compared to negative control miRNA (Figure 3D). Specificity of the caspase 3 was determined by the addition of caspase 3 inhibitor TSA before the addition of substrate in the assay. The results show that inhibitor binds to caspase 3 and inhibited 90% of miR-665 activated caspase 3 activity (Figure 3D). These results show that mimic miR-665 activated caspase 3 in neuroblastoma cells, suggesting that miR-665 can inhibit cell growth and reduced viable cells by caspase 3 dependent apoptosis.
3.4 miR-665 levels following transfection
miR-665 levles were quantitated in neuroblastoma cells transfected with negative control miRNA and miR 665 using real time qPCR. Mouse neuroblastoma cells have very low levels of endogenous miR-665 (Figure 4A); however, miR-665 expression increased 848-fold in cells transfected with mimic miR-665 compared to cells transfected with the negative control miRNA, cel miR-67 (Figure 4A and B). miRNA levels reportedly increased by over 1000-fold in cells transfected with miR 200a [19]. Our results strongly indicate that miR-665 upregulation decreased MYC and HDAC8 expression, thus inhibiting proliferation and inducing apoptosis in mouse neuroblastoma cells.
Figure 4.
Quantitation of miR-665 in transfected cells. miR-665 was quantitated via real-time qPCR normalized to the U6 gene from three biological replicates 48 h after transfection with negative control miRNA (cel-miR-67) or miR-665. From left, lane 1 and 14 (M), show DNA molecular weight ladder (A) lanes 2–7 (NC-1–NC3 and 665–1–665-3) show the U6 gene. Lanes 8–10 (NC-1–NC3) show miR-665 levels from cells transfected with negative control miRNA. Lanes 11–13 (665–1–665-3) show miR-665 levels from cells transfected with miR-665. The miR-665 fold increase in miR-665-transfected cells was quantitated using the 2-ΔΔCt method (B) miR665 levels are shown in cells transfected with negative control miRNA (black bar) and in miR-665-transfected cells (white). Error bars were calculated from the standard deviation from three biological replicates. *P < 0.54x10–6. (figures were printed from published article in “Oncotarget”, N.Prashad Vol 9, 33186–33201, 2018).
3.5 siRNA effect on mouse neuroblastoma cells
miRNA targets hundreds of m RNAs and suppresses their expression, however, siRNA targets a specific m RNA. In these experiments, siRNA for HDAC 8 (siRNA-HDAC 8) and siRNA for MYC (siRNA-c MYC) were used to substantiate the effects of miR-665 on neuroblastoma cells.
3.6 SiRNA effect on cell proliferation
NB cells were transfected with negative control siRNA, siRNA-HDAC 8, siRNA-c MYC and the combination of siRNA-HDAC 8 + siRNA-c MYC. After 48 hr. of growth, cell viability was determined with CellTiter assay (Promega). SiRNA-HDAC8 inhibited 42% and siRNA-c MYC inhibited 55% of cell proliferation, however, the combination of both siRNAs inhibited 86% of the growth of the cells (Figure 5A). Therefore, the combination of siRNA-HDAC8 plus siRNA-c MYC was more targeted towards mRNA of HDAC8 and c MYC and caused more effective apoptosis and loss of cells. These results show that HDAC 8 and MYC are critical targets and inhibition of both targets is required for the inhibition of neuroblastoma.
Figure 5.
siRNA effects on neuroblastoma cells.siRNA specific for HDAC8 (siRNA-HDAC8) or c-MYC (siRNA-c-MYC, a mixture of 4 siRNAs) were used to confirm the effects of miR665 in neuroblastoma cells. (A) siRNA effect on cell proliferation. Neuroblastoma cells were transfected with 50 nM siRNA-HDAC8, 100 nM siRNA-c-MYC, or both siRNAs together. Cell viability was measured via MTS assay. SEM bars represent the standard deviation from two independent experiments with three biological replicates each. *P < 0.005, **P < 0.001, ***P = 6.8x10–5. (B) Cell extracts from negative control siRNA- or siRNA-HDAC8-treated cells were used to quantify HDAC8 levels via ELISA. HDAC8 was down regulated in HDAC8-siRNA-transfected cells *P < 0.04. (C) Caspase 3 activity was quantified in cell extracts via Casp-3 kit. Caspase 3 activity increased in siRNA-HDAC8- and siRNA-c-MYC-transfected cells. SEM bars represent the standard deviation from two independent experiments with two biological replicates each. *P < 0.01, **P < 0.004. (figures were printed from published article in “Oncotarget”, N.Prashad Vol 9, 33186–33201, 2018).
3.7 SiRNA effect on HDAC 8 and C MYC
HDAC 8 and c MYC proteins were quantitated by antibody in ELISA in cell extracts prepared from the cells transfected with negative control siRNA and siRNA-HDAC 8. The results show that siRNA-HDAC 8 transfection inhibited 40% of HDAC 8 proteins (Figure 5B) as well as inhibited 35% of MYC protein. Inhibition of MYC may be indirect effect of HDAC 8 inhibition. HDAC8 inhibition increases acetylation of histones and alters gene expression, thus decreasing MYC expression. Therefore, miR-665 represses the expression of c MYC both at the transcription and at the post transcription levels. siRNA-HDAC 8 and siRNA-c MYC substantiated the effects of miR-665 on neuroblastoma cells.
3.8 siRNA activates caspase 3
Caspase 3 activity was measured in the cell extracts prepared from cells transfected with negative control siRNA, siRNA-HDAC8 and siRNA-c MYC. The results show that siRNA-HADC8 increased the activity of caspase 3 by 1.8-fold and siRNA –c MYC increased the activity of caspase 3 by 2.5-fold compared to negative control siRNA (Figure 5C). Therefore, the results of siRNA effects substantiate the effects of miR-665 on the activation of caspase 3.
3.9 Effect of miR-665 and siRNAs on histone acetylation
Our results show that miR-665 and siRNA-HADC8, decreased total HDAC activity and decrease HDAC 8 protein, therefore, we measured the acetylation of histones in the cell extracts and the results were compared among all treatments. MiR-665 transfected cells show increases in the acetylation of histones Ac-H2B by 25%, Ac-H3 by 40% and Ac-H4 by 50% compared to negative control miRNA transfected cells (Figure 6A). miR-665 acetylates predominantly H3 and H4 histones.
Figure 6.
Histone acetylation. Cell extracts from negative control miRNA-, miR-665-, negative control siRNA-, or siRNA-HDAC8 treated cells were used to quantitate histone acetylation via ELISA. Data represent standard deviations from two independent experiments. Negative control miRNA (white) and miR-665 transfection increased histone acetylation (black) (A) *P < 0.01, **P < 0.01, ***P < 0.04. Negative control siRNA (white) and siRNA-HDAC8 increased histone acetylation (black) (B) *P < 0.008, **P < 0.04, ***P < 0.001.
Likewise, Si RNA-HDAC8 treated cells also show increases in the acetylation of histones Ac-H2B by 38%, acetylation of Ac-H3 by 58% and show higher acetylation of Ac-H4 by 2-fold (200%) compared to negative control siRNA treated cells (Figure 6B). siRNA-HDAC8 acetylated predominately AC-H4 and correlate with the results of miR-665.
3.10 miR-665 targets c-MYC and HDAC8
Taken together, our results indicate that miR-665 targets c-MYC and HDAC8, decreasing their expression, increasing histone acetylation, and modulating expression of cell proliferation related genes. We propose a model (Figure 7)illustrating suppressor miR-665 involvement in the inhibition of neuroblastoma cell proliferation [10].
Figure 7.
Proposed model illustrating how suppressor miR-665 targets c-MYC and HDAC8 to inhibit neuroblastoma cell proliferation and maintain cellular homeostasis. (figures were printed from published article in “Oncotarget”, N.Prashad Vol 9, 33186–33201, 2018).
3.11 Effects of combination of siRNA-HDAC 8 ± siRNA-MYC on neuroblastoma cells in vitro
When cells were treated with the combination of siRNA HDAC 8 + siRNA-MYC, cell proliferation was inhibited by 86% [10]. Therefore, HDAC 8 and MYC are critical targets and effective blockade of both targets is required to ensure a maximum inhibition of neuroblastoma cell proliferation.
On the basis of these results, we hypothesized that neuroblastoma tumor xenograft growth in mice can be inhibited when treated with the combination of siRNA-MYC + siRNA- HDAC8.
3.12 Neuroblastoma tumor treatment with the combination of siRNA-HDAC8 + siRNA-MYC
We explored the therapeutic effect of the combination of siRNA-HDAC8 + siRNA-MYC treatment on neuroblastoma tumor xenograft in mice. A total of 1x106 mouse neuroblastoma cells in 50% Matrigel were inoculated subcutaneously in 6 weeks old female A/J mice. Tumors were formed with an average volume of 100 mm3, 12 days after cells were inoculated. A 3 nmol negative control siRNA (NC-siRNA) or a 3 nmol combination of siRNA-HDAC + siRNA-MYC complexed with Lipofectamine RNAi max (Invitrogen) were inoculated into 10 tumors each by intratumoral injections every 3rd day. Tumor growth was measured every 2 days with a caliper and volume was calculated with the formula, length X width2/2. The growth of control tumors treated with NC-siRNA increased, however, the tumors treated with the combination of siRNA-HDAC8 + siRNA-MYC show inhibition of the growth of tumors (Figure 8A). The rates of tumor growth were significantly decreased when treated with combined siRNA-MYC + siRNA-HDAC8 compared to tumors treated with control negative siRNA.
Figure 8.
(A) Effect of combination of siRNA on the growth of neuroblastoma tumor. Murine neuroblastoma cells, 1 × 106 cells in DMEM media with 50% matrigel in 100 ul were subcutaneously injected on the right flanks. After 12 days, tumor growth can be seen and tumors were measured with a caliper. When tumors reached 100 mm3 in size, mice were divided into two groups with 8 mice in each group. Negative control siRNA or combination of siRNA-MYC + siRNA-HDAC8 was mixed with Lipofectamine RNAi max (liposome) in DMEM media without fetal bovine serum and without antibiotic. siRNA complexed with Lipofectamine in a volume of 30 ul was delivered into tumors by intratumoral injection every third day. Tumors were measured every second day with a caliper and mice were weighed every third day. Tumor volume was calculator with a formula, V = length × width 2 /2. The numbers on X-axis show the number of siRNA treatments. Control tumor growth is shown by diamond (^) markers and the growth of tumors treated with siRNAs is shown by round (0) markers. SEM bars represent the standard deviation from 8 mice at each point P* < 0.031. (figure is printed from published article in “J. Cancer Biology and Therapeutics” N. Prashad V 6: 301–307 2020). (B) Mice with control and combination of siRNA treated tumors. Top row of mice with control tumors treated with NC siRNA and the bottom row of mice with tumors treated with the combination of siRNA-MYC + siRNA-HDAC. (C) Tumors from control and combination of siRNA treated mice. Top row representative control tumors treated with NC-siRNA and the bottom row representative tumors treated with the combination of siRNA-MYC + siRNA-HDAC8. (figure is printed from published article in “J. Cancer biology and therapeutics” N. Prashad V 6: 301–307 2020). (D) Weights of control and combination of siRNA treated tumors. Average of 8 control tumors was 1 gram and average of 8 tumors treated with combination of siRNA MYC + siRNA-HDAC8 was 0.186 gram. SEM bars represent the standard deviation from 8 tumors P** < 0.004.
All mice experiments were performed under IACUC approved animal study protocol.
Experiment was stopped when the control tumors reached an average volume of over 1200 mm3, then mice were euthanized by CO2 and tumors were removed and weighed. Pictures of mice with tumors were taken before tumors were removed (Figure 8B) and pictures of tumors removed and weighed are shown in (Figure 8C). The average wet weight of 8 control tumors treated with NC-siRNA and tumors treated with combination of siRNA-HDAC + siRNA-MYC is presented in Figure 8D. The average weight of tumors treated with the combination of siRNA-HDAC8 + siRNA-MYC was decreased by 5-fold [0.186 g] compared to average weight of control tumors [1 g] treated with NC-siRNA. Tumor xenograft experiment was repeated twice with 10 mice treated with NC-siRNA and 10 mice treated with a combination of siRNA-HDAC8 + siRNA-MYC.
3.13 The quantitation of targets HDAC 8 and MYC in tumors
Tumor targets HDAC 8 and MYC proteins were quantitated by ELISA in extracts prepared from tumors treated with negative control siRNA and combination of siRNA-HDAC 8 + siRNA-MYC treated tumors. The results indicate that targets HDAC 8 and MYC were decreased by 85% and 65% in tumors treated with the combination of siRNA-HDAC8 + siRNA-MYC compared to tumors treated with NC-siRNA (Figure 9A and B).
Figure 9.
(A, B) Quantitation of Myc and Hdac8 proteins from control and combination of siRNA treated tumors. Tumor targets Hdac8 and Myc proteins were quantitated by ELISA in extracts prepared from 3 tumors treated with negative control siRNA and 3 tumors treated with the combination of siRNA-HDAC 8 + siRNA-MYC. Average targets Hdac8 (A) and Myc (B) proteins were decreased by 85% and 65% in tumors treated with the combination of siRNA-HDAC8 + siRNA-MYC compared to tumors treated with NC-siRNA. SEM bars represent the standard deviation from 3 tumors (P* < 0.030, P** < 0.01). (figures printed from the article published in “J Cancer Biol Therap,” N. Prashad 6(1): 301–307 (2020)).
The results indicate that a decrease in the tumor targets HDAC 8 and MYC caused the inhibition of the growth of tumors.
4. Discussion
miRNAs are both oncogenic and tumor suppressors. In normal cells homeostasis is maintained by keeping equilibrium between oncogenic and suppressor miRNA. If this equilibrium is disrupted that can cause dysfunction with increases in oncogenic miRNA and decreases in suppressor miRNA. A decrease in a specific suppressor miRNA can cause overexpression of HDCAs, c MYC and MYCN which can alter gene expression and cause cancer. However, when suppressor miRNAs are added exogenously to these cells then these cells restore normal properties and show growth arrest and apoptosis Therefore, suppressor miRNAs seem to be critical in the maintenance of cellular homeostasis.
A decrease in suppressor miRNA can over express genes like c MYC, MYCN and HDACs and cause cancers. Over expression of c MYC and MYCN cause the down regulation of suppressor miRNAs. HDACs indirectly effect gene expression by the deacetylation of histones, therefore, this process can also effect the expression of miRNA.
Transfection of miR-665 into murine NB cells caused growth inhibition, cell cycle arrest, decreased total HDAC activity, decreased HDAC8 and MYC protein expression, activated caspase 3 and increased the acetylation of histones. miR-665 targets HDAC8, c MYC and MYCN oncogene and decreases their expression. These targets are validated by the co- transfection of luciferase reporter with target 3’ UTR and miRNA-665. Therefore, miRNA 665 directly targets HDAC 8, MYCN and c MYC in the inhibition of mouse neuroblastoma cells. This is the first report to show that miR-665 is a suppressor miRNA of mouse neuroblastoma.
In targeted therapy of cancer, critical genes and proteins involved in the tumorigenesis are identified and therapeutic agents’ miRNA and siRNA are used to inhibit the expression of target genes to inhibit the growth of cells in vitro and in vivo. SiRNA-mediated gene knockdown is much more potent and specific with only one mRNA target, whereas miRNA has multiple mRNA targets. siRNA therapeutic approach was used in gene targeting overexpressed cancer proteins in inhibiting cancer cell growth in vitro and inhibited tumor growth in vivo in the following mouse models: breast cancer mouse model, Glioma cells tumor and colon cancer tumor. MYCN, c-MYC, and HDAC8 may each contribute to neuroblastoma tumorigenesis. We reported that transfection of mimic suppressor miR-665 inhibited the expression of c-MYC and HDAC 8 and increased caspase 3 involved in apoptosis and inhibited the growth of neuroblastoma cells in vitro [10].
Our data also indicate that both c-MYC and HDAC 8 are critical targets and targeting these two targets with siRNA inhibited cell growth by 86% in vitro. The combination of siRNAs inhibited tumor growth in vivo by 80%, therefore, inhibiting more than one target is critical for the successful treatment of tumors in vivo.
5. Conclusion
Neuroblastoma is the most frequently diagnosed extracranial solid tumor in children. These tumors account for 15% of childhood deaths from cancer. Survival in one- year-old children is <30% despite aggressive therapies.
We used mouse neuroblastoma tumor model and identified MYC and HDAC8 are the critical targets in neuroblastoma tumorigenesis. Treatment of the tumors in mice with the combination of siRNA-MYC + siRNA-HDAC8 inhibited both the targets MYC and HDAC8 simultaneously and inhibited the growth of tumor by 80%. Therefore, inhibiting more than one target is critical for the successful treatment of tumors in vivo.
Acknowledgments
The author would like to thank Texas Children’s Hospital Flow Cytometry Core Facilities, Houston, Texas, for their help in performing cell cycle analysis and Dr. George Calin and associates at MD Anderson Cancer Center, Houston, Texas, for access to the luminometer plate reader.
Conflicts of interest
The author declares that they have no conflicts of interest.
Declarations
Ethics approval: Mice experiments were performed with the approval of the institutional Animal Care and Use Committee, IACUC at Nanospectra Biosciences Inc. Houston, Texas.
Grant support
TMC Internist, Houston, Texas provided partial funding for the chemical supplies used in this project.
\n',keywords:"neuroblastoma, miRNA, siRNA, MYC, HDAC8",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75151.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75151.xml",downloadPdfUrl:"/chapter/pdf-download/75151",previewPdfUrl:"/chapter/pdf-preview/75151",totalDownloads:6,totalViews:0,totalCrossrefCites:0,dateSubmitted:"November 4th 2020",dateReviewed:"January 14th 2021",datePrePublished:"February 25th 2021",datePublished:null,dateFinished:"February 9th 2021",readingETA:"0",abstract:"HDAC8, c MYC and MYCN are involved in the tumorigenesis of neuroblastoma. A mouse Neuroblastoma (NB) tumor model was used to understand the role of miRNA, miR-665 in NB tumorigenesis and cellular differentiation. During cellular differentiation of NB cells there is an up regulated miRNA-665. We found that HDAC 8, c MYC and MYCN are the direct targets of mimic miR-665 which was validated by luciferase reporter plasmid with 3’ UTR and ELISA. Mimic miR-665 inhibited cell proliferation, arrested cells in G1 stage and decreased S Phase in cell cycle. miR-665 increased the acetylation of histones and activated Caspase 3. This is the first report to recognize miRNA 665 as a suppressor miRNA of NB. The effects of miR-665 were confirmed with the transfection of siRNA for HDAC8 and siRNA for MYC. Individual siRNA- HDAC8 or siRNA-MYC inhibited 40–50% of cell proliferation in vitro, however, the treatment with the combination of both siRNA-MYC + siRNA- HDAC8 inhibited 86% of cell proliferation. Indicating that both the targets c MYC and HDAC 8 should be reduced to obtain a significant inhibition of cell proliferation. Intratumoral treatment of xenograft tumors in mice with the combination of siRNA-MYC + siRNA- HDAC8 reduced the levels of target c-MYC protein by 64% and target HDAC 8 protein by 85% and the average tumor growth reduced by 80% compared to control tumors treated with NC-siRNA. Our results suggest the potential therapeutic effect of suppressor miR-665 and the combination of siRNA-MYC + siRNA-HDAC8 for neuroblastoma treatment.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75151",risUrl:"/chapter/ris/75151",signatures:"Nagindra Prashad",book:{id:"10340",title:"Neuroblastoma",subtitle:null,fullTitle:"Neuroblastoma",slug:null,publishedDate:null,bookSignature:"Prof. Amit Agrawal",coverURL:"https://cdn.intechopen.com/books/images_new/10340.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"100142",title:"Prof.",name:"Amit",middleName:null,surname:"Agrawal",slug:"amit-agrawal",fullName:"Amit Agrawal"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Materials and methods",level:"1"},{id:"sec_2_2",title:"2.1 Reagents",level:"2"},{id:"sec_3_2",title:"2.2 Cells and cell culture",level:"2"},{id:"sec_4_2",title:"2.3 Transfections",level:"2"},{id:"sec_5_2",title:"2.4 Whole cell extracts",level:"2"},{id:"sec_6_2",title:"2.5 Quantitation of miR-665 in transfected cells",level:"2"},{id:"sec_7_2",title:"2.6 Total HDAC activity",level:"2"},{id:"sec_8_2",title:"2.7 HDAC8 and c-MYC protein quantitaion via ELISA",level:"2"},{id:"sec_9_2",title:"2.8 Caspase 3 activity",level:"2"},{id:"sec_10_2",title:"2.9 Target validation using luciferase expression plasmids",level:"2"},{id:"sec_11_2",title:"2.10 Histone acetylation",level:"2"},{id:"sec_12_2",title:"2.11 Neuroblastoma tumor model",level:"2"},{id:"sec_13_2",title:"2.12 Tumor extract preparation",level:"2"},{id:"sec_14_2",title:"2.13 Statistical analysis",level:"2"},{id:"sec_16",title:"3. Results",level:"1"},{id:"sec_16_2",title:"3.1 miR-665 inhibits cell proliferation",level:"2"},{id:"sec_17_2",title:"3.2 miR-665 targets HDAC 8, c MYC and MYCN",level:"2"},{id:"sec_18_2",title:"3.3 MiR-665 induced activation of caspase 3",level:"2"},{id:"sec_19_2",title:"3.4 miR-665 levels following transfection",level:"2"},{id:"sec_20_2",title:"3.5 siRNA effect on mouse neuroblastoma cells",level:"2"},{id:"sec_21_2",title:"3.6 SiRNA effect on cell proliferation",level:"2"},{id:"sec_22_2",title:"3.7 SiRNA effect on HDAC 8 and C MYC",level:"2"},{id:"sec_23_2",title:"3.8 siRNA activates caspase 3",level:"2"},{id:"sec_24_2",title:"3.9 Effect of miR-665 and siRNAs on histone acetylation",level:"2"},{id:"sec_25_2",title:"3.10 miR-665 targets c-MYC and HDAC8",level:"2"},{id:"sec_26_2",title:"3.11 Effects of combination of siRNA-HDAC 8 ± siRNA-MYC on neuroblastoma cells in vitro",level:"2"},{id:"sec_27_2",title:"3.12 Neuroblastoma tumor treatment with the combination of siRNA-HDAC8 + siRNA-MYC",level:"2"},{id:"sec_28_2",title:"3.13 The quantitation of targets HDAC 8 and MYC in tumors",level:"2"},{id:"sec_30",title:"4. Discussion",level:"1"},{id:"sec_31",title:"5. Conclusion",level:"1"},{id:"sec_32",title:"Acknowledgments",level:"1"},{id:"sec_32",title:"Conflicts of interest",level:"1"},{id:"sec_33",title:"Declarations",level:"1"},{id:"sec_34",title:"Grant support",level:"1"}],chapterReferences:[{id:"B1",body:'World Health Organization. 2014. Chapter 5. 16.'},{id:"B2",body:'Maris JM, Hogarty MD, Bagatell R, Cohn SL.. Neuroblastoma. Lancet. 2007;369 (9579):2106-2120.'},{id:"B3",body:'Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM, Dang CV, Thomas-Tikhonenko A, Mendell JT. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet. 2008;40(1):43-50.'},{id:"B4",body:'O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. C-myc regulated micrornas modulate e2f1 expression. Nature. 2005;435(7043):839-843.'},{id:"B5",body:'Dang CV. C-myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol. 1999;19(1):1-11.'},{id:"B6",body:'Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA. 2000;97(18):10014-10019.'},{id:"B7",body:'Oehme I, Deubzer HE, Wegener D, Pickert D, Linke JP, Hero B, Kopp-Schneider A, Westermann F, Ulrich SM, von Deimling A, Fischer M, Witt O. Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin Cancer Res. 2009;15(1):91-99.'},{id:"B8",body:'Glick RD, Swendeman SL, Coffey DC, Rifkind RA, Marks PA, Richon VM, La Quaglia MP. Hybrid polar histone deacetylase inhibitor induces apoptosis and cd95/cd95 ligand expression in human neuroblastoma. Cancer Res. 1999;59(17):4392-4399.'},{id:"B9",body:'Coffey DC, Kutko MC, Glick RD, Butler LM, Heller G, Rifkind RA, Marks PA, Richon VM, La Quaglia MP. The histone deacetylase inhibitor, CBHA, inhibits growth of human neuroblastoma xenografts in vivo, alone and synergistically with all-trans retinoic acid. Cancer Res. 2001;61(9):3591-3594.'},{id:"B10",body:'Prashad N. Mir-665 targets c-myc and hdac8 to inhibit murine neuroblastoma cell growth. Oncotarget. 2018; 9(69):33186-33201.'},{id:"B11",body:'Liang Y, Gao H, Lin SY, Sirna-based targeting of cyclin e overexpression inhibits breast cancer cell growth and suppresses tumor development in breast cancer mouse model. PLOS ONE. 2010;5(9):e12860.'},{id:"B12",body:'Uchida H, Tanaka T, Sasaki K, Kato K, Dehari H, Ito Y, Kobune M, Miyagishi M, Taira K, Tahara H, Hamada H. Adenovirus mediated transfer of sirna against survivin induced apoptosis and attenuated tumor cell growth in vitro and in vivo. Molecular Therapy. 2004;10(1):162-171.'},{id:"B13",body:'Oh BY, Lee RA, Kim KH. Sirna targeting livin decreases tumor in a xenograft model for colon cancer. World Journal of Gastroenterology. 2011;17(20):2563-2571.'},{id:"B14",body:'Zhang X, Ge YL, Tian RH. The knockdown of c-myc expression by RNAi inhibits cell proliferation in human colon cancer HT-29 cells in vitro and in vivo. Cell Mol Biol Lett. 2009;14(2):305-318.'},{id:"B15",body:'Prashad N. Targeting Myc and Hdac8 with a combination of SiRNAs inhibits Tumor Growth in murine Neuroblastoma Xenograft Model. Journal of Cancer Biology and Therapeutics. 2020; 6(1): 301-307'},{id:"B16",body:'Khandelia P, Yap K, Makeyev EV. Streamlined platform for short hairpin RNA interference and transgenesis in cultured mammalian cells. Proc Natl Acad Sci USA. 2011;108(31):12799-12804.'},{id:"B17",body:'Welch C, Chen Y and Stallings RL MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells. Oncogene. (2007); 26: 5017-5022'},{id:"B18",body:'Wei JS, Song YK, Durinck S, Chen QR, Cheuk AT, Tsang P,Zhang Q, Thiele CJ, Slack A, Shohet J, Khan J. The MYCN oncogene is a direct target of miR-34a. Oncogene. 2008; 27:5204-13.'},{id:"B19",body:'Li T, Xue Y, Wang G, Gu T, Li Y, Zhu yy, Chen L Multi-target sirna: therapeutic strategy for hepatocellular carcinoma. J Cancer. 2016; 7: 1317-1327'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Nagindra Prashad",address:"nagindra.prashad@gmail.com",affiliation:'
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What makes IntechOpen a great place to work?
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IntechOpen is a dynamic, vibrant company, where exceptional people are achieving great things. We offer a creative, dedicated, committed, and passionate environment but never lose sight of the fact that science and discovery is exciting and rewarding. We constantly strive to ensure that members of our community can work, travel, meet world-renowned researchers and grow their own career and develop their own experiences.
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If this sounds like a place that you would like to work, whether you are at the beginning of your career or are an experienced professional, we invite you to drop us a line and tell us why you could be the right person for IntechOpen.
Integrity - We are consistent and dependable, always striving for precision and accuracy in the true spirit of science.
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Openness - We communicate honestly and transparently. We are open to constructive criticism and committed to learning from it.
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Disruptiveness - We are eager for discovery, for new ideas and for progression. We approach our work with creativity and determination, with a clear vision that drives us forward. We look beyond today and strive for a better tomorrow.
\n\n
What makes IntechOpen a great place to work?
\n\n
IntechOpen is a dynamic, vibrant company, where exceptional people are achieving great things. We offer a creative, dedicated, committed, and passionate environment but never lose sight of the fact that science and discovery is exciting and rewarding. We constantly strive to ensure that members of our community can work, travel, meet world-renowned researchers and grow their own career and develop their own experiences.
\n\n
If this sounds like a place that you would like to work, whether you are at the beginning of your career or are an experienced professional, we invite you to drop us a line and tell us why you could be the right person for IntechOpen.
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