For The First Time, Scientists Uncover How Breast Cancer Metastasizes

"We have identified a mechanism of breast cancer metastasis, I wouldn’t say it's the mechanism because there may be several others," says Michael Detmar, MD, a dermatologist and principal investigator in the CBRC. "But this is certainly a major molecular mechanism of how breast cancer metastasizes to the lymph nodes."

Although cancer cells are believed to enter the lymph nodes through the lymphatic system—a multipurpose tangle of vessels—little is known about how tumor cells get from the primary tumor into the lymphatic system. In the February issue of Nature Medicine, Detmar, Mihaela Skobe, PhD, a postdoctoral fellow, and their colleagues report that the tumor cells appear to be exiting the tumor through a home-grown system of lymphatic vessels—one expressly cultivated by the tumor.

What is surprising about the discovery is that lymphatic vessels were not thought to exist in tumors. Part of the problem, says Detmar, is that until recently there has been no effective means of visualizing lymphatic vessels.

Using a new method for imaging lymphatic vessels, he and Skobe observed networks of lymphatic vessels deep inside breast tumor masses grown in mice. Upon closer inspection, the vessels appeared to be carrying tumor cells.

Most striking, the number of lymphatic vessels inside the tumor appeared to be highly correlated with the number of metastatic cells in the lymph nodes and lungs, suggesting that the lymphatic vessels were providing a conduit for the flow of metastatic tumor cells.

This grim statistic, if true also in humans, could be turned to a cancer patient's benefit, says Detmar. "In the future, we may be able to determine the amount of lymphatic vessels in a breast cancer specimen obtained from a patient," he says. "And it may potentially allow us to predict whether a tumor has a high risk of metastasis or a low risk depending on the density of lymph vessels in the tissue," he says.

Scientists have known for some time that to grow, tumors must induce the growth of new blood vessels, a process called angiogenesis. While lymphatic vessels have been observed to grow and function on the outskirts of a tumor, no one has ever observed them to do so inside a tumor. Many assumed that the pressures inside a tumor were so great that they would crush the lymphatic vessels, which are more delicate than blood vessels.

"The role of the lymphatic vessels in the tumor has been controversial, disputed or negated," Detmar says. "In fact, the dogma was that tumors do not have functioning lymphatic vessels."

To study the role of lymphatic vessels, he and Skobe implanted human breast cancer cells—each equipped with the genetic equivalent of a green fluorescent flare—into the mammary pads of mice. In half of the mice, the fluorescing cancer cells were additionally programmed to produce an excess of a protein, called VEGF-C, known to trigger lymphatic vessel growth. The tumors were allowed to grow for 12 weeks.

Using a newly discovered lymphatic vessel marker, called LYVE-1, the researchers looked for signs of new vessel growth in the tumors. While both sets of mice exhibited lymphatic growth at the periphery of their tumors, mice carrying the souped-up VEGF-C gene exhibited a massive invasion of lymphatic vessels deep inside their

tumors. The vessels were unusually large and contained tumor cells. Intriguingly, some of the vessels appeared to hook up with those surrounding the tumor, as though forming a highway leading out of the tumor.

Suspecting that the tumor cells might be using the lymphatic highways to metastasize, the researchers examined the lymph nodes and lungs — two common destinations for metastasizing breast cancer cells. Sure enough the VEGF-C-expressing mice exhibited a much higher incidence of lymph node metastasis. Even the lungs exhibited a greater influx of tumor cells—and the influx was proportional to the number of lymphatic vessels in the primary tumor.

"What this suggests is that the lung metastases may also have occurred through the lymphatic system—they may be going to the lymph nodes and spreading from there," says Detmar.

He and Skobe plan to look at different tumors such as prostate and colon cancers to see how much VEGF-C they produce and whether VEGF-C levels are correlated with lymphatic vessels in the tumors. A better understanding of how VEGF-C triggers the growth of lymphatic vessels could lead to new approaches to treating and preventing cancer metastasis, says Detmar.

"This could provide a new target for therapy," he says. "By blocking the interaction of VEGF-C with its receptor on the lymphatic system we may be able to block metastasis from occurring."

The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $200 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photo-medicine. In 1994, the MGH joined with Brigham and Women’s Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.