Researchers at Jefferson Medical College and Jefferson's Kimmel Cancer Center are gaining a better understanding of the cues that help guide cells to the right places in developing embryos.
Steven Farber, Ph.D., assistant professor of microbiology and immunology at Jefferson Medical College of Thomas Jefferson University in Philadelphia, and his co-workers have found that statins, the group of anti-cholesterol drugs that includes the popular Lipitor, interfere with a biochemical pathway vital to the migration of germ cells in embryonic zebrafish. In all organisms, including humans, germ cells are stem cells that are destined to become either sperm or egg cells, and they must migrate from one place in the developing embryo to another before development can occur.
A better understanding of germ cell migration, Dr. Farber says, and cell migration in general, might lead to insights into disease processes, including cancer. Cancer turns deadly when it spreads to other areas in the body.
Dr. Farber and his co-workers report their findings in the February 2004 issue of the journal Developmental Cell.
"We have identified an enzyme in zebrafish – and there is a companion paper in the journal identifying the same pathway in fruit flies – showing that if you interfere with this enzyme, germ cells don't migrate correctly," he says. "It's likely a general feature of all vertebrates, and not simply a fish-specific observation."
In earlier work, Dr. Farber had studied the effects of statins on lipid metabolism in zebrafish embryos. Dr. Farber knew that researchers at New York University School of Medicine had found that a mutation in a gene for an enzyme, HMG-CoAReductase, disrupted germ cell migration in fruit flies. In both the fruit fly and all vertebrate embryos, germ cells need to migrate through the developing embryo to their final destination, where they develop into sperm or egg cells. HMG-CoAReductase also plays a central role in cholesterol synthesis in both humans and zebrafish.
Using a special technique developed by a colleague, they actually visualized the effect of Lipitor on germ cells, which, he says, caused the cells to "get lost." The cells were unable to migrate to the correct place in the developing embryo. Dr. Farber's group found that HMG-CoAReductase is important not just for fly germ cell migration, but also for a model vertebrate system such as the zebrafish. These data, he says, suggest that this pathway is "a highly conserved feature" of animal development.
The researchers found that they could block the effects of Lipitor if they injected the zebrafish beforehand with mevalonate, which is what HMGCoAReductase makes. They continued along the pathway, step by step, chemically knocking out enzymes and replacing them with their products to see if they could restore the normal pathway. They subsequently determined that blocking a particular enzyme, geranylgeranyl transferase I, which is further along the pathway from HMG-CoAReductase and responsible for transferring a lipid to a target protein – a process called prenylation – resulted in abnormal germ cell migration.
The work may have larger implications. "It's still preliminary, but we suspect that this pathway is a model for long-range migration of cells in general," he says. "We've identified a pathway, but not the particular protein that is modified. This is a protein that needs a lipid added in order to enable migrating cells to find their home." He and his team currently are trying to identify this mystery protein.
It is also possible that this pathway is important in cancer metastasis. "It's a commonly held view among scientists that many pathways common to cancer are in some regard a recapitulation of the pathways involved in early development," says Dr. Farber. "A cancer cell growing out of control needs to metastasize to other areas to set up shop. We suspect this pathway is what enables a cancer cell to find a good place to grow a tumor. Targeting this pathway might be a logical anti-cancer treatment."
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