Inhibitors of the protein survivin might lower tumour risk
The ability of embryonic stem cells to form noncancerous tumours called teratomas is one of their defining traits. It is also a frightening one, particularly for those who hope to develop therapies from the cells. New research from Nissim Benvenisty and colleagues at the Hebrew University in Jerusalem helps to explain why human embryonic stem cells can form teratomas and may provide a way to keep teratomas in check1.
Teratomas are unusual because of the diverse sorts of tissues they form, but that weirdness is not what makes them interesting to Benvenisty. To him and his colleagues these tumours are interesting because, unlike most cancerous tumours, the embryonic stem (ES) cell tumours originate from a group of apparently normal cells instead of from a single abnormal cell. They wanted to know what gives such cells the ability to form tumours.
The researchers compared gene expression in undifferentiated human ES (hES) cells, teratomas and embryoid bodies, the clusters of cells that form in culture if ES cells are allowed to differentiate. The researchers reasoned that genes expressed in hES cells and teratomas, but not in differentiated cells, might be the ones that allowed hES cells to generate tumours. Of the 21 genes identified, BIRC5 seemed to be the best candidate for a gene that could contribute to tumour formation. It codes for survivin, a protein which both inhibits apoptosis and regulates cell division.
“"Tumor formation is a major safety concern in the use of human embryonic stem cells and our analysis discovered a gene that its inhibition dramatically reduces the tumor growth,” says Barak Blum, lead author on the paper. Peter Andrews, an expert on the biology of ES cells and embryonal carcinoma cells at the University of Sheffield, UK. He notes that survivin is located on the same arm of chromosome 17, one of the genomic regions that gets amplified when ES cells change in culture in ways that might be precancerous.
Survivin is expressed in most cancer and early-stage embryos, but it is almost completely absent from normal tissues. If survivin activity was disrupted by using a dominant negative plasmid, more hES cells and teratoma cells went into apoptosis. Similar, but less pronounced effects, were also seen with a drug combination that is believed to disrupt survivin activity (Taxol followed by Purvalanol A).
Previous work indicates that inhibiting survivin can induce apoptosis in cancer and ES cells but not in normal cells. This work suggests that survivin inhibitors might also be able to decrease the risk of hES cell teratoma formation and so facilitate the development of stem cell therapies. Such therapies would aim not to transplant ES cells themselves but rather the cells derived from them. Andrews cautions, however, that before such a strategy is considered, the effects of survivin on these cells would need to be assessed. “We would not want to kill derivatives that are required for a certain treatment.”
Currently, though, Benvenisty's efforts are focusing on safety. Although he believes that inhibiting BIRC5 might minimize the chances of tumour formation, he has also explored methodologies to separate differentiated and undifferentiated cells. “We believe that a combination of strategies is needed to address the major safety concerns regarding teratoma formation by human embryonic stem cells.”
Blum, B. et al. The anti-apoptotic gene survivin contributes to teratoma formation by human embryonic stem cells. Nature Biotechnol. advance online publication, 10.1038/nbt.1527 (1 March 2009).
About this article
Cite this article
Baker, M. Why hES cells make teratomas. Nat Rep Stem Cells (2009). https://doi.org/10.1038/stemcells.2009.36