Process Triggered by Some Anti-Cancer Drugs Causes Tumors in Mice, Study Finds

April 17, 2003

Tags: Jaenisch LabCancer

CAMBRIDGE, Mass. — It is well known that cancers frequently are caused by genetic mutations—random alterations along the long chain of molecules that make up the sequence of an organism’s DNA. Two studies published this week in Science now point to another culprit in tumor formation, a process that can cause chromosomes to become unstable by affecting changes in the methylation of the DNA, which renders a gene active or inactive by affecting how the DNA is packaged into proteins without changing gene sequences.

The findings are important, researchers say, because some anti-cancer drugs in clinical trials are designed to kill diseased cells by triggering the process under study—called hypomethylation—which lowers the level of methylation. Previous studies by scientists at Whitehead Institute for Biomedical Research have shown that drug-induced hypomethylation can protect against tumors arising in the intestinal tract (colon cancer). But in this new work, Whitehead scientists found that hypomethylation also may cause tumors in mice, suggesting that such drugs may do harm as well as good, said Rudolf Jaenisch, leader of the team that published these new studies.

“You have to know how you interfere with these cancer mechanisms,” said Jaenisch, adding that the same alteration of cellular chemistry that controls some cancers is now seen to cause cancer in other tissues. “At the moment we have two totally opposite results when we look in two different tissues. In the intestines, hypomethylation protects against cancer, and in the thymus it enhances cancer.”

As researchers search for explanations for what prompts cancer cells to proliferate and grow, an increasing number have begun to examine extra-genetic changes—problems that affect whether a gene is active or silent—not the gene’s sequence. One process receiving heavy scrutiny is among the most basic events in a cell’s nucleus during the life of the cell, methylation, during which methyl molecules, which can turn genes on or off, attach to the bases of an organism’s DNA.

In many cancer cells, too few methyl molecules attach to DNA, a condition scientists call hypomethylation. But until now, scientists didn’t know which came first—the cancer or the hypomethylation. François Gaudet, a graduate student in Jaenisch’s lab, spent several years developing mice transgenically designed to be hypomethylated.

“It was a shot in the dark to see whether we could generate animals that could actually survive, and at the same time be hypomethylated,” said Gaudet.

Gaudet’s mice expressed only about 10 percent of normal levels of methyltransferase, the enzyme that maintains normal levels of methylation. About 80 percent of the mice developed an aggressive form of leukemia, a tumor that is derived from the thymus. What’s more, the cancer cells detected were the same throughout a tumor, suggesting that the tumor grew from a single hypomethylated abnormal cell. And, in fact, a gene called c-myc, known to be associated with tumor formation, was seen to be overly active in the cells.

Gaudet found that the tumors had an extra copy of chromosome 15, the same chromosome where the c-myc gene is found. This explains higher activity of c-myc, he added. Chromosome aberrations such as trisomies—three copies of a chromosome instead of two—or chromosome loss are hallmarks of human tumors, particularly leukemia.

Knowing that hypomethylation can cause cancer raises questions about ongoing clinical trials, Gaudet said. “The induction of hypomethylation might treat cancer in some tissues but may induce cancer in other tissues,” Gaudet said. “It is important therefore to test the effect of hypomethylation on cancer in different tissues.”

Extending Gaudet’s work, Amir Eden, a postdoctoral fellow in Jaenisch’s lab, found that even mice engineered to develop tumors did so earlier when hypomethylated. Eden’s mice had mutations in genes that normally suppress tumors; when methylation was reduced in such mice, Eden found that they developed soft-tissue sarcomas earlier when compared to similarly mutated mice with normal methylation levels. In these mice, Eden could show that hypomethylation-induced chromosomal instability caused an increase in tumor formation.

The instability could be an asset to a cancer cell looking to multiply and cause trouble, Jaenisch said. “There seems to be a selective advantage for tumor cells to be hypomethylated, because its chromosomes are more unstable.”

The data offer “real food for thought about the role of losing methylation in cancer,” noted Stephen Baylin, a scientist at John Hopkins University in Baltimore, Md. But Baylin also cautioned that these findings in mice may not be seen in people. In the mice engineered at Whitehead Institute, the level of methylation likely was more reduced than in most human tumors. Moreover, he cautioned that unlike hypomethylation induced in cancers that develop in human adults, these hypomethylated mice carry a reduced methylation capacity for their entire lives, starting at the embryonic stage.

“Jaenisch may be right,” Baylin said, “but you have to be very careful about equating the situation that he’s looking at experimentally with what’s going on in human tumors,” an assertion also made by Jaenisch.

“It is very important to assess whether findings made in animal models apply to patients,” Jaenisch said.

Jaenisch’s lab plans to extend this work by looking at other tumors, such as those of the pancreas, breast and liver, changing methylation levels and observing the results. “I think it will reveal metabolic differences between tissues,” he said, “and may lead to a deeper understanding why reducing methylation levels seems to harm some cancers and benefit others.”

David Appell is a freelance writer living in Ogunquit, Maine.

This research was supported by grants from Max-Delbruck-Center and the Deutsche Forschungsgemeinshaft and the National Institutes of Health.

Full citation for print version
© Science, Vol 300, Issue 5618 pp 489-492, April 18, 2003
“ Induction of Tumors in Mice by Genomic Hypomethylation”
Authors: François Gaudet, Whitehead Institute, Massachusetts Institute of Technology, Ludwig Maximillians University; J. Graeme Hodgson, UCSF Comprehensive Cancer Center; Amir Eden, Laurie Jackson-Grusby, Jessica Dausman, all of Whitehead Institute and MIT; Joe W. Gray, UCSF Comprehensive Cancer Center; Heinrich Leonhardt, Ludwig Maximillians University; Rudolf Jaenisch (corresponding author), Whitehead Institute, MIT

Full citation for print version
© Science, Vol 300, Issue 5618, p 455, April 18, 2003
“ Chromosomal Instability and Tumors Promoted by DNA Hypomethylation”
Authors: Amir Eden, François Gaudet, Alpana Waghmare and Rudolf Jaenisch (corresponding author), all of Whitehead Institute and MIT

Whitehead Institute is a world-renowned non-profit research institution dedicated to improving human health through basic biomedical research.
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through its faculty, who hold joint MIT appointments.

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