1. Introduction
1.1. TP53 Mutations and CNS tumors
Central nervous systems (CNS) malignancies, as others cancers, are formed by the uncontrolled cell growth that involves the sequential accumulation of alterations in genes controlling cell proliferation, lifespan, responses to stress, relationships with neighbors, and gene homeostasis. These genetic alterations can be achieved by intragenic mutations, chromosome alterations or epigenetics modifications, all playing important role in the activation or inactivation of key genes, such as oncogenes and tumor suppressor genes. Some of these mutations can be most frequently encountered in specific cancers or group of cancers and correlated with tumor biologic behavior and have implications on diagnosis, prognosis or treatment [1].
Biomarkers are important oncology tools in diagnostic, monitoring disease progression, helping in determining prognosis and predicting therapeutic response. Biomarkers vary from specific proteins and antigens to unique genetic, epigenetic or cytogenetic profiles, but common to all markers is that they provide specific information to a disease process. They function as supplementary and rarely supplanting, the histopathologic examination of tissues that is still the mainstay of traditional oncologic pathology [2, 3]. For this reason, we intend to compile the vast information about the important contribution of
CNS cancers are heterogeneous diseases, arbitrarily grouped by the systems that are affected. The “WHO (World Health Organization) Classification of Tumors of the Central Nervous System” discriminates more than one hundred different diseases derived from different cell types, affecting patients of different ages, with a vast biological behavior and clinical implications. It is not our intention to describe the features of each CNS tumor. Hence, authors will follow the WHO classification for CNS tumors [4].
Commonly, advanced stage or aggressive behavior cancers have a higher frequency of
Among single-base substitutions, about 25% are C:G>T:A substitutions at CpG sites. CpG dinucleotides mutate at a rate 10 times higher than other nucleotides, generating transitions [18]. About 3%–5% of cytosines in the human genome are methylated at position 5’ by a postreplicative mechanism that is restricted to CpG dinucleotides and is catalyzed by DNA methyltransferases. The 5’ methylcytosine (5mC) is less stable than cytosine and undergoes spontaneous deamination into thymine at a rate five times higher than the unmethylated base. This process is enhanced by oxygen and nitrogen radicals, leading to a higher load of CpG transitions in cancers arising from inflammatory precursors such as Barrett’s mucosa or ulcerative colitis [19, 20]. Among the 22 CpG of the DNA-binding domain (DBD), three hotspot codons (175, 248, and 273) represent 60% of CpG mutations and another five residues (196, 213, 245, 282, and 306) account for 26% of these mutations. The lack of mutations at other CpG sites may reflect the fact that substitutions at these residues do not generate a dysfunctional protein. Although the same CpG hotspot mutations occur in many cancer types, other types of mutations tend to show differences among different cancers. Some of these differences have been linked to the effect of specific mutagens. This idea is endorsed by geographic differences which can be related to different environmental exposures [21].
All these mutational information about
Several studies have investigated the predictive value of
The majority of mutations led to protein accumulation in the nucleus of the cells, which can be detected by immunohistochemistry (IHC) assays. Although some studies have shown an association between p53 positive immunostaining and poor outcomes, several studies have produced conflicting results and expectations on the use of p53 as a useful clinical biomarker failed [23]. Therefore, it seems IHC is a poor surrogate for gene mutation detection, as many mutations do not lead to protein accumulation, and because accumulation of wild-type p53 may also occur in the absence of gene mutation, producing a high rate of false negative and positive results. Hence, the use of IHC leads to an unacceptable number of misclassified cases and to a greater inter-study variability [1, 22].
By contrast, the screening for
2. TP53 genetic alterations in CNS tumors
CNS tumors have historically been classified on the basis of morphological and, more recently, immunohistochemical features with less emphasis on their underlying molecular pathogenesis. The past two decades, however, have seen striking advances in basic brain tumor biology, especially with regard to malignant gliomas and medulloblastomas, the most common CNS cancers of adults and children, respectively [24, 25]. Molecular signatures of tumors may play roles as diagnostic, prognostic, and predictive markers and influence the clinical decision making process. A dynamic classification of tumors is critical for the continuous integration of newly established molecular tools. This topic focuses on various genetics and epigenetics
2.1. Gliomas
Gliomas are the most frequent primary brain tumors and include a variety of different histological types and malignancy grades. Although the cellular origin of gliomas is still unknown, experimental data in mice suggest an origin from neoplastically transformed neural stem or progenitor cells. However, histological classification of gliomas essentially relies on morphological similarities of the tumor cells with non-neoplastic glial cells and the presence of particular architectural features; thereby, most gliomas can be classified as astrocytic, oligodendroglial, mixed oligoastrocytic or ependymal tumors according to the criteria of the WHO classification of CNS tumors [4]. Clinical experiences derived from the prospective randomized clinical trials have shown that the histomorphological criteria alone might not be sufficient to predict the clinical outcome. Moreover, lately integrated genomic studies and exome sequencing have revealed the existence of multiple distinct molecular subtypes within histologically similar looking tumors [26]. For instance, even gliomas with identical histopathological features differ considerably regarding clinical course or response to therapy.
Knowledge of the genetic alterations in the various types and malignancy grades of gliomas has drastically increased over the past years. The evolution of classical tumor molecular and cytogenetic techniques, as well as the development of newer array-based assays of comparative genomic hybridization and RNA expression, allowed subclasses of gliomas to be identified based on molecular or gene expression patterns, showing substantial genetic and gene-expression heterogeneity within and between histologic grades of different histologic types of gliomas [27]. These approaches have identified point mutations and copy number changes (deletions, amplifications, gains) in several regions; deletions and loss of heterozygosity in tumors might point to genes involved in tumor suppression, whereas amplifications and gains might point to genes involved in initiation or progression processes (e.g. oncogenes) [28].
Numerous molecular abnormalities have been associated to the underlying biology of gliomas. The p53 pathway is nearly invariably altered in sporadic gliomas: loss of p53, through either point mutations that prevent DNA binding or deletion in chromosome 17p, is a frequent and early event in the pathological progression of secondary glioblastoma (GBM) [29, 30]. The importance of p53 in gliomagenesis is also underscored by the increased incidence of gliomas in LFS, a familial cancer-predisposition syndrome associated with germline p53 mutations [31]. This genetic linkage has been reinforced by a glioma-prone condition in mice engineered with a commonly observed Li-Fraumeni p53 mutation [32] as well as in p19ARF-null mice, albeit at a low frequency [33]. In human gliomas, p53 mutations are primarily missense mutations and target the evolutionarily conserved domains in exons 5, 7, and 8, thus affecting residues that are crucial to DNA binding [30].
The finding that a second promoter drives an alternatively spliced transcript at the
2.1.1. Astrocytic tumors
The incidence of
Studies assessing the presence of
Xanthoastrocytoma pleomorphic (PXAs) are rare astrocytic malignancies classified as grade II lesions by the WHO. Because of the relative rarity of this lesion, the molecular background is still unclear. Among the abnormalities frequently observed in astrocytic tumors, PXA shares only
Anaplastic astrocytomas, from a clinical, morphologic and genetic point of view, represents an intermediate stage on the route of progression to GBM. They exhibit high
An important clue to pathways involved in gliomagenesis may lie in the two GBM subtypes that have been clinically identified [50]. Primary GBM is typically present in older patients as aggressive, highly invasive tumor, usually without any evidence of prior clinical disease. Secondary GBM have a very different clinical history, being usually observed in younger patients who initially presented low-grade astrocytoma that transformed in GBM within 5–10 years of the initial diagnosis, regardless of prior therapy. The cataloging of genetic lesions in these GBM subtypes has identified differences in their genetic profiles, predominantly in the penetrance of specific genetic mutations. As a result, it has been proposed that primary and secondary GBMs represent two distinct clinical entities, each developing along distinct genetic pathways [50].
In secondary GBMs, 57% of mutations have been reported to be located in the two hotspot codons 248 and 273; however, in primary GBMs, mutations were more equally distributed through all exons, with only 17% occurring in codons 248 and 273 [67]. Furthermore, G:C > A:T transitions at CpG sites were significantly more frequent in secondary than in primary GBMs [67]. The less specific pattern of
Amplification of
But, have all these data any prognostic value for GBMs? Although there is some discordance among different studies, promising data have already been gained. Hence, some studies showed no association between
El Hallani
Considering the association between mutations and treatments, recent studies have shown that the status of the
2.1.2. Oligodendroglial and oligoastrocytic tumors
In contrast to diffuse astrocytomas, loss of 17p and
Watanabe
A number of genetic alterations have been correlated with poorer response to chemotherapy or worse overall survival in anaplastic oligodendrogliomas. Ino
Kim
2.1.3. Ependymal tumors
A number of studies have documented a correlation between p53 expression and tumor grade in ependymomas [90, 92, 93]. Sharma
Some authors have advocated that p53 immunolabeling are important prognostic markers in ependymomas. Zamecnik
2.2. Embryonal tumors
2.2.1. Medulloblastoma
The genetic and genomic understanding of medulloblastoma (MB) has evolved dramatically in the past few years, but the role of p53 in MB pathogenesis has only initiated to be elucidated. Patients with LFS, caused by a germline mutation in p53, develop MB at a higher incidence than the general population [97, 98]. Similarly, p53 deficiency in mice in combination with mutations in other genes, including poly (ADP-ribose) polymerase (PARP), the cell cycle regulatory protein retinoblastoma (Rb), or the Sonic hedgehog (Shh) receptor Patched1 (Ptch1), greatly increases tumor incidence [99, 100], indicating that loss of p53 can promote MB tumorigenesis. However, in contrast with the high incidence of p53 mutations in most human tumors, the
New support for a role for p53 in MB tumorigenesis came from a better understanding of heterogeneity underlying MB tumors. Recently, several groups were able to demonstrate that although morphologically similar, MBs could be divided into several subgroups on the basis of expression profiling [103, 104]. A consensus meeting resulted in the current molecular subclassification of MB into four subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4 [105]. Hopefully, in the near future, this subclassification will be used to select targeted therapies and improve understanding of the behavior of this disease.
As observed for other CNS, reports detailing the prognostic impact of
A large whole-genome and exome sequencing efforts recently published by different groups revealed an additional, albeit small number, of
Carvalho
Some researchers justify the p53 inactivation in MB tumors lacking
2.2.2. CNS primitive neuroectodermal tumors
The presence of
Although the presence of
Immunohistochemical staining for the p53 gene product is a good predictor of poor outcome in PNETs. Robert
2.2.3. Atypical teratoid/ Rhabdoid tumor
The role of p53 in atypical teratoid/ rhabdoid tumor (AT/RT) is also poorly understood. Cell lines established from malignant rhabdoid tumor (MRT) show overexpression of p53, without associated
2.3. Choroid plexus tumors
Choroid plexus tumors (CPT) are rare tumors, often occurring during childhood. Previous studies have shown high frequencies of germline
The prognostic role of p53 in choroid plexus carcinomas has been recently demonstrated. Tabori
2.4. Meningiomas
Few studies have examined the
In contrast the low frequency of
Many studies have examined benign and atypical/malignant meningiomas for over-expression of the p53 protein with diverse results: p53 over-expression has been reported in 0–10% of benign, 50–72.7% of atypical and 77–88.9% of anaplastic or malignant meningiomas [143]. Despite the differing rates, all of the studies are consistent, with atypical/malignant tumors showing higher rates of over-expression than benign meningiomas. However, studies on the biological significance of p53 over-expression are highly contradictory. While over-expression of p53 has been associated with recurrence in some studies [139, 144], no association has been found in others [133, 145]; and still other studies have suggested that expression of high levels of p53 may be protective against recurrence [146].
Terzi
3. Epigenetic mechanisms in CNS tumors
Epigenetics is defined as mitotically heritable changes in gene expression that are not due to changes in the primary DNA sequence. The coordinated interaction of these changes regulates gene expression activity and several types of epigenetic marks work in concert to drive appropriate gene expression, like DNA methylation at CpG dinucleotides, covalent modifications of histone proteins, non-coding RNAs, and other complementary mechanisms controlling higher order chromatin organization within the cell nucleus. Epigenetic alterations have been recognized as important mechanisms in neoplastic transformation, malignant progression of cancer, and although epigenetic changes are somatically inheritable, they are reversible and hence may represent actionable targets for novel therapies [148, 149]
Epigenetic changes are often observed at the earliest stages of neoplasia within the altered tissue stem and progenitor cells. These observations have led to the epigenetic progenitor model [149]. This model explains that transformation to a malignant state occurs in three steps. First, there is an expansion of an epigenetically permissive population due to an essential early epigenetic disruption of stem/progenitor cells. Second, an initiating genetic alteration in an oncogene or tumor suppressor gene occurs. Finally, genetic and epigenetic plasticity resulting in an enhanced ability to stably evolve the phenotype is observed. An important difference to the clonal genetic model is that the epigenetic ‘hits’ occur early, and are necessary to create an appropriate expansion of a polyclonal population, that is the cellular substrate for subsequent genetic alterations and transformation [150].
To better understand the multiple cellular pathways involved in their development, establishment markers of resistance to traditional therapies, and contribution to the development of targeted therapies, a comprehensive appreciation of the integrated genomics and epigenomics of CNS tumors is needed [151].
3.1. DNA methylation of gene TP53
Hypermethylation of promoters usually occurs at CpG islands. Methylation of
Analyses of methylation of
Amatya
Almeida
3.2. The new insights of MicroRNAs/TP53 in cancer
MicroRNAs (miRNA) are a large class of small, non-coding RNAs, 21 – 28 nucleotides long, produced naturally in cells after being cut into segments from larger strands of RNA by the enzyme Dicer. They function by binding to complementary sites on the 3’-untranslated region (3’-UTR) of genes and promoting the recruitment of protein complexes responsible for impairing translation and/or decreasing the stability of mRNA [161, 162]. A specific miRNA may simultaneously regulate multiple targets, thereby enabling complex changes in protein expression profiles. Furthermore, a single target can be regulated by multiple miRNAs, and upstream regulation of a given miRNA can involve multiple regulators at different steps of miRNA biogenesis. Thus, miRNAs take part in complex regulatory networks that may influence almost every cellular process [163]. Currently, 1, 048 human microRNAs are known to modulate approximately 3 % of all genes and up to 30 % of protein-coding genes. Vital for protein expression, microRNAs are integrally associated with both normal and abnormal biological processes [164].
miRNAs play important roles in the regulation of normal gene expression at developmental timing, cell proliferation and apoptosis [165]. As these processes are altered in cancer cells, there are in literature several studies that were undertaken to provide evidence for an involvement of miRNAs in cancer formation. miRNA-encoding genes as well as mRNA-encoding genes have been meanwhile classified as oncogenic or tumor suppressive genes according to their function in cellular transformation and expression in tumors [166, 167]. Furthermore, tumor cells seem to undergo a general loss of miRNA expression, and forced reduction of global miRNA expression promotes transformation [168]. Interestingly, miRNAs cluster within fragiles sites and other genomic regions frequently altered in cancers [169]. Because of their role in tumor formation, miRNAs may be very useful for the classification, diagnosis, prognosis, and therapy of malignancies [166, 167].
Profiling miRNA provides an attractive, novel, and non-invasive biomarker for tumor diagnosis and prognosis. Molecular biology techniques, such as Northern blot, RNase protection assay, and primer extension assay can measure expression of a miRNA. The small size of miRNAs initially hampered polymerase chain reaction-based methods. However, PCR-based techniques have become very popular since the development of adaptor-mediated quantitative real-time PCR (qRT-PCR) due to their high sensitivity [170]. Microarray techniques are widely used to comprehensively assay the entire miRNome (the global miRNA expression profile) in tissues or in cell lines [171]. In addition to microarray and qRT-PCR, miRNomes are obtained by
p53 is a transcription factor, so transactivates or represses many protein-encoding genes and this underlies much of its tumor suppressor function. Recently, it has been reported that p53 directly transactivates specifics miRNAs [174]. miRNA have also been shown to target p53 and/or components of p53 regulatory pathways affecting its activities directly and/or indirectly [175, 176].
Several reports shed light on the involvement of miRNAs in the p53 pathway. He
miR34s are induced after genotoxic stress in a p53-dependent manner
As cell cycle arrest, senescence, and apoptosis are tumor suppressive mechanisms, the inactivation of members of the miR-34 family, which induce these cellular responses, may be a selective advantage for cancer cells. Besides decreased expression of MiR-34 due to inactivating mutations of p53, the miR-34 encoding genes themselves may be targets for mutational or epigenetic inactivation in cancer. For example, loss of miR34a expression was observed in neuroblastoma, which may be due to the relatively common deletion of a region on chromosome 1p36, which encompasses miR-34a [183]. However, the mechanisms leading to decreased expression of miR-34s require further exploration.
Other miRNAs may be important in the p53 network. miR-30c, -103, -26a, -107, and-182 were induced clearly, although less robustly, upon DNA damage in a p53-dependent manner [181]. In another approach, the searching for p53-binding elements in DNA sequences near miRNAs identified miR-129 as a good candidate for regulation by p53 [184]. miR-125b, a brain-enriched microRNA, was identified as a bona fide negative regulator of p53 in both zebrafish and humans [185]. Recently, Hu
Since recent studies have indicated that p53 enters into miRNA world [187], some researchers provided important insights into the central roles of miRNAs in a well-known tumor suppressor network, the p53 pathway, which may provide a route to therapeutic miRNA intervention in CNS tumors. Shyamal
Recently, Suh
4. The cancer stem cell model
Until a few years ago, the brain was thought to lack a stem cell population, but actually, it is now known that there are two regions of the adult human brain that contain neural stem cells (NSCs) (a group of self-renewing cells in the nervous system that can generate both neurons and glia): the dentate gyrus of the hippocampus and the subventricular zone. NSCs can form neurons, astrocytes and oligodendrocytes
With the accumulation of knowledge concerning the stem cell and the mechanisms regulating their behaviour, it was noted that many of the characteristics of stem cells were also present in cancer. These findings reinforce the “cancer stem cell model”, which states that the cellular heterogeneity within the tumor is ascribed entirely to the differentiating tumor cells that derive from the cancer stem cells (CSCs), that can be defined as cells that possesses the capacity to self-renew and to originate the heterogeneous lineages of cancer cells that comprise the tumor. The term ‘‘tumor-initiating cell’’ also has been used to describe a cell with the potential to initiate a tumor. This term are essentially functionally equivalent to CSCs if it is used to refer to the subclones of cells within an established tumor that gives rise to a new tumor when transplanted [190-192].
CSCs were first observed by John Dick’s group in acute myeloid leukemia and posteriorly other researchers reported CSCs in solid tumors, including those formed by breast, colon, prostate, pancreatic, lung, liver and brain [193-196], Subsequently there has been a large amount of work to identify the cancer stem cell population, and to study its role in progression of disease and resistance to treatment, allowing many experimental therapies targeting cancer stem cells can be developed and tested in preclinical models [190, 195, 196].
CSCs have been isolated from a wide range of CNS neoplasms, including adult and pediatric, anaplastic oligodendrogliomas and malignant medulloblastomas [197]. For gliomas, several researchers isolated brain tumor stem cells (BTSC) from primary tumors based in the ability to form neurospheres NSCs do and other criteria: ability to be serially transplanted; unique ability to engraft; ability to recapitulate the tumor of origin morphologically and immunophenotypically in xenografts [198].
4.1. P53 role in neuronal and brain tumor stem cell
In the ependymal cell lining of the lateral ventricle wall as well as most cells of the subventricular zone, including astrocytes and progenitors, abundance of nuclear p53 is evident and in agreement with the down-regulation of p53 in differentiating cells observed during embryogenesis. The nuclear p53 immunoreactivity is absent or found at low levels in the majority of the mature brain, including differentiating cells in the rostral migratory stream, suggesting that p53 is preferentially expressed in neural precursors [113]. Several studies show the important role(s) of p53 in the regulation of mammary [199], hematopoietic [200], embryonic and neuronal stem cells [201] by regulating self-renewal, symmetric division, quiescence, survival, and proliferation.
Meletis
Armesilla-Diaz
While the role of p53 in apoptosis of neuronal cells was well elucidated [202, 204, 205], its function in astrocytes, oligodendrocytes and their precursors is poorly understood. Oligodendrocyte precursors cultured
CSCs exhibit genetic or chromosomal alterations in addition to aberrant differentiation properties, unlike the normal stem cells [208]. It is important to highlight the fundamental differences between normal stem cells and CSCs. The first are known for the vigilance with which their proliferation is controlled and for the care with which their genomic integrity is maintained, while CSCs lack such ability [209]. The cell-of-origin of CSCs remains elusive, however evidences indicate that CSCs may originate from malignant transformation of normal stem cells, because of the perennial nature and high proliferative potential characteristics of stem cells. Some studies have shown that oncogene activation or tumor suppressor gene inactivation increased the frequency of tumor formation in primitive nestin-expressing cells but not in the more differentiated glial fibrillary acidic protein (GFAP)-expressing astrocytes [210, 211] while other researches indicate that differentiated astrocytes and NSCs may be equally permissive to transformation when genomic alterations are introduced [212].
The role of p53 in BTSC has not been well established, however based on current understanding of its function in neural precursors available in the literature, several hypotheses may be develop. First, loss of p53 may increase the self-renewal and proliferation of neural stem and/or lineage-restricted progenitors, thereby expanding the pool of cells available for additional mutations in specifics oncogenes. Another hypothesis is that, depending on cellular context, p53 can both inhibit or promote cell differentiation, as well as influence cell fate decisions, so the differentiation program of neural precursors can be changed by p53 mutation. Lastly, accumulated evidences support a role for p53 in the suppression of cell migration, although much focus on p53 is directed at its growth inhibitory properties [213]. The neurogenic niche has been shown to be important for the maintenance of stem cells in an undifferentiated state, and the premature exit of NSCs from the neurogenic niche may alter their capacity for tissue invasion or differentiation program in the absence of p53 [214].
The number of studies concerning the cellular, molecular, and environmental factors that regulate p53 function in NSCs has increased drastically and brought a better understanding of these factors, and together with the advances in molecular biology techniques, provided much valuable information about the role of p53 in BTSCs. This scenario stimulates future studies exploring the significance of p53 alterations for prognosis and prediction of treatment response that would help development of individual treatment strategies as well as help clarifying the clinical importance of cancer stem cell biology.
5. p53-based gene therapy: GBMs as an example
Malignant tumors within the brain remain a therapeutic challenge, but current strategies tested in animal models as well as in the clinics have shown promising results. The rapid progress in knowledge of the p53 pathway have led to many different approaches to p53 based cancer therapy as mentioned previously and the field has excited great interest both academically and commercially [215]. The long awaited molecular treatment of GBM and other CNS tumors and utilization of knowledge surrounding p53 may then be foreseeable goals in the future. It will also be important and likely therapeutically be effective to combine gene therapy with other therapeutic modalities, including the standards-of-care [216].
Standard treatment of care for GBM, for example, consists of surgical resection, followed by radiotherapy and chemotherapy [217, 218]. Despite significant advances in current treatment approaches, including the gamma knife (radiation) and TMZ (chemotherapy) [217, 219], GBM continues to present a poor prognosis, with median survival still remains less than 15 months. It is important to remember that GBMs are the most common and least curable among CNS tumors [220]. Moreover, for this type of tumor, complete resection is practically impossible due to its diffuse nature and the proximity of the tumor to vital brain structures. Moreover, it often recurs in an area close to the original resection cavity [221]. The intrinsic resistance of glioblastoma cells to radiotherapy and chemotherapy confers another therapeutic challenge of this disease [222]. On the other hand it has been reported that invading GBM cells, which give rise to recurrences, are resistant to cytotoxic therapies due to the constitutive activation of antiapoptotic signaling pathways [221]. Novel therapeutic approaches and adjuvants to be employed in combination with standard therapeutic strategies are sorely needed for GBM patients, because although isolated traditional therapies allow an increase in the quality of life and survival of these patients, they are not curative and long-term survival is very rare [221, 223, 224].
Gene therapy for CNS tumors is evolving every year, especially for GBM, with the ultimate goal being specific delivery of therapeutic genes or oncolytic viruses to eliminate the tumor. Besides results in cell death, also enhanced immune responses to tumor antigens and disruption of the tumor microenvironment [216]. A variety of gene therapy strategies has been examined in GBM preclinical models and clinical trials and includes the use of selective replication-competent oncolytic viruses, non-replicating viral vectors or normal adult stem/progenitor cells for the delivery of immunostimulatory genes, cytotoxic genes and genes modulating the tumor microenvironment [216].
The fact that p53 pathway is activated in tumor cells, but not in normal cells, provides a potentially important therapeutic selectivity, indifferent of which signal in the tumor cells activates p53 following its restoration [225]. In this context, the evidences that tumor cells, but not normal cells, have a cellular environment that activates the p53 pathway would create a setting of an advantageous therapeutic index, whose main objective is the development of interventions that selectively kill tumor cells instead normal cells [225].
Different approaches to achieve this goal are already in various stages of development and a diversity of small druglike molecules targeting the p53 system have been developed and several are now in clinical trials. Of critical importance has been the development of: agents which can increase active p53 in tumor cells by interfering with the p53–MDM2 interaction are therefore considered to have therapeutic utility in sensitizing tumor cells for chemo-or radiotherapy, such as the Nutlins [226, 227]; molecules that activate p53 via direct interaction with p53 itself, as PRIMA-1, of which there is evidence of induction of expression of mediators of p53-dependent apoptosis such as Puma, Noxa, and Bax in cells with mutant p53 [228, 229]; small molecules activating p53 family members in a p53 mutant or deficient background; molecules activating p53 by inhibiting class III histone deacetylases, nuclear export, transcriptional and nucleolar distuption. These screens in combination with RNAi based approaches are of utmost importance for the discovery of new targets for therapy in the p53 pathway [215].
Transfection of wild-type p53 in order to normalize function in mutant p53-containing tumors has been a long-pursued goal of gene therapy. Mercer
To the generation of an effective systemic anti-tumor immune response, it is necessary the development of strategies that promote the GBM tumor cell death, which is essential not only to kill tumor cells and reduce tumor burden, but also to induce the release of inflammatory molecules from dying tumor cells [234]. Drug combinations have been developed to selectively kill cancer cells that lack p53 function while protecting normal cells. The potential to explore the defective checkpoint status of cells with inactive
This topic focused on GBM because of its poor prognosis and the target for most clinical trials. However, it is important to recognize that there are many other brain tumors which are also targets for gene therapy. Recently, Kunkele
6. Conclusion
After a detailed review of the literature about the role of the
Epigenetic events in
Due the difficulty to the use of traditional therapeutic modalities such as chemotherapy and radiotherapy in the CNS tumors, especially in high grade tumors, such as glioblastomas, , it is expected that in a near future molecular treatment that could be obtain more effective control of disease progression will be used, resulting in an improved clinical course of these patients. Over the years, with the increasing advances of molecular biology techniques, much information has been obtained on the role of p53 in carcinogenesis. Because of the critical role p53 plays in a variety of cancers, a diversity of approaches have been undertaken to target p53 and its altered signaling pathways. Different drugs targeting the p53 system in order to activate the p53 pathway have been developed and several are now in clinical trials, and have shown promising results.
Nomenclature
AT/RT | Atypical Teratoid/ Rhabdoid Tumor |
bFGF | Basic fibroblast growth factor |
|
B-cell CLL/Lymphoma 2 |
BTSC | Brain tumor stem cells |
CSC | Cancer stem cells |
|
Cyclin-dependent kinase 4 |
|
Cyclin-dependent kinase inhibitor 2A |
CNS | Central nervous systems |
CHD5 | Chromodomain helicase DNA binding protein 5 |
CPC | Choroid plexus carcinomas |
CPP | Choroid plexus papilloma |
CPT | Choroid plexus tumors |
|
Epidermal growth factor |
FISH | Fluorescence in Situ Hybridization |
GFAP | Glial fibrillary acidic protein |
GBM | Glioblastoma |
|
Isocitrate dehydrogenase 1 (NADP+) |
|
Iisocitrate dehydrogenase 2 (NADP+) |
IHC | Immunohistochemistry |
IARC | International Agency for Research on Cancer |
LFS | Li-Fraumeni syndromes |
LFL | Li-Fraumeni-like syndromes |
LOH | Loss of heterozygosity |
MRT | Malignant Rhabdoid Tumor |
|
MDM2 oncogene, E3 ubiquitin protein ligase |
|
Mdm4 p53 binding protein homolog |
MB | Medulloblastoma |
MET | Met proto-oncogene |
MS-PCR | Methylation-specific PCR |
miRNA | MicroRNAs |
MYC | v-myc avian myelocytomatosis viral oncogene homolog |
HNSCC | Head and Neck squamous cell carcinoma |
NES | Nuclear Exclusion Domain |
NLS | Nuclear Localization Domain |
NSC | Neural stem cell |
|
Neurofibromin 1 |
|
Cyclin-dependent kinase inhibitor 2A (encoding p14) |
|
Cyclin-dependent kinase inhibitor 2A (encoding p19) |
|
Cyclin-dependent kinase inhibitor 2A (encoding p15) |
|
Cyclin-dependent kinase inhibitor 2A (encoding p16) |
PTCH1 | Patched homolog 1 |
PNET | Primitive neuroectodermal tumor |
|
Phosphatase and tensin homolog |
qRT-PCR | Quantitative real-time PCR |
|
Retinoblastoma 1 |
siRNA | small interfering RNA |
SMARCB1 | SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 |
SSCP | Single strand conformation polymorphism |
SHH | Sonic hedgehog |
TMZ | Temozolomide |
|
Tumor protein p53 |
TSC1 | Tuberous Sclerosis 1 |
WHO | World Health Organization |
WT | Wild-type |
WNT | Wingless |
PXA | Xanthoastrocytoma pleomorphic |
Acknowledgments
Authors would like to thank PPGGBM-UFPA, IFPA and IEC for support. We also would like to thank the staffs at Francisco Mauro Salzano Laboratory (UFPA) and Laboratory of Tissue Culture and Cytogenetics (SAMAM, IEC). We are especially grateful to Dr. Cynthia Hawkins (Dept. of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada) for her important contribution.
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