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When a tumor cell begins the metastatic cascade by escaping from its primary site in an attempt to begin growing in another part of the body, success is far from assured. After slipping into the blood stream (often via the lymphatic system), the cell, either on its own or as part of a multitumor cell cluster, must maneuver past immune system cells hunting for easy prey. If it survives, the cell must then find a potentially vulnerable body part and gather the wherewithal to attach itself, invade, and set up shop to begin anew the process of uncontrolled cell division. In laboratory models, less than 1 in 1,000 tumor cells released into circulation form a new tumor.

Nevertheless, most cancer deaths are the result of metastatic disease. A relatively new field of research is attempting to find novel ways to attack metastasis, primarily by identifying new players in the metastatic cascade. The research is focused on a class of genes called metastasis suppressors.

By definition, metastasis suppressors affect only metastases, not the size or lethality of primary tumors, says Dr. Patricia Steeg, chief of the Women's Cancers Section in the NCI Center for Cancer Research (CCR). Dr. Steeg discovered the first metastasis suppressor gene, Nm23, in 1988.

Metastasis suppressors don't appear to have been mutated, as is the case, for example, with a number of oncogenes and tumor suppressor genes. Instead, they have been turned off, reducing their expression and, as a result, hampering their ability to keep escaped tumor cells in check. Reduced Nm23 expression, for instance, has been associated with metastasis in several cancers, including melanoma and breast cancer.

According to Dr. Dan Welch, director of the Metastasis Program at the University of Alabama at Birmingham Comprehensive Cancer Center, who discovered the metastasis suppressor gene dubbed KiSS1, 14 metastasis suppressor genes have been confirmed, the large majority since 2000. Even though the field is in its infancy, he notes, it has already produced important information.

Perhaps the most important finding has been that metastasis suppressors seem to work by blocking tumor cell growth at the secondary site.

"Suppression at the secondary site does not happen in exactly the same way [with each gene], but the net effect is that the tumor cells can do everything except grow when they get to the secondary site," Dr. Welch explains.

This is a critical fact, adds Dr. Steeg, because a great deal of metastasis research has focused on how primary tumor cells escape. But in many cancer patients "that has already happened by the time they find out they have a tumor and go to surgery," she explains. "So invasion's not something you can tackle therapeutically."

But because metastasis suppressors - and the genes they influence downstream in the intracellular signaling pathway - do their most important work at the secondary site, Dr. Steeg continues, "I think they are therapeutically tractable targets."

Some recent studies indicate she may be right. In a study published last month in Cancer Research, researchers from the University of Virginia, led by Dr. Dan Theodorescu, Paul Mellon Professor of Urology and Molecular Physiology, identified a potential new target and drug for disrupting metastasis. The results are an extension of their work in previous studies in which they identified RhoGDI2, a gene that suppresses lung metastases of bladder cancer.

In the new study, the researchers identified a gene, endothelin-1 ligand (ET-1), the increased expression of which directly correlates with RhoGDI2's decreased expression. Subsequently, in a mouse model of metastatic bladder cancer (the same one used to discover RhoGDI2), they found that atrasentan - an agent that specifically inhibits ET-1 - dramatically decreased lung metastases compared with untreated mice.

Results from Dr. Theodorescu's lab have also provided evidence that loss of RhoGDI2 in primary tumors of bladder cancer patients is associated with more frequent and faster development of metastatic disease.

Overall, the available evidence indicates that in some patients there "is a window where the cancer in the distant organ is at its most sensitive," Dr. Theodorescu says. "It has not established itself. It's a new colonist in a new land, and it has yet to get its footing. It could be wiped out or, if it isn't wiped out, we can at least keep it at bay."

Dr. Theodorescu is in discussion with pharmaceutical companies and NCI cooperative groups to conduct an adjuvant clinical trial to test whether blocking ET-1 activity can reduce the risk of lung metastases in patients with advanced bladder cancer at high risk of developing metastases, as well as validate a test that correlates RhoGDI2 expression with risk of metastatic bladder cancer.

Meanwhile, in May, Dr. Steeg's lab published a study in the Journal of the National Cancer Institute with an intriguing finding: in the case of Nm23, at least, it may be possible to turn the metastasis suppressor back on instead of focusing on other targets in its signaling pathway. In a metastatic breast cancer mouse model, administration of MPA, a hormone traditionally used in a common female contraceptive, increased Nm23 expression and decreased the formation of metastases in breast cancer cells that expressed the glucocorticoid receptor but not the progesterone receptor - an unexpected result because MPA is known clinically as a progestin. And in cell-line studies, MPA administration significantly reduced the formation of tumor colonies.

A phase I clinical trial is being planned to test the use of MPA in patients at increased risk for metastatic breast cancer to see if Nm23 expression can be increased, Dr. Steeg reports.

By Carmen Phillips