Malignant transformation is a known potential danger associated with stem cell transplantation. A study published recently in Public Library of Science claims to document the first reported case of a brain tumour developing from transplanted neural stem cells.
A 13 year old boy with ataxia telangiectasia (AT), who was homozygous for the North African Jewish C103T ATM gene mutation presented with recurrent headaches in 2005. In May 2001, March 2002 and July 2004 he had been treated in Moscow with repeated transplantation of foetal stem cells. MRI performed in 2005 to investigate the headaches revealed a right infratentorial lesion slightly compressing the brain stem and another lesion at the cauda equina. Surgery was performed and a tumour localised at L3-4 level attached to the cauda equina roots was removed. Additional ‘satellite’ lesions were identified attached to nerve roots rostral to the main lesion. Based on the tumour pathology, and as patients with AT are particularly sensitive to chemotherapy and radiotherapy, the patient was followed up conservatively.
The excised tumour consisted almost entirely of glioneural tumour. Much of the lesion was characterised by vague nodules of neurons and accompanying glial cells, with the latter consisting largely of astrocytes forming a circumferential rind about the lesion. The entire lesion was unassociated with cytologic malignancy, mitotic activity, microvascular proliferation or necrosis.
The fact that this tumour occurred after neural stem cell treatment and the unusual presentation of the disease raised the possibility of the tumour being donor-derived. Knowing that patients with AT are characterised by genetic instability the authors compared the tumour cells and the patient's peripheral blood cells using a range of techniques to assess the origin of the tumour. Fluorescent in-situ hybridisation using X and Y chromosome probes revealed that the tumour was composed of both XX and XY cells. PCR for the amelogenin gene X- and Y-specific alleles revealed that in the patients peripheral blood the signals from both alleles were equal, whereas in the tumour the X allele signal intensity was three times greater than that of the Y allele, suggesting
MicroRNA-10b (miR-10b) has previously been shown to be upregulated in glioblastoma tissues. A recent International Journal of Cancer paper describes a study which examined the expression level of miR-10b in glioma samples as compared to non-tumour brain samples and sought to identify any correlation between overexpression and tumour grade.
Samples from 43 gliomas (of different grades) and six GBM cell lines were used in the analysis. Using microarray hybridisation, the researchers first compared miRNA expression profiles between three paired GBM and non-tumour brain samples. A number of miRNAs (including miR-10b) were upregulated differentially in the GBM samples, and a number were also differentially downregulated in GBM samples.
Real-time PCR analysis revealed that miR-10b levels (in all of the 6 GBM cell lines tested) were higher than that of non-tumoural brain tissue. Analysis of miR-10b expression levels in the samples from the 43 glioma patients and 6 non-tumoural brain tissues revealed high miR-10b expression levels in all glioma samples. The expression of miR-10b in tumour samples, as compared with the control samples ranged from 0.08- to 364-fold, with a mean of 46.7-fold. When miR-10b expression levels were compared between different tumour types and grades within the 43 tumour samples, it was found to be extremely over-expressed in GBM samples.
The mean miR-10b level in high-grade glioma, including GBM and anaplastic astrocytoma was significantly higher than in low-grade gliomas, including low-grade glioma, oligodendrogliomas and ependymoma.
It is known that miR-10b inhibits the translation of HOXD10 mRNA, affecting the expression of downstream targets of this transcription factor. Two effectors of HOXD10 are RhoC and uPAR, which are known to have roles in invasion, migration and metastasis. Analysis of these two effectors in the same glioma samples using real-time PCR showed significant correlations between miR-10b and mRNA expressions of RhoC and between miR-10b and mRNA expressions of uPAR in all glioma samples.
Immunohistochemical analyses revealed correlation between miR-10b and the protein expressions of RhoC and uPAR. Both uPAR and RhoC were found to be significantly more highly expressed in tumours designated as ‘high miR-10b’ (those with greater than 25-fold expression of miR-10b), than in tumours designated ‘low miR-10b’ (those with less than 25-fold expression of miR-10b).
Examination of MRI images of GBM and anaplastic astrocytoma lesions (dividing them into two groups for analysis: multifocal lesions and single lesions) revealed that in the multifocal group the relative level of miR-10b ranged from 24.5- to 364-fold, with a mean of 157.9-fold and in the single-lesion group the relative level of miR-10b ranged from 0.3-271.5-fold, with a mean of 56.7-fold.
The authors conclude that this study of expression levels of miR-10b in a range of glioma types demonstrates that miR-10b is upregulated in not only high-grade gliomas but also in low-grade astrocytomas, oligodendrogliomas and ependymomas. Expression levels of miR-10b are associated with glioma malignancy and are much higher in GBM than in other gliomas. The authors further conclude that the higher expression levels of miR-10b in multifocal lesions (particularly in high-grade gliomas) might indicate that miR-10b has some role in glioma invasion.
Sasayama, T. et al. MicroRNA-10b is overexpressed in malignant glioma and associated with tumor invasive factors, uPAR and RhoC. Int. J. Cancer: 125, 1407-1413 (2009).
Booklet on the first documented, modern-day brain tumour surgery for a glioma which took place in London in 1884.
First documented glioma operation: The International Brain Tumour Alliance has produced a 62-page booklet commemorating the 125th anniversary in 2009 of the first documented,
modern-day surgery to remove a glioma in November 1884. Bulk copies of the booklet are available (subject to availability) for free distribution at oncology and neurosurgery and other relevant brain tumour scientific conferences, as well as patient conferences, on payment of the cost involved in freighting supplies of the booklet to your location from the UK. Contact IBTA Co-Director Kathy Oliver (kathy@theibta.org) for further details. Individual copies are available to order (for the cost of postage and packing) from the IBTA website at www.theibta.org
The booklet contains a Preface by Emeritus Professor David GT Thomas of London, which can be viewed here: http://www.theibta.org/PrefaceGodleeBooklet.pdf, and a Glioma Timeline prepared by Dr Frederick G Barker II (Historian at the AANS/CNS Section on Tumors, USA), which can be viewed here: http://www.theibta.org/GliomaTimeline.pdf
EANO invites trained nurses to apply for a educational travel grant to visit a centre committed to the care of patients with Neuro-oncological illness to experience the procedures of a centre , or attend to a course or a conference dedicated to Neuro-oncology.