Rethinking Metastasis

A metastatic cell migrates to other parts of the bodyDr. Raouf Guirgus, NCI.

Most cancer deaths result from metastasis, the spread of cancer from a tumor to other parts of the body. Researchers have long thought that metastasis comes at a late stage of cancer. A new study suggests that the process may start long before that.

The traditional model of metastasis is that cancer cells need to accumulate mutations and become fully malignant before they break away from a tumor and enter the bloodstream or lymphatic system (the system that produces, stores, and carries the cells that fight infections). The cells spread to other parts of the body, where they then grow into metastatic tumors.

Some recent results have raised doubts about this sequence, and a team of researchers at Memorial Sloan-Kettering Cancer Center led by Dr. Harold Varmus set out to test the idea. Their work was supported by grants from NIH's National Cancer Institute (NCI), the Martell Foundation and the U.S. Department of Defense.

For their experiments, the team used transgenic mice that they had previously created. The mice express oncogenes—genes that promote the uncontrolled growth of cancer cells—in mammary epithelial cells only when fed a chemical switch, doxycycline. Without doxycycline, the mice don't express the transgenic oncogenes and have normal mammary glands. Within 3 to 4 weeks after doxycycline exposure, they develop tumors.

The researchers injected mammary cells from these mice into the tail veins of other mice that were being fed a diet with doxycycline. This ensured that the injected cells could transform only in the bloodstream or tissues of the recipient mouse.

In the September 26, 2008, issue of Science, the researchers reported that all 4 recipient mice developed lung tumors within 6 weeks after injection of the cells. Control mice that didn't receive doxycycline didn't develop any tumors. The researchers then confirmed their results with a similar mouse model. These elegant experiments show that oncogenes can cause mouse mammary cells to become tumors within the lung.

To see if the transgenic mammary cells could survive in the bloodstream and lung without oncogene expression, the researchers injected the cells into mice that were never exposed to doxycycline. The oncogenes were tagged to track their expression, but no signal was detected in the lungs of recipient mice during 4 months of monitoring. When the mice were given doxycycline 1.5, 8 or 17 weeks after injection of the cells, the cells put out a detectable signal within 2 weeks. This experiment shows that normal mammary cells are capable of traveling to and surviving in the lungs.

This study suggests that metastases might arise from normal cells that travel to other parts of the body early in the cancer process and then become malignant only when their oncogenes are activated. This possibility could account for dormancy and late relapse in human breast cancer. Researchers, however, don't know if premalignant cells can enter the circulation to become sources of later metastatic tumors. The authors argue that their experiments show the idea needs to be further explored.

—by Harrison Wein, Ph.D.