Tumor development involves epigenetic changes, including the activation of oncogenes and the silencing of tumor suppressor genes, but to what extent these epigenetic changes can be reprogrammed is largely unknown. Now, a study in the August 2 Genes and Development reveals that the nuclear transplantation of a cancer cell nucleus into an oocyte can reverse its cancer phenotype and produce embryonic stem cells with developmental potential.

"How interesting," said Frederick Domann, from the University of Iowa, referring to the ability to reprogram a cancer cell nucleus. "I think this will have a broad impact on our understanding of epigenetic mechanisms," Domann, who was not involved in the study, told The Scientist.

In addition to genetic changes, epigenetic modifications, such as the methylation of DNA and the acetylation/deacetylation of histones, are increasingly being found to affect the characteristics of tumors. "The phenotype of a cancer cell is obviously determined by genetic changes, but the question is how much of this phenotype is epigenetic?" said Rudolf Jaenisch, from the Whitehead Institute for Biomedical Research, and senior author of the study. "Nuclear cloning is an epigenetic problem, since the egg is able to reprogram the somatic nucleus. Thus, the most unbiased way to ask [the above question] is to expose a cancer cell nucleus to an egg and see if you can change its developmental potential."

Jaenisch, lead author Konrad Hochedlinger, and their colleagues therefore decided to determine if the nuclei of murine leukemia, lymphoma, breast, and Ras-inducible melanoma cancer cells would allow development when introduced into an oocyte with its nucleus previously removed (nuclear transplantation). Although some of the cancer cell nuclei were unable to induce development, others supported organized division cleavages and produced blastocysts, while one of these, from a Ras-inducible melanoma, also gave rise to embryonic stem cells, termed NT ES cells.

The research team went on to further study this embryonic stem cell line, finding that the injection of these cells into blastocysts allowed the production of chimeric mice, in which the NT ES cells contributed to multiple organs, including the skin, heart, and liver. This suggested that the oocyte cytoplasm was able to reprogram the melanoma nuclei into a pluripotent embryonic state.

"This says that the major part of the phenotype of the melanoma donor cell is determined by epigenetic alterations, because they are all reversible," Jaenisch told The Scientist. Nevertheless, as expected, the genetic changes possessed by the original melanoma, revealed to be various chromosomal aberrations, were not reversible, resulting in the chimeric mice all developing tumors.

"One would like to test a large number of tumors to see if the epigenetic contribution to cancer is universal," said Jean-Pierre Issa, from the University of Texas at Houston, who was not involved in the study. Issa cautioned that the tumor that gave the best results was not a spontaneous tumor, and instead came from an artificially created Ras-inducible cell line, which may be more easily reprogrammed. Nonetheless, "it is clear that a melanoma cell can give rise to a normal immune system, among other normal tissues, despite its multiple genetic defects," Issa told The Scientist.

"This is an extremely important area, in terms of using nuclear transfer, in particular on cancer cells, to determine what is reprogrammable and what is not," said Stephen Baylin, from John Hopkins School of Medicine, who was not involved in the study. "We now need to understand exactly what is being reprogrammed, and thus what we can and can't get around," said Baylin.

Issa and Domann agreed and said they feel the research thus further illustrates the potential of anticancer drugs that modify cellular components involved in epigenetic changes. "One could say that this experiment confirms the promise of such a therapeutic approach. Rather remarkably, the first DNA methylation inhibitor was just approved for usage in human cancer, specifically the myelodysplastic syndrome," said Issa.