Donor-Derived Brain Tumor Following Neural Stem Cell = Transplantation in an Ataxia Telangiectasia Patient

Neural stem cells are currently = being=20 investigated as potential therapies for neurodegenerative = diseases,=20 stroke, and trauma. However, concerns have been raised over the = safety of=20 this experimental therapeutic approach, including, for example, = whether=20 there is the potential for tumors to develop from transplanted = stem=20 cells.

Methods and Findings

A boy with ataxia telangiectasia = (AT) was=20 treated with intracerebellar and intrathecal injection of human = fetal=20 neural stem cells. Four years after the first treatment he was = diagnosed=20 with a multifocal brain tumor. The biopsied tumor was diagnosed as = a=20 glioneuronal neoplasm. We compared the tumor cells and the = patient's=20 peripheral blood cells by fluorescent in situ hybridization using = X and Y=20 chromosome probes, by PCR for the amelogenin gene X- and = Y-specific=20 alleles, by MassArray for the ATM patient specific mutation and = for=20 several SNPs, by PCR for polymorphic microsatellites, and by human = leukocyte antigen (HLA) typing. Molecular and cytogenetic studies = showed=20 that the tumor was of nonhost origin suggesting it was derived = from the=20 transplanted neural stem cells. Microsatellite and HLA analysis=20 demonstrated that the tumor is derived from at least two=20 donors.

Conclusions

This is the first report of a human = brain=20 tumor complicating neural stem cell therapy. The findings here = suggest=20 that neuronal stem/progenitor cells may be involved in = gliomagenesis and=20 provide the first example of a donor-derived brain tumor. Further = work is=20 urgently needed to assess the safety of these=20 therapies.

Supporting=20 Information

References

Editors' Summary

Background.

Most of the cells in the human body = are highly=20 specialized (=E2=80=9Cdifferentiated=E2=80=9D). The brain and the = spinal cord, for=20 example, contain two main cell types=E2=80=94neurons, which = transmit electrical=20 signals to and from the brain, and glial cells, which support and = protect=20 the neurons. If these essential neural cells become damaged or = diseased,=20 the body cannot replace them. Scientists think, however, that it = might be=20 possible to use =E2=80=9Cneural stem cell=E2=80=9D transplants to = replace the neural cells=20 that are lost in neurodegenerative diseases (for example, = Parkinson's=20 disease) or damaged by strokes or trauma. Stem cells are = undifferentiated=20 cells that replicate indefinitely and that have the potential to = develop=20 into many different specialized cells. Pluripotent stem cells = (which are=20 able to develop into any kind of specialized cell) can be isolated = from=20 early human embryos; =E2=80=9Cmultipotent=E2=80=9D stem cells = (which develop into only a=20 few cell types) can be isolated from many differentiated tissues,=20 including the brain. Human fetuses (unborn offspring from the end = of the=20 8th week after conception) are thought to be a particularly good = source of=20 neural stem cells because many new neural cells are made in fetal=20 brains.

Why Was This Study = Done?

Although stem cell transplantation = might=20 provide treatments for many debilitating diseases, some concerns = have been=20 raised over its safety. In particular, some experts fear that = tumors might=20 sometimes develop from transplanted stem cells. Tumor cells = actually=20 behave very much like stem cells=E2=80=94they divide indefinitely = and they tend to=20 be undifferentiated. It is very important, therefore, that every = patient=20 who receives a human stem cell transplant is carefully followed up = to see=20 whether any tumors develop as a result. In this study, the = researchers=20 describe a case in which multiple, slow-growing, donor-derived = brain=20 tumors formed in a patient after the transplantation of human = fetal neural=20 stem cells.

What Did the Researchers Do = and=20 Find?

Beginning in 2001, fetal neural stem = cells=20 were injected several times into the brain and the fluid = surrounding it of=20 a boy with ataxia telangiectasia at a Moscow hospital. Ataxia=20 telangiectasia, a rare disorder characterized by degeneration of = the brain=20 region that controls movement and speech, occurs when both copies = of the=20 ATM gene (human cells contain two copies of most genes) = contain a=20 genetic change that stops the production of functional ATM = protein. In=20 2005, the boy had a magnetic resonance imaging scan at the Sheba = Medical=20 Center (Israel) because of recurrent headaches. The scan revealed = abnormal=20 growths in his brain and spinal cord. In September 2006, when the = boy was=20 14, the spinal cord growth was surgically removed. This growth has = never=20 reappeared but the mass in the boy's brain has continued to grow = slowly.=20 The material removed from the boy's spinal cord contained both = neurons and=20 glial cells, the researchers report, and resembled a glioneuronal = tumor.=20 In addition, it contained both XX (female) and XY (male) cells and = the=20 tumor cells had two normal copies of the ATM gene. = Finally, a=20 technique called HLA typing showed that the tumor contained cells = from at=20 least two donors.

What Do These Findings = Mean?

These findings indicate that the = growth in the=20 patient's spinal cord was donor-cell derived and contained cells = from two=20 or more donors, at least one of whom was female. Although the = growth in=20 the patient's brain has not been examined, the multiple masses = seen in=20 this patient probably arose independently from transplanted cells = injected=20 at different sites, suggest the researchers. Importantly, the slow = growth=20 of the tumors and the well-differentiated appearance of the cells = removed=20 from the patient suggest that the tumors are relatively benign.=20 Donor-derived cells might have been able to establish tumors in = this=20 particular patient because people with ataxia telangiectasia often = have an=20 impaired immune system and the immune system normally helps to = reject=20 tumor cells. Nevertheless, this first example of a donor-derived = brain=20 tumor developing after fetal neural cell transplantation is = worrying and=20 suggests that further work should be done to assess the safety of = this=20 therapy.

Additional = Information.

Please access these Web sites via = the online=20 version of this summary at http://www.pubmedcentral.nih.gov/redirect3.cgi?&&= ;auth=3D0dg3f8t6tAn24gvJ_hkEzhlGPsJ6XBoUPWlbs1Am_&reftype=3Dextlink&a= mp;artid=3D2642879&article-id=3D2642879&iid=3D176926&issue-id= =3D176926&jid=3D277&journal-id=3D277&FROM=3DArticle%7CFront%2= 0Matter&TO=3DExternal%7CLink%7CURI&rendering-type=3Dnormal&&a= mp;http://dx.doi.org/10.1371/journal.pmed.1000029.

The US National Institutes of Health provides = information=20 about stem cells and their potential = uses
The International Society for Stem Cell = Research=20 also provides information about all aspects of stem cells for = the public=20 and for professionals
The US National Human Neural Stem Cell Resource = provides=20 specific information about neural stem cells for the public and = for=20 scientists
The US National Cancer Institutes has a fact sheet = about ataxia=20 telangiectasia

Supporting=20 Information

References

Introduction

Research in recent years has demonstrated = that=20 neurogenesis constitutively occurs in specific regions of the = adult=20 mammalian brain and that there are substantial numbers of = multipotent=20 stem/precursor cells from many parts of the brain that may be used = therapeutically [1=E2=80=934].=20 The fetal brain, characterized by active neurogenesis, has been = suggested=20 to be a promising source of therapeutic neural stem cells [5].=20 Neural stem cells are being investigated as potential therapies = for=20 neurodegenerative diseases, stroke, and trauma [1=E2=80=934,6=E2=80=939].=20 Such cells have also been suggested as potential therapies for = infants and=20 children affected by genetic and acquired diseases characterized = by=20 neurological deterioration [1,5].

Neural tissue-derived stem cells, = phenotype-specified=20 progenitor cells derived from pluripotential embryonic stem cells = (ESC),=20 and neural cells derived from various transdifferentiated = non-neural stem=20 cells have all been investigated in preclinical studies for their = ability=20 to generate neurons and glia [1,3=E2=80=935],=20 and the use of neural stem cells in clinical trials has been = described [10].

However, there are potential dangers associated = with stem=20 cell therapy, such as malignant transformation [2,3].=20 The injection of pluripotent ESC or ESC-derived precursor cells in = rodents=20 leads frequently to the development of teratomas or = teratocarcinomas [6,11,12],=20 although the tumorigenic potential of ESC seems to be greatly = reduced when=20 cells are predifferentiated in vitro before implantation [7,8,13].=20 Importantly, ESCs seem more prone to generate tumors when = implanted into=20 the same species from which they were derived [11].=20 Therefore it has been noted that the absence of tumors after = implantation=20 of human stem cells into rodents does not exclude their occurrence = in the=20 human brain [2].=20 Recently the use of human ESC-derived dopaminergic neurons = enriched by=20 coculture with telomerase-immortalized midbrain astrocytes = resulted in=20 undifferentiated expansion suggesting there was a potential for = tumor=20 development when injected to rodents [14].

We describe here a patient affected by the = neurodegenerative hereditary disorder ataxia telangiectasia (AT) = who was=20 treated by repeated transplantations of fetal neural stem cells = and who=20 developed a multifocal brain tumor.

Supporting=20 Information

References

Methods

Fetal Neural Stem Cell = Isolation and=20 Preparation

Isolation, preparation, and = characterization=20 of fetal neural stem cells were performed as published [15]=20 and described in Text=20 S1. The details are derived from a medical report describing = the=20 procedure and the protocol for the isolation and preparation of = the=20 transplanted cells, which were given to the parents of the=20 patient.

Pathology

The specimen was fixed in 10% = neutral buffered=20 formalin, routinely processed, and embedded in paraffin. It was = cut at 5=20 =CE=BCm for histochemical (hematoxylin=E2=80=93eosine, Luxol fast = blue-PAS, Masson=20 trichrome) and immunohistochemical staining (streptavidin-biotin=20 peroxidase complex method). Antisera were directed against S-100 = protein=20 (Dako; 1:1,600, polyclonal), glial fibrillary acidic protein = (GFAP) (Dako;=20 1:4,000, polyclonal), neurofilament protein (NF) (Dako; 1:800, = 2F11),=20 synaptophysin (ICN; 1:40, SY38), Neu-N (Chemicon; 1:10,000), = epithelial=20 membrane antigen (EMA) (Dako; 1:50, E29), p53 protein (Dako; = 1:2,000,=20 DO7), and Ki-67 antigen (Dako; 1:300, MIB-1).

Combined Analysis of Morphology = and=20 Interphase Fluorescence In Situ Hybridization

Morphology and interphase fluorescence in = situ=20 hybridization (I-FISH) of cells obtained from touch preps of the = resected=20 tumor at the single cell level were viewed using the Duet = multiparametric=20 imaging system (Bioview) as previously described [16].=20 May Grunwald Giemsa (MGG)-stained touch preps were scanned, and=20 coordinates and images of all the cells were saved for comparison = with=20 FISH analysis. Slides were destained and an I-FISH procedure with = a CEP XY=20 DNA probe kit (Vysis) was applied: X chromosome, SpectrumGreen; Y=20 chromosome, SpectrumOrange.

The fluorescent signals in the specific = cells were=20 viewed in parallel with the morphology of the same cells scanned=20 previously (original magnification =C3=971,000).

MALDI-TOF Mass Spectrometry = Genotyping of=20 the ATM C103T Mutation and SNPs

Detection of the ATM C103T mutation [17]=20 and genotyping of 24 SNPs including the rs7294 (VKORC1 9041G/A) = [18]=20 were carried out using the SEQUENOM MassArray MALDI-TOF mass = spectrometer.=20 Genomic DNA was extracted from blood samples, buccal smear (BS), = tumor=20 tissue, and laser capture microdissection (LCM)-isolated tumor = cells.=20 Homogenous mass EXTEND (hME) assays were designed according to the = manufacturer's protocol. Each assay involves PCR amplification of = the=20 region containing the mutation/SNP of interest, Shrimp Alkaline=20 Phosphatase treatment to remove excess dNTPs, addition of DNA = polymerase=20 along with a mixture of dideoxy and deoxy NTPs that allows = extension of=20 the hME primer through the mutation/polymorphic site and generates = allele-specific extension products. This step is followed by = cleanup of=20 the extension reaction to remove salt, spotting of the extension = product=20 into 384 Sequenom proprietary SpectroCHIP, and the analysis of the = spotted=20 product using the MALDI-TOF mass spectrometry.

Sequences of the oligonucleotides used for = the=20 detection of the ATM mutation and SNPs using the Sequenom = MassArray are=20 provided in Table=20 S1.

PCR of Tetranucleotide Repeats = and=20 Amelogenin Homologous X and Y Alleles

Multiplex tetranucleotide repeat PCR = was=20 performed on 2 ng of genomic DNA using the AmpFlSTR SGM Plus kit = (Applied=20 Biosystems), which contains tetranucleotide repeat loci plus the = X-Y=20 homologous gene amelogenin labeled in three different colors = (blue, 5-FAM;=20 green, JOE; and yellow, NED). Amplified PCR products were = subjected to=20 capillary electrophoresis in an ABI Prism 3100 (Applied = Biosystems)=20 automated DNA sequencer using the conditions recommended by the=20 manufacturer. The GeneScan 3.7 Analysis software (Applied = Biosystems) was=20 used for the analysis of the PCR products.

Human Leukocyte Antigen = Typing

Human leukocyte antigen (HLA) typing = was=20 determined from DNA samples extracted from peripheral blood (PB), = BS, and=20 the tumor, and from cloned amplified HLA A*, B*, and DRB1* alleles = from=20 the tumor using the primers described in the XIIth HLA Workshop=20 proceedings and the cloning kits supplied by QIAGEN. Following the = cloning=20 procedure DNA was extracted and samples were typed for HLA A*, B*, = and=20 DRB1*. The methodologies used for HLA typing were reverse-sequence = specific oligonucleotide probes (SSOP) using the Luminex platform = with=20 kits supplied by Tepnel.

LCM of Tumor Cell Nuclei

LCM of tumor cell nuclei was = performed using=20 the PALM Microbeam laser system from 5-=CE=BCm-thick sections of = paraffin=20 embedded tissue stained with hematoxylin=E2=80=93eosine placed on = membrane-coated=20 slides.

Supporting=20 Information

References

Results

Report of Case

The patient's parents gave written = informed consent=20 (as outlined in the PLoS consent form, http://www.pubmedcentral.nih.gov/redirect3.cgi?&&= ;auth=3D0LS6ITN8HttLod8TrzYPxLimicIPtdESWXOko25Fj&reftype=3Dextlink&a= mp;artid=3D2642879&article-id=3D2642879&iid=3D176926&issue-id= =3D176926&jid=3D277&journal-id=3D277&FROM=3DArticle%7CBody&am= p;TO=3DExternal%7CLink%7CURI&rendering-type=3Dnormal&&http://= journals.plos.org/plos_consent_form.pdf)=20 to publication of his case details. In addition, the parents have=20 confirmed to the authors that the patient is aware of the = existence of the=20 complication described in this paper and that he is aware it is = discussed=20 in a scientific publication, which is available on the = internet.

A 13-y-old boy with AT, who is homozygous for the = North=20 African Jewish C103T ATM gene mutation presented to the Sheba = Medical=20 Center in February 2005 with recurrent headaches. On examination = he had=20 severe neurological deficits characteristic of AT, affecting = mainly his=20 motor functions and making him wheelchair bound. The patient's=20 intelligence was normal and he is highly motivated at school and = socially=20 active. His recent detailed immunologic and hematological status = is given=20 in Table=20 S2. Since the age of 7 y he has been treated for = hypogammaglobulinemia=20 at the Sheba Medical Center with monthly intravenous = immunoglobulin.

In May 2001 at the age of 9 y, in March 2002 at the = age of 10=20 y, and in July 2004 at the age of 12 y, he was taken by his = parents to be=20 treated in Moscow with repeated transplantation of fetal stem = cells (see=20 Text=20 S1 for details as supplied to the parents by the patient's = physicians=20 in Moscow). The treating team at the Sheba Medical Center was not = involved=20 in this treatment.

MRI performed in February 2005 to investigate the = headaches=20 revealed a right infratentorial lesion slightly compressing the = brain stem=20 and another lesion at the cauda equina (Figure=20 1A and 1B).=20 The lesions grew slowly as evidenced by repeat MRIs in June and = July 2006.=20 In September 2006 at the age of 14 y, surgery was performed and a = tumor=20 localized at L3=E2=80=934 level attached to the cauda equina nerve = roots was=20 removed. Additional =E2=80=9Csatellite=E2=80=9D lesions were = identified attached to nerve=20 roots rostral to the main lesions (Figure=20 2A and 2B).

Figure=20 1

Pre-Operative=20 MRI

Figure=20 2

Intra-Operative=20 View

Since surgery the patient's general = condition has=20 remained stable. During follow up there has been slow growth of = the tumor=20 adjacent to the right infratentorial lesion with some compression = on the=20 brain stem. MRI of the infratentorial tumor at diagnosis and in = January=20 2008 illustrates that the mass has more than doubled in volume (Figure=20 S1). MRI of the spinal cord in July 2007 did not reveal = significant=20 growth compared to the postoperative imaging and there is no overt = clinical deterioration. Based on the pathology and since patients = with AT=20 are extremely sensitive to chemotherapy and radiotherapy it was = decided to=20 follow up the patient conservatively and to repeat surgery only if = indicated by clinical deterioration.

Histology

The specimen consisted of three fragments = of tumor=20 ranging in size from 0.4 to 1 cm in greatest dimension. The = pathology=20 specimen (Figures=20 3=E2=80=935)=20 consisted almost entirely of glioneural tumor and only in small = part of a=20 remnant of the proximal filum terminale accompanied by scant = benign=20 adipose tissue, a not uncommon incidental finding at that site. No = nerve=20 root tissue was included. Much of the lesion was characterized by = vague=20 nodules of neurons and accompanying glial cells. The latter, = consisting=20 largely of astrocytes, formed a circumferential rind about the = lesion and=20 served to demarcate ill-defined aggregates of intermingled neurons = and=20 astrocytes. The neurons, all relatively mature, varied in = cytologic=20 characteristics to include (a) medium size neurons with open = chromatin,=20 small nucleoli, and relatively small quantities of pale cytoplasm = lacking=20 Nissl substance and (b) sizeable neurons with larger nuclei, = distinct=20 nucleoli, more amphophilic cytoplasm, and discernible Nissl = substance.=20 Neuronal dysmorphism, including binucleation, was infrequent. = Staining for=20 both synaptophysin and neurofilament protein was noted only in = association=20 with the neurons and their processes. Also conspicuous were two = glial=20 elements, one ependymal and the other astrocytic in nature. = Comprising=20 much on one tissue fragment, the monomorphous ependymal cells were = tanycytic in appearance, featuring elongate nuclei and very long, = aligned,=20 heavily fibrillated processes. In contrast, the astrocytes = possessed oval=20 nuclei, eccentric cytoplasm, and scant processes. = Immunohistochemical=20 stains showed strong s-100 protein and glial fibrillary acidic = protein=20 (GFAP) reactivity in the glial element. Epithelial membrane = antigen (EMA)=20 staining was scant and took the form of rare, paranuclear dots = within the=20 cytoplasm of the ependymal cells.

Figure=20 3

Hematoxylin=E2=80=93Eosine = Staining of the = Tumor

Figure=20 5

Histology = and=20 Immunohistochemistry of the=20 Tumor

Figure=20 4 Immunohistochemistry of=20 the Tumor

The entire lesion was unassociated with = cytologic=20 malignancy, mitotic activity, microvascular proliferation, or = necrosis.=20 Low to moderate strength p53 staining was seen in 40% of = astrocytic and=20 40% of ependymal cells. The MIB-1 preparation showed very low = level=20 staining (1%). Also indicative of slow lesion growth was the = finding of=20 vascular hyalinization, a feature accentuated on Masson trichome=20 stain.

Cytogenetic and Molecular = Analysis of=20 Tumor

The occurrence of a tumor following = administration=20 of neural stem cells and the unusual presentation of an = extra-axial=20 multifocal glioneural neoplasm in the proximity of the injection = sites=20 raised the possibility of a donor-derived tumor. In order to = explore this=20 possibility cytogenetic and molecular approaches were used. Since = the=20 patient is affected by AT, known to be characterized by genetic=20 instability [19],=20 we used several complementary methodologies to prove that the = nonidentity=20 of the tumor and the patient is not due to chromosomal and genetic = instability. FISH using X- and Y-chromosome specific probes on = touch preps=20 from the tumor biopsy revealed that the tumor removed from the = male=20 patient is composed of both XX and XY cells (Figure=20 6A). Analysis of the homologous amelogenin gene X- and = Y-specific=20 alleles in the patient's PB and tumor reveals that, while in the = PB the=20 signals from the two alleles are equal, in the tumor the X allele = signal=20 intensity is three times that of the Y allele (Figure=20 6B). This result further supports the presence of cells = originating=20 from a female donor. Analysis of the ATM gene North African Jewish = C103T=20 mutation using the SEQUENOM MassArray (Figure=20 7A) identified both parents of this patient as heterozygous = for this=20 mutation while homozygosity was demonstrated in the patient's PB = and BS.=20 Analysis of DNA extracted from undissected tumor revealed the = presence of=20 both the mutant and the normal allele. DNA extracted from LCM = isolated=20 tumor cells (Figure=20 S2) carried only the normal allele, and the mutant allele is = not=20 detected, proving that the tumor is of donor origin. We analyzed = 24 known=20 SNPs using the SEQUENOM MassArray on DNA samples from the tumor, = the=20 patient's PB and BS, and the parents' PB (list of all SNPs tested = is given=20 in Table=20 S1). Three SNPs, rs1043550, rs7294, and rs1061170, were = informative=20 and identified a tumor-specific allele that is not present in the = patient=20 PB or BS. One of them, rs7294 (VKORC1 9041G/A), proves = conclusively that=20 the tumor genotype could not originate from the patient or his = parents. Figure=20 7B shows the analysis of this SNP in the DNA obtained from the = tumor=20 biopsy and in LCM isolated tumor cells, in comparison to the = pattern=20 observed in PB of the patient and his parents. The patient and his = parents=20 are homozygous for the A allele, the undissected tumor revealed = the=20 presence of both the A and G alleles, while DNA extracted from LCM = isolated tumor cells carried only the G allele. This result = further=20 supports the fact that the tumor is of nonhost origin and = precludes the=20 rare possibility of tetragametic chimerism by showing that the = nonhost=20 allele is not represented in the parental germline [20].

Figure=20 6

Analysis = of X and Y=20 Chromosomes of the Tumor Cells Using I-FISH and PCR Analysis = of the=20 Amelogenin X- and Y-Specific Alleles Showing the Presence of = Female=20 Cells in the = Tumor

Figure=20 7

Analysis = of the ATM=20 C103T Mutation and the VKORC1 G9041A (rs7294) Polymorphism = Showing=20 Foreign Origin of the Tumor=20 Cells

Analysis with polymorphic microsatellite=20 tetranucleotide repeat markers of DNA from the tumor and DNA = extracted=20 from PB and BS obtained from the patient clearly showed that a = number of=20 alleles of nonhost origin are present in the tumor (Figure=20 8A and Table=20 S3). The number of nonrecipient alleles detected in the tumor=20 indicates that more than one donor cell population is present. A = possible=20 alternative explanation for the presence of additional variants in = the DNA=20 microsatellite profile in tumors is genomic instability resulting = from=20 mismatch repair defect [21].=20 We therefore investigated further the number of possible donors = present in=20 the tumor by detailed HLA analysis. HLA typing of the patient's PB = and BS,=20 and the tumor biopsy is shown in Figure=20 8B. The analysis conclusively identified the presence of two = HLA A*,=20 four HLA B*, and four HLA DRB1* nonhost alleles in the tumor. The = presence=20 of additional HLA A*, B*, and DRB1* alleles not present in the = patient=20 germline HLA or in his parents, confirms the presence of nonhost = donor=20 cells in the tumor. The presence of four additional alleles of HLA = B* and=20 DRB1* confirms the presence of cells originating from at least two = donors.

Figure=20 8

Analysis = of DNA=20 Tetranucleotide Repeats by Fluorescent PCR and Indicating = the Origin=20 of Tumor Cells from at Least Two=20 Donors

Supporting=20 Information

References

Discussion

We describe here a patient with AT who = was treated=20 repeatedly with fetal neural stem cells and who developed a = multifocal=20 brain tumor. Histology and immune phenotyping of the resected mass = led to=20 the diagnosis of a glioneuronal tumor. This is the first report of = a human=20 brain tumor developing from transplanted neural stem cells. The = results=20 obtained from the various cytogenetic and molecular studies = performed on=20 the tumor led us to conclude that the tumor is derived from the = neural=20 stem cells obtained from at least two aborted fetuses that were=20 administered a few years earlier. This case therefore confirms = that the=20 concerns raised regarding the risk of tumor development resulting = from=20 therapeutic transplantation of neural stem/precursor cells were = not=20 unfounded.

The cellular composition of the glioneural tumor = encountered=20 in this unique case is not surprising given the use of neuronal = stem=20 cells. Glia and neurons, the two principal cell types comprising = the=20 central nervous system, were both represented and well = differentiated.=20 Unlike conventional glioneuronal tumors occurring spontaneously in = the=20 human nervous system, the glial element of this patient's tumor = was=20 bitypic, including not only astrocytes but ependymal cells as = well.=20 Ependymal cells are only rarely encountered in association with = neurons in=20 human mixed glial and neuronal tumors [22].=20 The benign, morphologically mature nature of the sampled tumor = could only=20 be a reflection of differentiation and maturation.

The slow but demonstrated growth of both this = patient's=20 lesions is in keeping with the low MIB-1 labeling index noted. = Lacking a=20 biopsy of the subtentorial tumor, the histogenetic relationship to = the=20 biopsied tumor remains to be determined. The similar growth rate = of both=20 processes suggests that both may be glioneuronal in nature. As = separate=20 stem cell injections were involved in the proximity of the two = lesions=20 there is no need to postulate spinal seeding of the intracranial = tumor to=20 the lumbar sac. The multiple lumbar sac deposits may be entirely=20 independent and morphologically distinct, their occurrence = representing=20 multifocal implantation at the time of stem cell injection rather = than a=20 manifestation of seeding of a single implant.

The slow growth of the tumors, the benign character = of the=20 biopsied tumor, and the low MIB-1 labeling index suggest a = favorable=20 prognosis, although it should be noted that all available = information=20 regarding the clinical behavior of such tumors is based on = endogenous=20 tumors and does not necessarily reflect the clinical behavior of a = tumor=20 of exogenous origin.

While most naturally occurring tumors are = monoclonal, cancers=20 developing in exceptional situations favoring tumorigenesis are = often=20 oligo- or multiclonal. For example, embryonal tumors such as=20 retinoblastoma occurring in individuals carrying a germline = mutation in a=20 tumor suppressor gene [23]=20 and virally induced malignancies such as Epstein-Barr virus = (EBV)-related=20 post-transplant lymphoproliferative diseases [24]=20 often contain several distinct clones. The therapeutic use of = fetal neural=20 stem cells derived from several donors and treated in vitro by = growth=20 factors in the described case may have created a high risk = situation where=20 abnormal growth of more than one cell occurred.

Germinal regions such as the subventricular zone = have long=20 been proposed as the areas where gliomas originate. In animal = models,=20 regions of the brain with stem cell populations are more sensitive = to=20 chemical or viral oncogenesis than areas with a low proportion of=20 proliferating cells [25,26].=20 While neoplastic transformation of fully differentiated glia is = widely=20 assumed to be involved in gliomagenesis, this report describing = the=20 development of a glioneural neoplasm from transplanted neural stem = cells=20 supports an alternative mechanism, namely the development of the = tumor=20 from neural stem/progenitor cells [25,26].=20 It is possible that the in vitro expansion of fetal neural stem = cells in=20 conditioned medium supplemented with growth factors such as bFGF = and EGF=20 promoted transformation [27].=20 In addition it is possible that neuronal stem cells injected to = ectopic=20 sites where they are free of normal developmental control = mechanisms=20 provided by the physiological microenvironment may undergo = abnormal growth=20 and differentiation.

In recent years the possibility of transmission and = engraftment of malignant and premalignant cells has emerged as an=20 important mechanism for cancer development and propagation [28].=20 We have shown that all canine transmissible venereal tumors (TVT)=20 originate from the same tumor and spread by malignant cell = transplantation=20 [29,30].=20 Another illustrative model for transplanted tumors is the = Tasmanian devil=20 facial-tumor disease [31].=20 Donor origin tumors have also been described in humans, in cases = of=20 maternal to fetal transmission of cancer [28,32]=20 and in solid organ transplant recipients [33].=20 In the majority of such cases of tumor transplantation immune = surveillance=20 failure can be attributed to immunodeficiency. The patient = described, like=20 other AT patients, suffers from immune deficiency, which may have=20 prevented rejection of the transplanted cells. This = immunodeficiency may=20 explain the persistence of donor cells from at least two donors = several=20 years after the experimental therapy.

In some transplanted tumor models such as the TVT,=20 donor-derived tumor can subsequently regress because of immune = rejection.=20 Such results suggest that modulation of the immune system could be = a=20 possible future therapy in the patient described here. However, = the immune=20 deficiency of our patient is not severe (see Table=20 S2), which suggests that even relatively immunocompetent = patients may=20 also fail to reject neural stem cells and be at risk for tumor=20 development. In addition, a child's developing central nervous = system may=20 provide an environment that promotes tumorigenesis, especially in=20 combination with the abnormal AT host environment characterized by = deranged cellular responses to stress. Cases of astrocytoma have = been=20 reported in children with AT [34].

Studies of leukemia in monozygotic twins and = screening of=20 neonatal blood samples for leukemia-specific genetic aberrations = have=20 shown that in most childhood leukemias premalignant cells are = already=20 present in utero [35].=20 It usually takes months or years for frank leukemia to develop, = suggesting=20 a need for additional hit(s) for clinically evident disease to = occur. It=20 is estimated that one child out of 20 is born with a preleukemic = clone [35].=20 Initiation of disease in utero by chromosomal translocations = exceeds the=20 rate of overt leukemia by some 100-fold. A similar ratio has been = shown in=20 putative premalignant lesions detected at autopsy by = histopathology,=20 resembling neuroblastoma and Wilms tumor compared with the actual=20 frequency of clinically evident tumors [35].=20 These findings overall suggest that in several common pediatric = cancers=20 the occurrence of premalignant stem/progenitor cells might be very = common=20 prenatally, but the transition to overt disease is rare. This = hypothesis=20 may be relevant to premalignant fetal neural stem cells as well = and should=20 be borne in mind when fetal neural stem cell therapy is = considered.

The only type of malignancy that has been clearly = shown to=20 develop as a result of stem cell therapy in humans is donor type = leukemia=20 following hematopoietic stem cell transplantation [36].=20 It appears that donor type leukemia may occur substantially more=20 frequently with a cord blood source of stem cells than with adult = bone=20 marrow or PB stem cells [36].=20 Umbilical cord stem cells are more immature than their adult = counterparts.=20 Similarly, one can suggest that the less differentiated fetal = neural stem=20 cells are potentially more prone to transformation than adult = neural stem=20 cells.

Stem cell therapy and neural stem cells, = in=20 particular, provide hope to patients affected by devastating = diseases.=20 However, such innovative treatments also carry substantial risks = and the=20 potential for malignant transformation of transplanted cells has = been=20 raised [2,3].=20 The occurrence of a donor origin brain tumor in the patient = described here=20 provides the first proof that the concerns raised are valid. Any=20 innovative therapeutic approach carries predictable and = unpredictable=20 risks. For example the impressive success of gene therapy for = children=20 suffering from SCID-X1 was marred by the occurrence of leukemia = resulting=20 from viral integration leading to oncogene activation [37].=20 Yet also =E2=80=9Cconventional=E2=80=9D therapies such as = chemotherapy, radiotherapy, and=20 bone marrow transplantation used to treat life threatening = diseases, are=20 associated with morbidity and mortality. Our findings therefore do = not=20 imply that the research in stem cell therapeutics should be = abandoned.=20 They do, however, suggest that extensive research into the biology = of stem=20 cells and in-depth preclinical studies, especially of safety, = should be=20 pursued in order to maximize the potential benefits of = regenerative=20 medicine while minimizing the risks.

Supporting Information

Figure S1: Head Coronal Cuts with Gadolinium = Injection=20 Showing the Tentorial Lesion on the Right Side

From (A) 2005 to (B) January 2008, the tumor has = grown=20 significantly, more than doubling in volume.

(196 KB DOC)

Click=20 here for additional data file.^{=20
(200K)}

Figure S2: LCM of Tumor Cell Nuclei

(A) High power photomicrograph showing tumor cells=20 intermingled with small capillaries (hematoxylin=E2=80=93eosine = stain,=20 magnification =C3=97400). Arrows indicate the tumor cells selected = for=20 isolation by LCM.

(B) The same section following microdissection of = tumor=20 nuclei (hematoxylin=E2=80=93eosine stain, magnification = =C3=97400). Arrows indicate=20 sites of removed tumor cell nuclei.

(264 KB DOC)

Click=20 here for additional data file.^{=20
(268K)}

Table S1: Oligonucleotides Used for the Detection of = the ATM=20 Mutation and SNPs Using the SEQUENOM MassArray

(46 KB DOC)

Click=20 here for additional data file.^{=20
(46K)}

Table S2: Patient's Recent Immunological and = Hematological=20 Laboratory Data

(53 KB DOC)

Click=20 here for additional data file.^{=20
(53K)}

Table S3: Microsatellite Loci Analysis of Patient PB = and=20 Tumor Cells

(27 KB DOC)

Click=20 here for additional data file.^{=20
(28K)}

Text S1: Protocol for Stem Cell = Preparation

(26 KB DOC)

Click=20 here for additional data file.^{=20
(26K)}

Acknowledgments

We thank the Kahn Family Fund for Humanitarian = Support for=20 their generous support of our research. We thank R. Kalt, E. = Moscovich, B.=20 Brilovich, K. Siegalov, and G. Ishoiev for excellent technical = assistance.=20 GR holds the Djerassi Chair in Oncology, Tel Aviv University. We=20 acknowledge the Russian physicians and YL for providing details of = the=20 treatment in Moscow.

Abbreviations

AT	ataxia telangiectasia
BS	buccal smear
ESC	embryonic stem cell
HLA	human leukocyte antigen
I-FISH	interphase fluorescence in situ hybridization
LCM	laser capture microdissection
PB	peripheral blood

Footnotes

Author contributions. = NA, RL, SC,=20 and GR designed the experiments/the study. NA, AH, BWS, YC, LT, = NP, DW,=20 AT, and SC collected data or did experiments for the study. NA, = AH, YC,=20 RL, LT, NP, MK-M, DW, LL-T, AT, SC, and GR analyzed the data. NA, = AH, BWS,=20 RL, LT, MK-M, LL-T, AT, SC, and GR contributed to writing the = paper.

Funding: The authors received no = specific=20 funding for this study.

Competing = Interests: The=20 authors have declared that no competing interests = exist.

Supporting=20 Information

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Articles=20 from PLoS = Medicine are=20 provided here courtesy of
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'this' to reuse same window, else ""=0A= // windowname: Reference name for window=0A= // additional: Attributes for window.open, from:=0A= // width, height, resizable, scrollbars, toolbar, location, = directories,=0A= // status, menubar, copyhistory.=0A= // Notes: Book version always provides menubar, toolbar, etc.=0A= //=0A= function startTargetBook(link,windowname,width,height,additional)=0A= {=0A= startTarget(link,windowname,width,height,additional)=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function startTarget(link,windowname,width,height, additional)=0A= {=0A= if(! window.focus)=0A= return;=0A= =0A= var sizestring =3D ",width=3D" + width + ",height=3D" + height;=0A= var opt =3D = "menubar=3Dno,toolbar=3Dno,status=3Dno,scrollbars=3Dyes,resizable=3Dyes,d= ependent=3Dyes,location=3Dno";=0A= var allOptions =3D opt + sizestring;=0A= if (additional) { allOptions =3D allOptions + ',' + additional; }=0A= =0A= windowname =3D String(windowname).replace(/-/g, "_")=0A= var moveToXDefault =3D 75=0A= var moveToYDefault =3D 50=0A= =0A= var moveToX =3D moveToXDefault=0A= var moveToY =3D moveToYDefault=0A= var yAdj =3D 50=0A= var yAdjDelta =3D 25=0A= =0A= var barNames =3D ['menubar', 'toolbar', 'statusbar']=0A= for (var idx in barNames)=0A= { =0A= if (String(allOptions).lastIndexOf(barNames[idx] + '=3Dyes') > =0A= String(allOptions).lastIndexOf(barNames[idx] + '=3Dno'))=0A= yAdj +=3D yAdjDelta=0A= }=0A= =0A= try {=0A= if (window.screen.width && width > 0)=0A= moveToX =3D Math.ceil((window.screen.width - width)) - 15=0A= moveToX =3D (moveToX > 0 ? moveToX : moveToXDefault)=0A= =0A= if (window.screen.height && height > 0)=0A= moveToY =3D Math.ceil((window.screen.height - height)) - yAdj=0A= moveToY =3D (moveToY > 0 ? moveToY : moveToYDefault)=0A= }=0A= catch (e) {}=0A= =0A= var wLeftTopCornerOptions =3D ',left=3D' + moveToX + ',top=3D' + = moveToY + ',screenX=3D' + moveToX + ',screenY=3D' + moveToY=0A= =0A= allOptions =3D allOptions + wLeftTopCornerOptions=0A= =0A= w =3D window.open ("", windowname, allOptions)=0A= w.focus()=0A= =0A= link.target=3Dwindowname=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function focuswin(windowname)=0A= {=0A= windowname =3D String(windowname).replace(/-/g, "_")=0A= w =3D = window.open("",windowname,"menubar=3Dyes,scrollbars=3Dyes,toolbar=3Dyes,l= ocation=3Dyes,status=3Dyes,directories=3Dyes,resizable=3Dyes");=0A= w.focus();=0A= =0A= return true;=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function reverseString (inStr)=0A= {=0A= var outStr =3D ''=0A= =0A= for (i =3D0; i <=3D inStr.length; i++)=0A= {=0A= outStr =3D inStr.charAt(i) + outStr=0A= }=0A= =0A= return outStr=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function reverseAndReplaceString (inStr, findStr, newStr)=0A= {=0A= return reverseString(inStr).replace(findStr, newStr)=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function initUnObscureEmail (className, innerHTML)=0A= {=0A= =0A= try{=0A= if (window.addEventListener)=0A= window.addEventListener('load', function() {unObscureEmail = (className, innerHTML)}, false)=0A= else if (window.attachEvent)=0A= window.attachEvent('onload', function() {unObscureEmail = (className, innerHTML)})=0A= }catch(e){=0A= }=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function unObscureEmail (className, innerHTML)=0A= {=0A= try {=0A= if (typeof(unObscuredEmails) =3D=3D 'undefined')=0A= unObscuredEmails =3D new Array()=0A= =0A= if (! 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