June 09, 2003
Epigenetic Factors Reverse Nucleus Cancer State

Transfer of a cell nucleus from a cancer cell to a normal cell does not turn the normal cell into a cancer cell.

Nuclei removed from mouse brain tumor cells and transplanted into mouse eggs whose own nuclei have been removed, give rise to cloned embryos with normal tissues, even though the mutations causing the cancer are still present. This research, from scientists at St. Jude Children's Research Hospital, appears in the June 1 issue of Cancer Research.

The finding demonstrates that the cancerous state can be reversed by reprogramming the genetic material underlying the cancer, according to James Morgan, Ph.D., a member of the St. Jude Department of Developmental Neurobiology, and lead author of the study. The findings also indicate that genetic mutations alone are not always sufficient to cause a cell to become cancerous.

“Specifically, it shows that so-called epigenetic factors are key elements in the development and maintenance of tumors,” Morgan said.

Epigenetic factors are those that influence the cell’s behavior. Examples include environmental effects and chemical modification.

“The concept of epigenetic factors having a role in cancer is already largely accepted,” Morgan said. “In fact, it’s already known that epigenetic alterations of chromosomes can cause certain rare forms of cancer. And some anti-cancer agents actually target epigenetic changes. But this is the first formal proof of the theory in a living animal.”

Unlike mutations, epigenetic modifications of DNA are potentially reversible molecular events that cause changes in gene expression. Some genes that help prevent the development of cancer (e.g., tumor suppressor genes) can be targets of epigenetic factors. The inactivation of such a gene might make the DNA more vulnerable to developing a cancer-causing mutation.

A cell is an incredibly complex state machine. The transition of a cell into a cancerous state may require (at least in some cases) more than just a set of mutations in the nucleus. The challenge is going to be to figure out what it is about an egg cell that allows it to turn the nucleus from a cancerous cell back into a non-cancerous state.

The epigenetic state that is producing this effect might be enzymes that methylate (attach methyl groups to) nuclear DNA. Or it might be molecules that bind to DNA at sites in the nucleus where binding will shut down replication. Or possibly the key might not be something that is in the egg cells. The key could be that the egg cell cytoplasm is missing some compounds that are necessary to maintain rapid cell division. Those compounds might even be essential for telling the nucleus to make enzymes that make more of those compounds. There are just a lot of imaginable ways that the epigenetic state difference might be working to convert a cancerous nucleus back into a non-cancerous state.

Note that they transferred the nuclei from cancer cells into eggs, not into regular cells. An egg has only half the normal amount of DNA that a normal cell has since it has only one member of each pair of chromosomes. An egg's epigenetic state is very different from that of adult cells. It is so different that it is possible in some species to put adult non-cancerous cell nucleuses into eggs to make embryos. This doesn't work every time but it can be used to clone animals.

It would be interesting to know whether this transfer of a cancer cell nucleus into a different type of cell has ever been tried with non-egg cells as targets.

Update: Providing what may be a clue to how a nucleus could be shifted back to a non-cancerous state, a sey of recent papers point to an important role for methylation in cancer development. (free registration at The Scientist site required)

Minna's team has gone on to characterize RASSF1 expression in more than 1,000 tumor samples. "I would say that after p53, it's the most frequently inactivated tumor suppressor gene," says Minna. Some already have begun to link RASSF1A status with prognosis. "Several studies have now shown that the presence of RASSF1A methylation confers worse prognosis on non-small-cell lung cancer patients," he says.5

What will be interesting to see is whether epigenetic changes such as methylation are being caused by mutations elsewhere in the genome.

Share |      Randall Parker, 2003 June 09 02:58 AM  Biotech Manipulations


Comments
shikha said at June 25, 2004 4:25 AM:

How does a normal cell turns to cancerous cell?

Sensei Bainshufu said at November 8, 2004 9:31 AM:

Nicely done

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