Agents of metastasis: four proteins conspire in breast cancer spread.

While scientists have made significant progress in finding and combating the perpetrators of cancer growth, they've had less success in nailing down the proteins that facilitate the spread, or metastasis, of cancer.

Scientists working with mice have now demonstrated that four proteins appear to work in concert to both grow and spread tumor cells. The proteins had turned up previously in metastatic tumors.

The rogues' gallery includes an inflammatory enzyme called cyclooxygenase 2 (COX2), a protein known as epiregulin that's involved in cell growth, and two enzymes that have been implicated in the growth of new blood vessels that nourish tumors.

To test the proteins' roles, the researchers implanted metastatic human-breast cancer cells into healthy breast tissue in mice. The team had genetically engineered the cells going into some animals so that the tumors would fail to produce some or all of the proteins.

Rapid growth occurred in tumors with the full complement of proteins. But tumors lacking one or two of the proteins showed slow growth, and growth stalled completely in rumors lacking all four.

In further tests, tumors lacking the proteins developed short blood vessels with few branches, while tumors producing the proteins grew highly branched, leaky vessels, the researchers report in the April 12 Nature.

Such leaks provide avenues for cancer cells to escape into the blood. However, metastasis requires more than just travel. Tumor cells must take root in an unfamiliar organ and grow there.

A separate test of breast cancer cells injected intravenously into mice showed that curtailing production of all four proteins inhibited lung colonization, says study coauthor Joan Massague, a molecular biologist at the Howard Hughes Medical Institute and Memorial Sloan-Kettering Cancer Center in New York City.

The researchers also analyzed mice in which breast cancer cells with the full complement of proteins had migrated to the lungs. Some of those animals received a set of drugs that suppress the proteins. Those that didn't showed tumor growth in the unfamiliar tissues within 24 days, whereas drug-treated mice had only what the team called micrometastases, which remained trapped in lung capillaries rather than spreading into the lung.

The experiments reveal new details of metastasis and identify specific proteins that act in its many stages, says Gerhard Christofori of the University of Basel in Switzerland in an accompanying Nature commentary.

However, "people have cured cancer in mice before," says molecular biologist Rene Bernards of the Netherlands Cancer Institute in Amsterdam. While innovative, the new tests lasted only a few weeks--a time frame in which many people also respond well to treatment for metastases, says Bernards. He also points out that the cancer burden placed on the animals was proportionately much smaller than a person with breast cancer might face.

Nevertheless, Bernards says, "singling out a subgroup [of proteins] to see how relevant they are in the metastasis process is an extremely powerful approach."

The drugs that can squelch the four implicated proteins include two medications already on the market: cetuximab (Erbitux), an anticancer agent, and celecoxib (Celebrex), an anti-inflammatory. A drug that inhibits the other two proteins has been tested in people but isn't on the market.