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

Abstract

Background

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

Methods and Findings

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

Conclusions

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

Abstract

Gideon Rechavi and colleagues describe the case of a boy with ataxia telangiectasia who developed a brain tumor after neural stem cell therapy.

Editors' Summary

Background.

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

Why Was This Study Done?

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

What Did the Researchers Do and Find?

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

What Do These Findings Mean?

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

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000029.

• The US National Institutes of Health provides information about stem cells and their potential uses

• The International Society for Stem Cell Research also provides information about all aspects of stem cells for the public and for professionals

• The US National Human Neural Stem Cell Resource provides specific information about neural stem cells for the public and for scientists

• The US National Cancer Institutes has a fact sheet about ataxia telangiectasia