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Novel Perspectives on p53 Function in Neural Stem Cells and Brain Tumors

Novel Perspectives on p53 Function in Neural Stem Cells and Brain Tumors Hindawi Publishing Corporation Journal of Oncology Volume 2011, Article ID 852970, 11 pages doi:10.1155/2011/852970 Review Article Novel Perspectives on p53 Function in Neural Stem Cells and Brain Tumors Sanna-Maria Hede, Inga Nazarenko, Monica Nister, ´ and Mikael S. Lindstrom ¨ Department of Oncology-Pathology, Karolinska Institute, CCK R8:05, SE-17176 Stockholm, Sweden Correspondence should be addressed to Mikael S. Lindstrom, ¨ mikael.lindstrom@ki.se Received 2 August 2010; Revised 18 October 2010; Accepted 29 October 2010 Academic Editor: Shih Hwa Chiou Copyright © 2011 Sanna-Maria Hede et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Malignant glioma is the most common brain tumor in adults and is associated with a very poor prognosis. Mutations in the p53 tumor suppressor gene are frequently detected in gliomas. p53 is well-known for its ability to induce cell cycle arrest, apoptosis, senescence, or differentiation following cellular stress. That the guardian of the genome also controls stem cell self- renewal and suppresses pluripotency adds a novel level of complexity to p53. Exactly how p53 works in order to prevent malignant transformation of cells in the central nervous system remains unclear, and despite being one of the most studied proteins, there is a need to acquire further knowledge about p53 in neural stem cells. Importantly, the characterization of glioma cells with stem-like properties, also known as brain tumor stem cells, has opened up for the development of novel targeted therapies. Here, we give an overview of what is currently known about p53 in brain tumors and neural stem cells. Specifically, we review the literature regarding transformation of adult neural stem cells and, we discuss how the loss of p53 and deregulation of growth factor signaling pathways, such as increased PDGF signaling, lead to brain tumor development. Reactivation of p53 in brain tumor stem cell populations in combination with current treatments for glioma should be further explored and may become a viable future therapeutic approach. 1. Introduction diverse cellular programs such as cell cycle arrest, apoptosis, differentiation, DNA repair, autophagy, and senescence [8]. The most frequent form of brain tumor in adults is One prevailing hypothesis is that GB could arise and glioma [1]. Gliomas are classified as astrocytomas, oligo- recur because of malignant transformation of neural stem dendrogliomas, oligoastrocytomas, and ependymomas [2]. cells residing in protected niche areas [9]. Recently, novel Astrocytoma is the most common subclass of glioma and functions of p53 in stem cells have been characterized is graded on a WHO scale of I to IV, whereas oligo- including suppression of pluripotency and inhibition of dendrogliomas and oligoastrocytomas are usually classified stem cell self-renewal [10]. Despite being one of the most as grade II or grade III [3]. Grade IV astrocytic tumor, extensively studied proteins, there is still a need to acquire commonly known as glioblastoma (GB), is the deadliest form further knowledge and insight into p53 function in stem of brain tumor that despite multimodal therapy only shows a cells including neural stem cells. What function of p53 is the median survival of 12–15 months [4]. Recent transcriptome most important one to inactivate for brain tumor initiation and genome profiling of brain tumors in combination with and progression? Could it be the ability of p53 to restrain advances in stem cell biology has led to an improved self-renewal and to promote differentiation, or is it the pro- understanding of the molecular pathology of this disease and apoptotic and cell cycle regulating activity? Here we discuss revealed novel targets for therapy [5]. the role of p53 in gliomagenesis and the significance of p53 The p53 tumor suppressor gene is frequently mutated in relation to brain tumor stem cells. We review the literature or deleted in human tumors and is often found mutated regarding the neoplastic potential of neural stem cells, and or lost early in glioma formation [6, 7]. p53 can trigger we describe how the loss of p53 in parallel with deregulation 2 Journal of Oncology of growth factor signaling pathways promotes brain tumor [13, 27]. Another common and critical tumor suppressor development. Finally, we discuss how the reactivation of gene alteration in GB is loss of function of PTEN that occurs p53 in brain tumor stem cell populations could become in both primary and secondary GB [28]. one viable approach to suppress proliferation and induce Accumulated experimental and clinical evidence suggests differentiation and apoptosis of these cells. that the loss of p53 function is a key initial event in glioma development in combination with other genetic and epigenetic alterations [6, 7, 26, 29–34]. Numerous studies 2. Glioma Genetics and Glioma Cell of Origin have also been carried out in order to investigate the effects of p53 overexpression in glioma cells. Evidently, p53 can block 2.1. p53 Pathway Inactivation in Glioma. Gliomas often display mutations in the ARF-MDM2-p53 and p16INK4a- cell cycle progression and induce morphological changes CDK4-RB tumor suppressor pathways resulting in increased resembling differentiation in glioma cell lines [35–37]. Given genomic instability, loss of G cell cycle checkpoint control, these findings, therapeutic targeting of the p53 pathway still seems highly interesting in glioma. and evasion of apoptosis [2, 11]. Deregulation of the PI3K/AKT/mTOR signaling pathway and hyperactivation of receptor-tyrosine kinases (e.g., PDGFRα and EGFR) are 2.2. Neural Stem Cells. Tissue stem cells are considered to frequently observed in gliomas [2, 11]. GBs can be classified be rare cells within organs with the ability to self-renew as primary or secondary but are morphologically similar and to give rise to all types of cells within the said organ [1]. Aprimary GB arises with no signsofpreviouslower- [38]. Examples of tissue stem cells include hematopoietic grade tumor and often displays loss of the INK4A/ARF stem cells, neural stem cells, and mammary gland stem cells tumor suppressor gene locus, PTEN mutation, and EGFR [38]. Embryonic stem cells on the other hand are isolated amplification and/or mutation [1]. Secondary GBs show a from the inner cell mass of blastocysts, are pluripotent, previous history of progression from a lower-grade tumor and can give rise to all cell types of the body [39]. Neural and TP53 mutations are frequent [2]. Recently, transcrip- stem cells are the self-renewing cells that generate the main tome and genome profiling of GBs has revealed additional cells of the central nervous system (astrocytes, neurons, and genetic differences, and new subclasses of GB have been oligodendrocytes) [40]. New neurons are thought to be born defined [12–14]. throughout adulthood in predominantly two regions of the mouse brain [41]. These are the subventricular zone of the TP53 mutations occur early in glioma progression, and lateral ventricle wall, from where new neuronal progenitor grade II astrocytomas commonly display TP53 mutations or loss of heterozygosity on chromosome 17p where TP53 cells migrate to the olfactory bulb via the rostral migratory stream [42, 43], and the subgranular zone of hippocampus resides [15, 16]. TP53 mutations are infrequent in medul- [44]. Reynolds and Weiss were the first to isolate neural loblastomas, pilocytic grade I astrocytomas, and ependymo- mas [7]. The p53 tumor suppressor restricts cell growth and progenitor and stem cells from adult mouse brain [45]. Within the subventricular zone, cells can be classified as proliferation following stress and is known as the guardian of the genome [17]. p53 has pleiotropic anticancer functions type B neural stem cells and type C transit-amplifying cells that give rise to neuroblasts (type A) [46]. Neural stem and plays a role in senescence, apoptosis, differentiation, cells are often studied in vitro using a method referred to autophagy, metabolism, and angiogenesis [18]. These diverse cellular effects can be attributed to the regulation of hun- as the neurosphere assay developed by Reynolds and Weiss [45], see also [47] for an update. Neural stem cells have the dreds of different genes directly by p53 [8, 19]. The transcrip- properties of self-renewal, clonogenic capacity, and ability tional function of p53 is stimulated through increased levels of the protein coupled to conformational changes triggered to engraft, migrate, and give rise to differentiated progeny [41, 46, 48]. by different posttranslational modifications or p53- binding proteins [20]. While approximately half of all human tumors contain a mutation or deletion of TP53, the rest of the tumors 2.3. Glioma Cell of Origin and the Cancer Stem Cell Hypoth- often have inactivation of p53 through other mechanisms esis. Several common tumor forms, including brain tumors, including viral infection, loss of ARF, or overexpression of have been shown to harbor a fraction of cells with stem- MDM2 [21]. The MDM4 and MDM2 proteins suppress like features referred to as cancer stem cells [49]. The p53’s transcriptional activity and target p53 for proteasomal cancer stem cells are considered to be a relatively small degradation, respectively [22]. It is therefore not a surprise population of cells that are capable of self-renewal, and the to learn that MDM2 gene amplifications are present in 10% progeny of which can undergo differentiation to generate the of primary GBs and that amplifications of MDM4 are found phenotypic heterogeneity observed in solid tumors [50, 51]. in about 4% of GBs [23, 24]. Gliomas are also seen in Cancer stem cell populations have been found in many the Li-Fraumeni syndrome, a familial cancer predisposing malignancies including those from breast [52], brain [53], syndrome characterized by germ line TP53 mutations [25, pancreas [54], colon [55], and the hematopoietic system 26]. It has been a widely held notion that somatic TP53 (acute myelogenic leukemia) [56]. Cancer stem cells show mutations are common in low-grade gliomas and secondary GBs but more uncommon in primary GB. However recent malicious behavior including prolonged exit from the cell studies, which also included additional sequencing of TP53, cycle (quiescence), resistance to chemotherapeutic agents, revealed that mutations are prevalent in primary GBs as well efficient DNA repair, and resistance to apoptosis [57–60]. Journal of Oncology 3 Using the approach of Reynolds and Weiss [45], several less is known about p53 function in astrocytes, oligoden- groups reported on the growth of adult and pediatric glioma drocytes and their precursors. Oligodendrocyte precursors cells cultured and propagated in the form of neurospheres, cultured in vitro can undergo p53-dependent differentiation also known in this context as “gliospheres” [61–65]. The cells although the cells appear to have a low basal level of p53 capable of self-renewal and of forming new gliospheres and expression [87]. Both astrocytes and oligodendrocytes can with the ability to initiate the formation of a new tumor undergo apoptosis following infection with an adenovirus in nude mice are known as the brain tumor stem cells. expressing p53 [88]. Although speculative, cells of the These cells can also be referred to as brain tumor initiating glial lineage may be more prone towards p53-induced cells or glioma stem cells. It was shown that gliospheres differentiation and senescence following stress than neuronal have an increased growth potential and features of aberrant cells. differentiation when directly compared to normal neuro- What is the function of p53 in the neural stem cells? The spheres from the adult brain [66]. Cell sorting is based on enhanced proliferative capacity of neural precursors from expression of the cell surface marker CD133 selected for Trp53 knockout mice was described in the early 90s [89]. glioma cells with stem-like features [53], and CD133-positive Later, it was found that p53 is expressed at higher levels brain tumor cells are relatively resistant to radiation when in cells in the neural stem cell niche than in other regions compared to CD133-negative cells [57]. The clinical value of the adult mouse brain [73]. Cells in the brain’s lateral of CD133-expression in tumors remains unclear, but some ventricle stem cell niche displayed an increased proliferation groups have reported that the increased expression of CD133 rate in Trp53 knockout mice compared to wild-type [73]. is associated with a poor prognosis [67, 68]. However, recent It was also found that a p53 deficiency in neurospheres studies indicate that also CD133-negative brain tumor cells resulted in increased self-renewal capacity, increased cell can initiate tumor development and act as brain tumor stem proliferation and a reduction in apoptosis [73]. Analysis cells [69]. of the stem cell transcriptome from wild type and Tp53 It is at present discussed whether cancer stem cells knockout mice identified several genes that were down- represent a minority of the tumor cells [70]. If most cells regulated in p53-null neurospheres, importantly p21 and within the tumor are endowed with stem cell properties, p27, established negative regulators of cell proliferation [73]. why should we focus our energy on targeting a specific sub- In a related study, Gil-Perotin et al., found a p53-dependent population of cells? Debated is also whether cancer stem effect on differentiationthe and they could determine that cells originate from normal stem cells or from differentiated loss of p53 increased the number of Tuj1 neuroblasts in cells that have acquired the ability to self-renew [50], and the subventricular zone in vivo [31]. Regions with mild this discussion is especially dynamic within the brain tumor to moderate hyperplasia, resembling “microtumors” were research community [5, 71, 72]. It still remains unclear also apparent in some Trp53 knockout mice [31]. The if gliomas (in general) originate from multipotent neural increase in cell number was apparently not due to loss stem or progenitor cells, restricted neural progenitors, or of apoptosis, as it could be compensated for, and it was mature glia cells that have undergone the process of de- argued that this is the reason for why there are no tumors differentiation [71]. in Trp53 knockout mice [31]. Also by using olfactory bulb neural stem and progenitor cells cultured as neurospheres it was found, in agreement with the previous studies, that 3. Novel Functions of p53 in Neural Stem Cells loss of p53 can promote neurosphere formation and stem cell self-renewal [90]. Furthermore, loss of p53 facilitated A number of recent studies show that p53 has a critical differentiation of progenitor cells into Tuj1-positive neurons, function in neural [73], mammary [74], hematopoietic [75, with a corresponding moderate decrease in mature astrocytes 76] and embryonic stem cells [77] by regulating self-renewal, [90]. In summary, a number of studies show that the loss of symmetric division, quiescence, survival, and proliferation. p53 provides an advantage to neural stem cells and/or early Two main functions of p53 can be distinguished in relation progenitor cells [31, 73, 90]. However, the loss of p53 alone to stem cell behavior. These can be described as the does not cause brain tumors within the relatively short life abilities of p53 to induce differentiation and to suppress de- span of Trp53 knockout mice [91]. differentiation and evidence in the literature supports a role p53-mediated control of stem cell functions has also been for p53 in both of these processes [10, 78–81]. studied in other tissues. For example, p53 has a critical role in In the mouse brain, p53 is critical for induction of regulating hematopoietic stem cell quiescence [75, 76]. Tran- scriptome analysis identified Gfi-1 and Necdin as p53 target apoptosis in neural progenitors and postmitotic neurons during development of the central nervous system [33], and a genes involved in regulating quiescence [76]. In mammary subset of Trp53 knockout mice develop exencephaly [82, 83]. gland stem cells, p53 controls polarity of mammary epithelial Furthermore, neuronal cells are sensitive to p53-dependent stem cell divisions [74]. In bone formation, the loss of p53 apoptosis following irradiation, exposure to chemothera- not only accelerates early osteogenesis from mesenchymal stem cells but actually prevents terminal differentiation to peutic agents, and ischemia [84]. p53 regulates cell cycle progression and apoptosis but it can also directly modulate a mature osteocytic phenotype [92]. These studies taken the transcription of genes that are specifically required for together further strengthen the notion that p53 controls stem cell self-renewal and differentiation, but that it may not only neuronal differentiation [81, 84]. The role of p53 in apoptosis of neuronal cells is relatively well understood [85, 86], but do so in a cell-type-specific manner. 4 Journal of Oncology 4. Brain Tumor Stem Cells and p53 Oct-3/4, Sox2, c-Myc, and Klf4 [100]. Of interest is also the recently established function of the p53 pathway in suppress- 4.1. Inactivation of p53 in Neural Stem Cells. Perhaps the ing reprogramming of normal cells to induced pluripotent suppression of incipient cancer stem cells is one activity stem cells (iPSCs) [101–104]. Silencing of p19ARF, an by which p53 can inhibit tumor growth [8], but what are upstream regulator of p53, facilitates reprogramming as well the mechanistic links between p53 and the emergence of [105]. It remains unclear how p53 blocks reprogramming cancer stem cells, if any? p53 was found to repress the of cells to iPSCs, but one possibility is that it could be cancer stem cell marker gene CD44 in an experimental related to the higher sensitivity of iPSCs to stress than breast tumor model [93]. Overexpression of CD44 on the the more differentiated cells from which they were initially other hand blocked p53-dependent apoptosis, leading to derived [80]. The process of creating iPSCs resembles the expansion of tumor-initiating cells [93]. It would be of creation of tumor cells by specific factors and highlights interest to determine if similar mechanisms are involved the similarity between iPSCs and cancer stem cells [79]. also in brain tumor development, but exactly how the loss GBs frequently overexpress genes typical of neural stem of p53 function leads to transformation of normal cells in cells including Sox2 [106], Myc [27]and Oct4 [107]. A the central nervous system remains unclear. Development hallmark of some poorly differentiated tumors, including of a brain tumor may begin with a mutation in the p53 GB, is a stem cell signature [108]. The malignant progression gene which makes neural stem cells proliferate faster and of glioma may be associated with the emergence of such a perhaps also migrate out of the niche like their specialized signature [109]. Therefore, targeting pluripotency-associated progenies [9]. Wang and coworkers carried out a series molecules such as Myc and Sox2, combined with reactivation of experiments using mice engineered to have an internal of p53, specifically in brain tumor stem cell populations deletion mutation in Tp53, Δ exon 5-6, specifically in neural could become one approach to effectively reduce tumor stem and progenitor cells [94]. They found that a majority of growth. In fact, c-Myc is required for brain tumor stem mice developed malignant brain tumors and that the same cell growth [110], and in normal neural stem cells, loss mutant p53 was detected in the tumor cells but not in normal of c-Myc on its own attenuates self-renewal and induces cells. Mutant p53 protein was detectable in a minority of differentiation towards the glial lineage [111]. proliferative neural stem cells two months after birth. It In this context it should also be mentioned that p53 plays was argued that it is presumably the mutant-p53-expressing a specific role in the DNA-damage response of embryonic cell population with features of transit-amplifying cells that stem cell [77]. Embryonic stem cells lack a distinct G /S cell drives tumor initiation [94]. The hypothesis that stem cells cycle checkpoint [112], but new evidence shows that p53 in residing in the subventricular zone can give rise to gliomas is response to DNA damage acts to induce differentiation and also supported by other studies [9, 29, 95, 96]. An interesting to suppress expression of the pluripotency factor Nanog [77]. point of view is that tissue stem cells remain undifferentiated Whether a similar mechanism is involved in the neural stem due to environmental cues in their particular niche, and the cell stress response, remains of interest to determine. stem cells differentiate when they leave that niche, or no longer receive proper signals from the niche [97]. GB was initially considered to be a monoclonal tumor 4.3. Other Regulators of p53 in Brain Tumor Stem Cells. and the patterns of clonal expansion of cells with mutant p53 We must also take into account the function and expres- supported this notion [34]. However, given the heterogeneity sion of proteins and microRNAs that regulate p53. Olig2 of GB taken together with the recent findings that there is a central-nervous-system-restricted transcription factor are coexisting populations of cells with different p53 status highly expressed in brain tumor stem cells and required within the same tumor, we must also consider polyclonal for neural progenitor cell proliferation [113]. Olig2 directly events [98]. GB is composed of several types of cells, suppresses p21, a downstream key target of p53, and Olig2 and some phenotypes or clones may be better suited for is therefore presumably an important antagonist of the p53 the specific environment but they could still coexist with pathway during glioma development [113]. Interestingly, other sub-optimal lines of tumor cells [71]. One of these loss of p21 increases the proliferative capacity of neural sub-optimal lines could however following a novel and stem cells [114]. Another important regulator of p53 is different type of stress adapt and instead become the most Gli1, a downstream mediator of Hedgehog signaling. Gli1 successful line, and this type of event could contribute to can repress p53 activity and Gli1 promotes an increase treatment resistance of GB [5, 71]. Phenotypically different in neural stem and progenitor cell pools [115]. However, subpopulations of cells may even benefit from each other and p53 in turn can suppress Gli1 function and proper Gli1 thus remain coexisting in the tumor [99]. As with regard to subcellular localization [116]. Interestingly, Gli1 function p53, perhaps the majority of tumor cells benefit from having also depends on Nanog [116]. These studies revealed novel mutant p53 or no p53 at all, but may some tumor cells thrive intricate signaling networks in stem cells and how they are when carrying wild-type p53? connected to p53 [117]. Recently, Bcl2L12 (Bcl2-like 12) a protein found overexpressed in GB that prevents apoptosis, 4.2. Stem Cell Signatures in Brain Tumor Cells. Pluripotent was shown to interact with and inhibit p53 [118]. As stem cells can be generated from normal fibroblast cultures, mentioned, loss of the tumor suppressor PTEN is a frequent and in principle four key pluripotency genes essential for the event in brain tumors [28]. Interestingly, PTEN is critical production of pluripotent stem cells were defined, namely: in restricting neural stem cell self-renewal and proliferation Journal of Oncology 5 similar to p53 [119, 120], and the combined loss of p53 was created to mimic human secondary GBs character- and PTEN promotes a synergistic increase in neural stem ized by combined PDGFRA overexpression/amplification and TP53 deletion/mutation, and results did prove that cell self-renewal associated with elevated levels of c-Myc and this combination is instrumental in generating GBs. A rapid growth of gliomas in vivo [27, 121]. In turn, c-Myc previous report described a significant association between promotes an even more malignant phenotype of the tumor PDGFRA expression, as analyzed at the mRNA level by in [27]. Finally, regulation of the p53 pathway by microRNAs is situ hybridization and LOH17p in human gliomas [132]. likely to be of importance also in brain tumor development Recently, by the help of high-throughput genome and and brain tumor stem cells [122]. transcriptome analyses, human secondary GBs were shown to be similar to the proneural type of primary GBs and associated with PDGFRA amplification, TP53 and PTEN 5. Interplay between p53 and Overactive deletion/mutation, IDH1 mutation and also disturbances in PDGF Signaling the PI3K signaling pathway, and finally by the expression of oligodendrocyte markers [133]. A number of recent studies using animal models have provided compelling evidence that gliomas can be induced Loss of function of p53, together with overactive growth factor signaling, contributes to glioma formation. In the from neural stem cells, provided combinations of several transgenic mice expressing PDGF-B in astrocytes, tumors different tumor suppressors are deleted (e.g., Pten, Nf1 and developed in homozygously deleted Trp53 but not in Trp53) [29, 94–96]. Loss of p53 in neural stem cells has heterozygous mice [32]. Furthermore, PDGF-B retrovirus- in mouse models been proven as an important step in induced brain tumors developed at a higher frequency and the initiation of gliomas [123]. Using a different approach, with shorter latency when injections were performed in others have shown that persistent mitogen signaling (e.g., Trp53-null than in wild type mice, and in a Trp53-null PDGF-B) can promote gliomagenesis also in lineage- background these tumors showed higher p-Akt and lower restricted progenitor cells giving rise to oligodendroglioma- Pten levels [134]. Still, the mechanism of the combined like tumors [124]. Therefore, development of gliomas may PDGF-B/Trp53 null effect has not yet been clearly defined. take divergent pathways and start in different cell types One guess is that the Trp53-null status directly or indirectly and locations [5]. Oligodendrocyte progenitor cells express allows for proliferation of Pdgfrα-positive precursors in PDGFRα and can be induced to proliferate when stimulated the brain and/or for upregulation of Pdgfra expression at with PDGF [125]. The use of retrovirus or adenovirus the promoter level. Cultured, otherwise normal Trp53-null vectors to introduce PDGF-B in newborn mice brains mostly results in Gfap−/Ng2+/Olig2+ tumors that by transcriptome brain cells show an increased survival and proliferation in vitro, coupled with upregulation and activation of Pdgf- analysis are similar to oligodendrogliomas [126–128]. This receptors [134]. Other mechanisms need to be considered as is true even if the virus is directed to neural precursors well. PDGF signaling is known to expand the pool of glial by the Nestin-tva or Gfap-tva systems [129, 130]. The progenitors generated from neural stem cells [135]. Given oligodendroglioma-like features have been interpreted as due the fact that the lack of p53 may in addition result in an to PDGF’s ability to modulate the balance between neuronal undifferentiated state of these cells, an increase in the number and glial cells generated from neural stem cells, in favor of of glial precursors promoted by PDGF, possibly induced to oligodendrocyte progenitors [127]. migrate [136], but unable to differentiate further, may be all In a recent report, transgenic mice were generated that it takes to create a lethal neoplasm in the mouse brain. expressing PDGF-B in brain under control of the human We need to consider that the human brain has tighter control GFAP promoter [32]. These mice were shown to be similar mechanisms than the mouse brain, but The Cancer Genome to wild type mice, but on a Tp53-null background they Atlas (TCGA) and other similar high-throughput screening developed large GB-like brain tumors at a high frequency, in projects provide us with excellent tools to identify additional spite of the fact that Tp53-null mice do not otherwise develop molecules and mechanisms affected in human brain tumors brain tumors [32, 91]. The tumors were very heterogenous, [12]. displaying many different cell lineage markers, including stem cell markers. Early lesions displayed abundant Gfap- positive cells, although the larger tumors partly lost the 6. Therapeutic Opportunities expression of Gfap. The Gfap promoter is most active around birth and remains active in both astrocytes and neural Treatment of brain tumor patients is extremely challenging stem cells of the adult brain; however; the mice developed because the normal brain is highly susceptible to damage brain tumors only in adult life, at 2–6 months of age [32]. during therapy, the brain has a very limited capacity to Therefore, distinct possibilities of glioma cells of origin need repair itself, and several drugs cannot cross the blood- to be considered including (1) adult neural stem cells that brainbarrier to act on tumors in the CNS [5]. Brain tumor lose their differentiation capacity and (2) mature astrocytes cells are also highly infiltrative and can hide in apparently that dedifferentiate due to the lack of p53. These PDGF- normal parts of the brain [137]. Paradoxically, nonmalignant induced experimental gliomas are similar to human GBs neuronal cells are highly vulnerable to stress and respond in that the glial tumor cells express Pdgfrα whereas the with the induction of p53-dependent apoptosis [84], yet vasculature expresses Pdgfrβ in pericytes [131]. The model glioma-derived cells show resistance to apoptosis-inducing 6 Journal of Oncology stimuli [138]. Standard treatment for GB is surgery, radiation This occurred in the absence of any major effects on the bulk therapy and concomitant and adjuvant treatment with the of tumor cells [74]. In another study it was found that mutant chemotherapeutic agent temozolomide [139]. Temozolo- p53 reactivation with the drug ellipticine when combined mide is an alkylating agent found to have beneficial effects with 5-fluorouracil led to depletion of colon cancer stem cells in the palliative treatment of GB [140]. Whereas glioma cell in vitro [154]. Perhaps the reactivation of p53 specifically in lines expressing mutant p53 are sensitized to temozolomide, brain tumor stem cells could induce permanent differenti- the status of p53 does not seem to affect the response ation or apoptosis followed by tumor regression? Apoptosis of brain tumor stem cells treated with this drug [141]. is however not frequently seen upon retroviral expression or Despite the fact that the survival outlook for GB patients activation of endogenous p53 in glioma cell lines [36], but remains poor, recent years have seen progress towards longer overexpression of p53 by adenovirus may sensitize glioma survival, as summarized in an excellent review [4]. Several cells to apoptosis [155]. Indeed, adenoviral expression of p53 targeted therapies are currently in preclinical or clinical has been extensively tested in glioma [156]. phase I–III trials and examples include small molecule or There are some pitfalls when it comes to p53 reactivation antibody inhibitors of receptor tyrosine kinases, angiogenesis that need to be discussed. For instance, maintaining wild regulators, histone deacetylases, heat shock proteins and type p53 could have a prosurvival effect on tumors that are mTOR [4, 142]. Early results from monotherapy trials have not intrinsically prone to apoptosis [157]. In tumors resistant been rather disappointing, but a number of emerging drug to cell death, p53 may favor DNA repair and differentiation candidates used in combination are expected to further over apoptosis or senescence [157]. For example, wild- prolong survival of brain tumor patients [4, 142]. type-p53-containing glioma cell lines are more resistant to What about specific targeting of brain tumor stem cytotoxic agents than cell lines with mutant p53 [158]. cells? As mentioned, brain tumor stem cell populations We must also take into consideration that activation of show resistance to drugs and toxic agents, display efficient p53 may lead to the emergence of treatment resistant DNA repair, and low tendency to undergo apoptotic cell brain tumor cells that express mutant p53 or that have death [72]. Screenings to find novel small molecules that completely lost p53. Moreover, persistent activation of p53 specifically target cancer stem cell populations have been in nearby residing normal neural stem cells could have carried out. Salinomycin is a novel small molecule that adverse negative sideeffects such as stem cell depletion and targets breast tumor stem cells and selectively reduces the premature organ aging [58, 159]. Whereas activation of proportion of these cells relative to the effect of paclitaxel p53 traditionally has been viewed as the main avenue, the [143]. Development of similar drugs to be used in brain potential medical applications of inhibiting p53 should also tumor therapy is therefore desired. Molecular targets in brain be realized. In fact, inhibiting p53 protects normal cells from tumor stem cell populations could for instance be different radiation-induced cell death and can improve recovery after components of the PTEN-PI3K-AKT-WNT signaling net- ischemia in the central nervous system [160]. Unfortunately, works that drive cell growth [144]. Another approach could inhibition of p53 activity in nontumorigenic cells could have be to target brain tumor stem cells with small molecules that a procarcinogenic effect, although encouraging results from can induce differentiation, for example, histone deacetylase studies in hematopoietic cells indicate that this might not be inhibitors [145]. Ribosomal DNA transcription (the RNA thecase[161]. pol I machinery) is also an emerging target in cancer therapy [146]. Depleting cells of ribosomes by blocking production of ribosomal proteins was shown to induce p53-dependent 7. Concluding Remarks inhibition of cell proliferation and morphological differen- tiation of glioma cells in vitro [147]. Selective inhibition of There are a number of remaining unresolved issues with ribosome biogenesis in stem-like cell populations in brain regard to the existence and phenotype of brain tumor stem tumors as another kind of differentiation therapy should be cells and how similar they are to normal neural stem cells [5, explored further. 71]. The hypothesis that a normal neural stem or progenitor Oneprime candidateis of coursep53 itself. Restoration cell can evolve to become a brain tumor stem cell perhaps of the p53 tumor suppressor function holds promise in through a mutation in p53 is a very reasonable one and cancer therapy [148, 149]. Tumors with dysfunctional or no has got substantial experimental support [27, 29, 31, 94]. p53 have been shown to undergo apoptosis or senescence in Several lines of evidence in the literature indicate that loss vivo upon functional restoration of p53 [150, 151]. When it of p53 affects the properties of adult neural stem cells by comes to the tumor cells, we first need to distinguish cells providing a proliferative advantage [31, 73, 90]. Although with no p53 from cells with mutant p53, and cells retaining loss of p53 on its own does not give rise to brain tumors in wild-type p53. Activation of endogenous wild-type p53 with mice, it allows for rapid tumor development in the presence small molecules, reactivation of mutant p53, or transfer of of persistent mitogen signaling, oncogene activation and the p53 gene should therefore be considered [152]. Nutlin-3 subsequent mutational events [32]. However, we must also is a compound that disrupts the binding between MDM2 and be aware that there are presumably different cellular origins p53 leading to activation and accumulation of free p53 [153]. for gliomas and that they could originate from various Interestingly, activation of endogenous wild type p53 with regions of the brain [5]. 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Novel Perspectives on p53 Function in Neural Stem Cells and Brain Tumors

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Copyright © 2011 Sanna-Maria Hede et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Publishing Corporation Journal of Oncology Volume 2011, Article ID 852970, 11 pages doi:10.1155/2011/852970 Review Article Novel Perspectives on p53 Function in Neural Stem Cells and Brain Tumors Sanna-Maria Hede, Inga Nazarenko, Monica Nister, ´ and Mikael S. Lindstrom ¨ Department of Oncology-Pathology, Karolinska Institute, CCK R8:05, SE-17176 Stockholm, Sweden Correspondence should be addressed to Mikael S. Lindstrom, ¨ mikael.lindstrom@ki.se Received 2 August 2010; Revised 18 October 2010; Accepted 29 October 2010 Academic Editor: Shih Hwa Chiou Copyright © 2011 Sanna-Maria Hede et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Malignant glioma is the most common brain tumor in adults and is associated with a very poor prognosis. Mutations in the p53 tumor suppressor gene are frequently detected in gliomas. p53 is well-known for its ability to induce cell cycle arrest, apoptosis, senescence, or differentiation following cellular stress. That the guardian of the genome also controls stem cell self- renewal and suppresses pluripotency adds a novel level of complexity to p53. Exactly how p53 works in order to prevent malignant transformation of cells in the central nervous system remains unclear, and despite being one of the most studied proteins, there is a need to acquire further knowledge about p53 in neural stem cells. Importantly, the characterization of glioma cells with stem-like properties, also known as brain tumor stem cells, has opened up for the development of novel targeted therapies. Here, we give an overview of what is currently known about p53 in brain tumors and neural stem cells. Specifically, we review the literature regarding transformation of adult neural stem cells and, we discuss how the loss of p53 and deregulation of growth factor signaling pathways, such as increased PDGF signaling, lead to brain tumor development. Reactivation of p53 in brain tumor stem cell populations in combination with current treatments for glioma should be further explored and may become a viable future therapeutic approach. 1. Introduction diverse cellular programs such as cell cycle arrest, apoptosis, differentiation, DNA repair, autophagy, and senescence [8]. The most frequent form of brain tumor in adults is One prevailing hypothesis is that GB could arise and glioma [1]. Gliomas are classified as astrocytomas, oligo- recur because of malignant transformation of neural stem dendrogliomas, oligoastrocytomas, and ependymomas [2]. cells residing in protected niche areas [9]. Recently, novel Astrocytoma is the most common subclass of glioma and functions of p53 in stem cells have been characterized is graded on a WHO scale of I to IV, whereas oligo- including suppression of pluripotency and inhibition of dendrogliomas and oligoastrocytomas are usually classified stem cell self-renewal [10]. Despite being one of the most as grade II or grade III [3]. Grade IV astrocytic tumor, extensively studied proteins, there is still a need to acquire commonly known as glioblastoma (GB), is the deadliest form further knowledge and insight into p53 function in stem of brain tumor that despite multimodal therapy only shows a cells including neural stem cells. What function of p53 is the median survival of 12–15 months [4]. Recent transcriptome most important one to inactivate for brain tumor initiation and genome profiling of brain tumors in combination with and progression? Could it be the ability of p53 to restrain advances in stem cell biology has led to an improved self-renewal and to promote differentiation, or is it the pro- understanding of the molecular pathology of this disease and apoptotic and cell cycle regulating activity? Here we discuss revealed novel targets for therapy [5]. the role of p53 in gliomagenesis and the significance of p53 The p53 tumor suppressor gene is frequently mutated in relation to brain tumor stem cells. We review the literature or deleted in human tumors and is often found mutated regarding the neoplastic potential of neural stem cells, and or lost early in glioma formation [6, 7]. p53 can trigger we describe how the loss of p53 in parallel with deregulation 2 Journal of Oncology of growth factor signaling pathways promotes brain tumor [13, 27]. Another common and critical tumor suppressor development. Finally, we discuss how the reactivation of gene alteration in GB is loss of function of PTEN that occurs p53 in brain tumor stem cell populations could become in both primary and secondary GB [28]. one viable approach to suppress proliferation and induce Accumulated experimental and clinical evidence suggests differentiation and apoptosis of these cells. that the loss of p53 function is a key initial event in glioma development in combination with other genetic and epigenetic alterations [6, 7, 26, 29–34]. Numerous studies 2. Glioma Genetics and Glioma Cell of Origin have also been carried out in order to investigate the effects of p53 overexpression in glioma cells. Evidently, p53 can block 2.1. p53 Pathway Inactivation in Glioma. Gliomas often display mutations in the ARF-MDM2-p53 and p16INK4a- cell cycle progression and induce morphological changes CDK4-RB tumor suppressor pathways resulting in increased resembling differentiation in glioma cell lines [35–37]. Given genomic instability, loss of G cell cycle checkpoint control, these findings, therapeutic targeting of the p53 pathway still seems highly interesting in glioma. and evasion of apoptosis [2, 11]. Deregulation of the PI3K/AKT/mTOR signaling pathway and hyperactivation of receptor-tyrosine kinases (e.g., PDGFRα and EGFR) are 2.2. Neural Stem Cells. Tissue stem cells are considered to frequently observed in gliomas [2, 11]. GBs can be classified be rare cells within organs with the ability to self-renew as primary or secondary but are morphologically similar and to give rise to all types of cells within the said organ [1]. Aprimary GB arises with no signsofpreviouslower- [38]. Examples of tissue stem cells include hematopoietic grade tumor and often displays loss of the INK4A/ARF stem cells, neural stem cells, and mammary gland stem cells tumor suppressor gene locus, PTEN mutation, and EGFR [38]. Embryonic stem cells on the other hand are isolated amplification and/or mutation [1]. Secondary GBs show a from the inner cell mass of blastocysts, are pluripotent, previous history of progression from a lower-grade tumor and can give rise to all cell types of the body [39]. Neural and TP53 mutations are frequent [2]. Recently, transcrip- stem cells are the self-renewing cells that generate the main tome and genome profiling of GBs has revealed additional cells of the central nervous system (astrocytes, neurons, and genetic differences, and new subclasses of GB have been oligodendrocytes) [40]. New neurons are thought to be born defined [12–14]. throughout adulthood in predominantly two regions of the mouse brain [41]. These are the subventricular zone of the TP53 mutations occur early in glioma progression, and lateral ventricle wall, from where new neuronal progenitor grade II astrocytomas commonly display TP53 mutations or loss of heterozygosity on chromosome 17p where TP53 cells migrate to the olfactory bulb via the rostral migratory stream [42, 43], and the subgranular zone of hippocampus resides [15, 16]. TP53 mutations are infrequent in medul- [44]. Reynolds and Weiss were the first to isolate neural loblastomas, pilocytic grade I astrocytomas, and ependymo- mas [7]. The p53 tumor suppressor restricts cell growth and progenitor and stem cells from adult mouse brain [45]. Within the subventricular zone, cells can be classified as proliferation following stress and is known as the guardian of the genome [17]. p53 has pleiotropic anticancer functions type B neural stem cells and type C transit-amplifying cells that give rise to neuroblasts (type A) [46]. Neural stem and plays a role in senescence, apoptosis, differentiation, cells are often studied in vitro using a method referred to autophagy, metabolism, and angiogenesis [18]. These diverse cellular effects can be attributed to the regulation of hun- as the neurosphere assay developed by Reynolds and Weiss [45], see also [47] for an update. Neural stem cells have the dreds of different genes directly by p53 [8, 19]. The transcrip- properties of self-renewal, clonogenic capacity, and ability tional function of p53 is stimulated through increased levels of the protein coupled to conformational changes triggered to engraft, migrate, and give rise to differentiated progeny [41, 46, 48]. by different posttranslational modifications or p53- binding proteins [20]. While approximately half of all human tumors contain a mutation or deletion of TP53, the rest of the tumors 2.3. Glioma Cell of Origin and the Cancer Stem Cell Hypoth- often have inactivation of p53 through other mechanisms esis. Several common tumor forms, including brain tumors, including viral infection, loss of ARF, or overexpression of have been shown to harbor a fraction of cells with stem- MDM2 [21]. The MDM4 and MDM2 proteins suppress like features referred to as cancer stem cells [49]. The p53’s transcriptional activity and target p53 for proteasomal cancer stem cells are considered to be a relatively small degradation, respectively [22]. It is therefore not a surprise population of cells that are capable of self-renewal, and the to learn that MDM2 gene amplifications are present in 10% progeny of which can undergo differentiation to generate the of primary GBs and that amplifications of MDM4 are found phenotypic heterogeneity observed in solid tumors [50, 51]. in about 4% of GBs [23, 24]. Gliomas are also seen in Cancer stem cell populations have been found in many the Li-Fraumeni syndrome, a familial cancer predisposing malignancies including those from breast [52], brain [53], syndrome characterized by germ line TP53 mutations [25, pancreas [54], colon [55], and the hematopoietic system 26]. It has been a widely held notion that somatic TP53 (acute myelogenic leukemia) [56]. Cancer stem cells show mutations are common in low-grade gliomas and secondary GBs but more uncommon in primary GB. However recent malicious behavior including prolonged exit from the cell studies, which also included additional sequencing of TP53, cycle (quiescence), resistance to chemotherapeutic agents, revealed that mutations are prevalent in primary GBs as well efficient DNA repair, and resistance to apoptosis [57–60]. Journal of Oncology 3 Using the approach of Reynolds and Weiss [45], several less is known about p53 function in astrocytes, oligoden- groups reported on the growth of adult and pediatric glioma drocytes and their precursors. Oligodendrocyte precursors cells cultured and propagated in the form of neurospheres, cultured in vitro can undergo p53-dependent differentiation also known in this context as “gliospheres” [61–65]. The cells although the cells appear to have a low basal level of p53 capable of self-renewal and of forming new gliospheres and expression [87]. Both astrocytes and oligodendrocytes can with the ability to initiate the formation of a new tumor undergo apoptosis following infection with an adenovirus in nude mice are known as the brain tumor stem cells. expressing p53 [88]. Although speculative, cells of the These cells can also be referred to as brain tumor initiating glial lineage may be more prone towards p53-induced cells or glioma stem cells. It was shown that gliospheres differentiation and senescence following stress than neuronal have an increased growth potential and features of aberrant cells. differentiation when directly compared to normal neuro- What is the function of p53 in the neural stem cells? The spheres from the adult brain [66]. Cell sorting is based on enhanced proliferative capacity of neural precursors from expression of the cell surface marker CD133 selected for Trp53 knockout mice was described in the early 90s [89]. glioma cells with stem-like features [53], and CD133-positive Later, it was found that p53 is expressed at higher levels brain tumor cells are relatively resistant to radiation when in cells in the neural stem cell niche than in other regions compared to CD133-negative cells [57]. The clinical value of the adult mouse brain [73]. Cells in the brain’s lateral of CD133-expression in tumors remains unclear, but some ventricle stem cell niche displayed an increased proliferation groups have reported that the increased expression of CD133 rate in Trp53 knockout mice compared to wild-type [73]. is associated with a poor prognosis [67, 68]. However, recent It was also found that a p53 deficiency in neurospheres studies indicate that also CD133-negative brain tumor cells resulted in increased self-renewal capacity, increased cell can initiate tumor development and act as brain tumor stem proliferation and a reduction in apoptosis [73]. Analysis cells [69]. of the stem cell transcriptome from wild type and Tp53 It is at present discussed whether cancer stem cells knockout mice identified several genes that were down- represent a minority of the tumor cells [70]. If most cells regulated in p53-null neurospheres, importantly p21 and within the tumor are endowed with stem cell properties, p27, established negative regulators of cell proliferation [73]. why should we focus our energy on targeting a specific sub- In a related study, Gil-Perotin et al., found a p53-dependent population of cells? Debated is also whether cancer stem effect on differentiationthe and they could determine that cells originate from normal stem cells or from differentiated loss of p53 increased the number of Tuj1 neuroblasts in cells that have acquired the ability to self-renew [50], and the subventricular zone in vivo [31]. Regions with mild this discussion is especially dynamic within the brain tumor to moderate hyperplasia, resembling “microtumors” were research community [5, 71, 72]. It still remains unclear also apparent in some Trp53 knockout mice [31]. The if gliomas (in general) originate from multipotent neural increase in cell number was apparently not due to loss stem or progenitor cells, restricted neural progenitors, or of apoptosis, as it could be compensated for, and it was mature glia cells that have undergone the process of de- argued that this is the reason for why there are no tumors differentiation [71]. in Trp53 knockout mice [31]. Also by using olfactory bulb neural stem and progenitor cells cultured as neurospheres it was found, in agreement with the previous studies, that 3. Novel Functions of p53 in Neural Stem Cells loss of p53 can promote neurosphere formation and stem cell self-renewal [90]. Furthermore, loss of p53 facilitated A number of recent studies show that p53 has a critical differentiation of progenitor cells into Tuj1-positive neurons, function in neural [73], mammary [74], hematopoietic [75, with a corresponding moderate decrease in mature astrocytes 76] and embryonic stem cells [77] by regulating self-renewal, [90]. In summary, a number of studies show that the loss of symmetric division, quiescence, survival, and proliferation. p53 provides an advantage to neural stem cells and/or early Two main functions of p53 can be distinguished in relation progenitor cells [31, 73, 90]. However, the loss of p53 alone to stem cell behavior. These can be described as the does not cause brain tumors within the relatively short life abilities of p53 to induce differentiation and to suppress de- span of Trp53 knockout mice [91]. differentiation and evidence in the literature supports a role p53-mediated control of stem cell functions has also been for p53 in both of these processes [10, 78–81]. studied in other tissues. For example, p53 has a critical role in In the mouse brain, p53 is critical for induction of regulating hematopoietic stem cell quiescence [75, 76]. Tran- scriptome analysis identified Gfi-1 and Necdin as p53 target apoptosis in neural progenitors and postmitotic neurons during development of the central nervous system [33], and a genes involved in regulating quiescence [76]. In mammary subset of Trp53 knockout mice develop exencephaly [82, 83]. gland stem cells, p53 controls polarity of mammary epithelial Furthermore, neuronal cells are sensitive to p53-dependent stem cell divisions [74]. In bone formation, the loss of p53 apoptosis following irradiation, exposure to chemothera- not only accelerates early osteogenesis from mesenchymal stem cells but actually prevents terminal differentiation to peutic agents, and ischemia [84]. p53 regulates cell cycle progression and apoptosis but it can also directly modulate a mature osteocytic phenotype [92]. These studies taken the transcription of genes that are specifically required for together further strengthen the notion that p53 controls stem cell self-renewal and differentiation, but that it may not only neuronal differentiation [81, 84]. The role of p53 in apoptosis of neuronal cells is relatively well understood [85, 86], but do so in a cell-type-specific manner. 4 Journal of Oncology 4. Brain Tumor Stem Cells and p53 Oct-3/4, Sox2, c-Myc, and Klf4 [100]. Of interest is also the recently established function of the p53 pathway in suppress- 4.1. Inactivation of p53 in Neural Stem Cells. Perhaps the ing reprogramming of normal cells to induced pluripotent suppression of incipient cancer stem cells is one activity stem cells (iPSCs) [101–104]. Silencing of p19ARF, an by which p53 can inhibit tumor growth [8], but what are upstream regulator of p53, facilitates reprogramming as well the mechanistic links between p53 and the emergence of [105]. It remains unclear how p53 blocks reprogramming cancer stem cells, if any? p53 was found to repress the of cells to iPSCs, but one possibility is that it could be cancer stem cell marker gene CD44 in an experimental related to the higher sensitivity of iPSCs to stress than breast tumor model [93]. Overexpression of CD44 on the the more differentiated cells from which they were initially other hand blocked p53-dependent apoptosis, leading to derived [80]. The process of creating iPSCs resembles the expansion of tumor-initiating cells [93]. It would be of creation of tumor cells by specific factors and highlights interest to determine if similar mechanisms are involved the similarity between iPSCs and cancer stem cells [79]. also in brain tumor development, but exactly how the loss GBs frequently overexpress genes typical of neural stem of p53 function leads to transformation of normal cells in cells including Sox2 [106], Myc [27]and Oct4 [107]. A the central nervous system remains unclear. Development hallmark of some poorly differentiated tumors, including of a brain tumor may begin with a mutation in the p53 GB, is a stem cell signature [108]. The malignant progression gene which makes neural stem cells proliferate faster and of glioma may be associated with the emergence of such a perhaps also migrate out of the niche like their specialized signature [109]. Therefore, targeting pluripotency-associated progenies [9]. Wang and coworkers carried out a series molecules such as Myc and Sox2, combined with reactivation of experiments using mice engineered to have an internal of p53, specifically in brain tumor stem cell populations deletion mutation in Tp53, Δ exon 5-6, specifically in neural could become one approach to effectively reduce tumor stem and progenitor cells [94]. They found that a majority of growth. In fact, c-Myc is required for brain tumor stem mice developed malignant brain tumors and that the same cell growth [110], and in normal neural stem cells, loss mutant p53 was detected in the tumor cells but not in normal of c-Myc on its own attenuates self-renewal and induces cells. Mutant p53 protein was detectable in a minority of differentiation towards the glial lineage [111]. proliferative neural stem cells two months after birth. It In this context it should also be mentioned that p53 plays was argued that it is presumably the mutant-p53-expressing a specific role in the DNA-damage response of embryonic cell population with features of transit-amplifying cells that stem cell [77]. Embryonic stem cells lack a distinct G /S cell drives tumor initiation [94]. The hypothesis that stem cells cycle checkpoint [112], but new evidence shows that p53 in residing in the subventricular zone can give rise to gliomas is response to DNA damage acts to induce differentiation and also supported by other studies [9, 29, 95, 96]. An interesting to suppress expression of the pluripotency factor Nanog [77]. point of view is that tissue stem cells remain undifferentiated Whether a similar mechanism is involved in the neural stem due to environmental cues in their particular niche, and the cell stress response, remains of interest to determine. stem cells differentiate when they leave that niche, or no longer receive proper signals from the niche [97]. GB was initially considered to be a monoclonal tumor 4.3. Other Regulators of p53 in Brain Tumor Stem Cells. and the patterns of clonal expansion of cells with mutant p53 We must also take into account the function and expres- supported this notion [34]. However, given the heterogeneity sion of proteins and microRNAs that regulate p53. Olig2 of GB taken together with the recent findings that there is a central-nervous-system-restricted transcription factor are coexisting populations of cells with different p53 status highly expressed in brain tumor stem cells and required within the same tumor, we must also consider polyclonal for neural progenitor cell proliferation [113]. Olig2 directly events [98]. GB is composed of several types of cells, suppresses p21, a downstream key target of p53, and Olig2 and some phenotypes or clones may be better suited for is therefore presumably an important antagonist of the p53 the specific environment but they could still coexist with pathway during glioma development [113]. Interestingly, other sub-optimal lines of tumor cells [71]. One of these loss of p21 increases the proliferative capacity of neural sub-optimal lines could however following a novel and stem cells [114]. Another important regulator of p53 is different type of stress adapt and instead become the most Gli1, a downstream mediator of Hedgehog signaling. Gli1 successful line, and this type of event could contribute to can repress p53 activity and Gli1 promotes an increase treatment resistance of GB [5, 71]. Phenotypically different in neural stem and progenitor cell pools [115]. However, subpopulations of cells may even benefit from each other and p53 in turn can suppress Gli1 function and proper Gli1 thus remain coexisting in the tumor [99]. As with regard to subcellular localization [116]. Interestingly, Gli1 function p53, perhaps the majority of tumor cells benefit from having also depends on Nanog [116]. These studies revealed novel mutant p53 or no p53 at all, but may some tumor cells thrive intricate signaling networks in stem cells and how they are when carrying wild-type p53? connected to p53 [117]. Recently, Bcl2L12 (Bcl2-like 12) a protein found overexpressed in GB that prevents apoptosis, 4.2. Stem Cell Signatures in Brain Tumor Cells. Pluripotent was shown to interact with and inhibit p53 [118]. As stem cells can be generated from normal fibroblast cultures, mentioned, loss of the tumor suppressor PTEN is a frequent and in principle four key pluripotency genes essential for the event in brain tumors [28]. Interestingly, PTEN is critical production of pluripotent stem cells were defined, namely: in restricting neural stem cell self-renewal and proliferation Journal of Oncology 5 similar to p53 [119, 120], and the combined loss of p53 was created to mimic human secondary GBs character- and PTEN promotes a synergistic increase in neural stem ized by combined PDGFRA overexpression/amplification and TP53 deletion/mutation, and results did prove that cell self-renewal associated with elevated levels of c-Myc and this combination is instrumental in generating GBs. A rapid growth of gliomas in vivo [27, 121]. In turn, c-Myc previous report described a significant association between promotes an even more malignant phenotype of the tumor PDGFRA expression, as analyzed at the mRNA level by in [27]. Finally, regulation of the p53 pathway by microRNAs is situ hybridization and LOH17p in human gliomas [132]. likely to be of importance also in brain tumor development Recently, by the help of high-throughput genome and and brain tumor stem cells [122]. transcriptome analyses, human secondary GBs were shown to be similar to the proneural type of primary GBs and associated with PDGFRA amplification, TP53 and PTEN 5. Interplay between p53 and Overactive deletion/mutation, IDH1 mutation and also disturbances in PDGF Signaling the PI3K signaling pathway, and finally by the expression of oligodendrocyte markers [133]. A number of recent studies using animal models have provided compelling evidence that gliomas can be induced Loss of function of p53, together with overactive growth factor signaling, contributes to glioma formation. In the from neural stem cells, provided combinations of several transgenic mice expressing PDGF-B in astrocytes, tumors different tumor suppressors are deleted (e.g., Pten, Nf1 and developed in homozygously deleted Trp53 but not in Trp53) [29, 94–96]. Loss of p53 in neural stem cells has heterozygous mice [32]. Furthermore, PDGF-B retrovirus- in mouse models been proven as an important step in induced brain tumors developed at a higher frequency and the initiation of gliomas [123]. Using a different approach, with shorter latency when injections were performed in others have shown that persistent mitogen signaling (e.g., Trp53-null than in wild type mice, and in a Trp53-null PDGF-B) can promote gliomagenesis also in lineage- background these tumors showed higher p-Akt and lower restricted progenitor cells giving rise to oligodendroglioma- Pten levels [134]. Still, the mechanism of the combined like tumors [124]. Therefore, development of gliomas may PDGF-B/Trp53 null effect has not yet been clearly defined. take divergent pathways and start in different cell types One guess is that the Trp53-null status directly or indirectly and locations [5]. Oligodendrocyte progenitor cells express allows for proliferation of Pdgfrα-positive precursors in PDGFRα and can be induced to proliferate when stimulated the brain and/or for upregulation of Pdgfra expression at with PDGF [125]. The use of retrovirus or adenovirus the promoter level. Cultured, otherwise normal Trp53-null vectors to introduce PDGF-B in newborn mice brains mostly results in Gfap−/Ng2+/Olig2+ tumors that by transcriptome brain cells show an increased survival and proliferation in vitro, coupled with upregulation and activation of Pdgf- analysis are similar to oligodendrogliomas [126–128]. This receptors [134]. Other mechanisms need to be considered as is true even if the virus is directed to neural precursors well. PDGF signaling is known to expand the pool of glial by the Nestin-tva or Gfap-tva systems [129, 130]. The progenitors generated from neural stem cells [135]. Given oligodendroglioma-like features have been interpreted as due the fact that the lack of p53 may in addition result in an to PDGF’s ability to modulate the balance between neuronal undifferentiated state of these cells, an increase in the number and glial cells generated from neural stem cells, in favor of of glial precursors promoted by PDGF, possibly induced to oligodendrocyte progenitors [127]. migrate [136], but unable to differentiate further, may be all In a recent report, transgenic mice were generated that it takes to create a lethal neoplasm in the mouse brain. expressing PDGF-B in brain under control of the human We need to consider that the human brain has tighter control GFAP promoter [32]. These mice were shown to be similar mechanisms than the mouse brain, but The Cancer Genome to wild type mice, but on a Tp53-null background they Atlas (TCGA) and other similar high-throughput screening developed large GB-like brain tumors at a high frequency, in projects provide us with excellent tools to identify additional spite of the fact that Tp53-null mice do not otherwise develop molecules and mechanisms affected in human brain tumors brain tumors [32, 91]. The tumors were very heterogenous, [12]. displaying many different cell lineage markers, including stem cell markers. Early lesions displayed abundant Gfap- positive cells, although the larger tumors partly lost the 6. Therapeutic Opportunities expression of Gfap. The Gfap promoter is most active around birth and remains active in both astrocytes and neural Treatment of brain tumor patients is extremely challenging stem cells of the adult brain; however; the mice developed because the normal brain is highly susceptible to damage brain tumors only in adult life, at 2–6 months of age [32]. during therapy, the brain has a very limited capacity to Therefore, distinct possibilities of glioma cells of origin need repair itself, and several drugs cannot cross the blood- to be considered including (1) adult neural stem cells that brainbarrier to act on tumors in the CNS [5]. Brain tumor lose their differentiation capacity and (2) mature astrocytes cells are also highly infiltrative and can hide in apparently that dedifferentiate due to the lack of p53. These PDGF- normal parts of the brain [137]. Paradoxically, nonmalignant induced experimental gliomas are similar to human GBs neuronal cells are highly vulnerable to stress and respond in that the glial tumor cells express Pdgfrα whereas the with the induction of p53-dependent apoptosis [84], yet vasculature expresses Pdgfrβ in pericytes [131]. The model glioma-derived cells show resistance to apoptosis-inducing 6 Journal of Oncology stimuli [138]. Standard treatment for GB is surgery, radiation This occurred in the absence of any major effects on the bulk therapy and concomitant and adjuvant treatment with the of tumor cells [74]. In another study it was found that mutant chemotherapeutic agent temozolomide [139]. Temozolo- p53 reactivation with the drug ellipticine when combined mide is an alkylating agent found to have beneficial effects with 5-fluorouracil led to depletion of colon cancer stem cells in the palliative treatment of GB [140]. Whereas glioma cell in vitro [154]. Perhaps the reactivation of p53 specifically in lines expressing mutant p53 are sensitized to temozolomide, brain tumor stem cells could induce permanent differenti- the status of p53 does not seem to affect the response ation or apoptosis followed by tumor regression? Apoptosis of brain tumor stem cells treated with this drug [141]. is however not frequently seen upon retroviral expression or Despite the fact that the survival outlook for GB patients activation of endogenous p53 in glioma cell lines [36], but remains poor, recent years have seen progress towards longer overexpression of p53 by adenovirus may sensitize glioma survival, as summarized in an excellent review [4]. Several cells to apoptosis [155]. Indeed, adenoviral expression of p53 targeted therapies are currently in preclinical or clinical has been extensively tested in glioma [156]. phase I–III trials and examples include small molecule or There are some pitfalls when it comes to p53 reactivation antibody inhibitors of receptor tyrosine kinases, angiogenesis that need to be discussed. For instance, maintaining wild regulators, histone deacetylases, heat shock proteins and type p53 could have a prosurvival effect on tumors that are mTOR [4, 142]. Early results from monotherapy trials have not intrinsically prone to apoptosis [157]. In tumors resistant been rather disappointing, but a number of emerging drug to cell death, p53 may favor DNA repair and differentiation candidates used in combination are expected to further over apoptosis or senescence [157]. For example, wild- prolong survival of brain tumor patients [4, 142]. type-p53-containing glioma cell lines are more resistant to What about specific targeting of brain tumor stem cytotoxic agents than cell lines with mutant p53 [158]. cells? As mentioned, brain tumor stem cell populations We must also take into consideration that activation of show resistance to drugs and toxic agents, display efficient p53 may lead to the emergence of treatment resistant DNA repair, and low tendency to undergo apoptotic cell brain tumor cells that express mutant p53 or that have death [72]. Screenings to find novel small molecules that completely lost p53. Moreover, persistent activation of p53 specifically target cancer stem cell populations have been in nearby residing normal neural stem cells could have carried out. Salinomycin is a novel small molecule that adverse negative sideeffects such as stem cell depletion and targets breast tumor stem cells and selectively reduces the premature organ aging [58, 159]. Whereas activation of proportion of these cells relative to the effect of paclitaxel p53 traditionally has been viewed as the main avenue, the [143]. Development of similar drugs to be used in brain potential medical applications of inhibiting p53 should also tumor therapy is therefore desired. Molecular targets in brain be realized. In fact, inhibiting p53 protects normal cells from tumor stem cell populations could for instance be different radiation-induced cell death and can improve recovery after components of the PTEN-PI3K-AKT-WNT signaling net- ischemia in the central nervous system [160]. Unfortunately, works that drive cell growth [144]. Another approach could inhibition of p53 activity in nontumorigenic cells could have be to target brain tumor stem cells with small molecules that a procarcinogenic effect, although encouraging results from can induce differentiation, for example, histone deacetylase studies in hematopoietic cells indicate that this might not be inhibitors [145]. Ribosomal DNA transcription (the RNA thecase[161]. pol I machinery) is also an emerging target in cancer therapy [146]. Depleting cells of ribosomes by blocking production of ribosomal proteins was shown to induce p53-dependent 7. Concluding Remarks inhibition of cell proliferation and morphological differen- tiation of glioma cells in vitro [147]. Selective inhibition of There are a number of remaining unresolved issues with ribosome biogenesis in stem-like cell populations in brain regard to the existence and phenotype of brain tumor stem tumors as another kind of differentiation therapy should be cells and how similar they are to normal neural stem cells [5, explored further. 71]. The hypothesis that a normal neural stem or progenitor Oneprime candidateis of coursep53 itself. Restoration cell can evolve to become a brain tumor stem cell perhaps of the p53 tumor suppressor function holds promise in through a mutation in p53 is a very reasonable one and cancer therapy [148, 149]. Tumors with dysfunctional or no has got substantial experimental support [27, 29, 31, 94]. p53 have been shown to undergo apoptosis or senescence in Several lines of evidence in the literature indicate that loss vivo upon functional restoration of p53 [150, 151]. When it of p53 affects the properties of adult neural stem cells by comes to the tumor cells, we first need to distinguish cells providing a proliferative advantage [31, 73, 90]. Although with no p53 from cells with mutant p53, and cells retaining loss of p53 on its own does not give rise to brain tumors in wild-type p53. Activation of endogenous wild-type p53 with mice, it allows for rapid tumor development in the presence small molecules, reactivation of mutant p53, or transfer of of persistent mitogen signaling, oncogene activation and the p53 gene should therefore be considered [152]. Nutlin-3 subsequent mutational events [32]. However, we must also is a compound that disrupts the binding between MDM2 and be aware that there are presumably different cellular origins p53 leading to activation and accumulation of free p53 [153]. for gliomas and that they could originate from various Interestingly, activation of endogenous wild type p53 with regions of the brain [5]. 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