Two mouse studies have found that tumor cells can metastasize via the lymph nodes. One study demonstrated that cancer cells from lymph-node metastases accounted for most cells in lung metastases. The other study found that tumor cells can spread from the lymph nodes to the lungs by entering the bloodstream.

Researchers have long debated whether metastases in the lymph nodes can disperse to distant sites or whether the nodes have no role in cancer progression. Now, two studies, which tackled the question by tracking labeled tumor cells in mice, support the idea that cancer cells can spread from lymph nodes as well as from the primary tumor itself. The work also suggests that tumor cells in the lymph nodes can directly enter the blood instead of detouring through the lymphatic system.

In the first study, Timothy Padera, PhD, of Massachusetts General Hospital in Boston, and colleagues engineered cells from murine mammary tumors, melanomas, and squamous cell carcinomas to express Dendra2, a fluorescent protein that switches from green to red when exposed to a certain wavelength of light. They then engrafted the cancer cells into mice, allowed a tumor to form, and surgically removed it after it had seeded cells into the draining lymph node. Next, they photoconverted only tumor cells in the lymph node, changing the protein from green to red.

The researchers detected red melanoma and mammary tumor cells in the blood and lungs of the animals. “We weren't sure we'd see spreading from the lymph node,” says Padera. Overall, they determined that 70% of the mammary cancer cells and 68% of the melanoma cells in the rodents' lungs had come from the sentinel lymph node. They did not find photoconverted squamous cell carcinoma cells outside of the lymph node.

The researchers then performed a second experiment, injecting green-labeled mammary tumor cells into one lymph node and red-labeled tumor cells into the mammary fat pad on the other side of the body. They found cells of both colors in the lungs, demonstrating that cancer cells from lymph-node lesions and the primary tumor can establish lung metastases.

In the second study, Dontscho Kerjaschki, MD, of the Medical University of Vienna in Austria, and colleagues simulated metastasis in mice by injecting breast cancer cells into a lymph node behind the knee. Two days after the injection, tumor cells had begun wrapping around and entering small vessels in the node known as high endothelial venules, the scientists found. When they injected the lymph node with tumor cells that expressed a red protein, they saw that some of the cells moved to the lung.

That the cells slipped from the lymph node into the blood contradicts the widely accepted view that they can reach the bloodstream only by first passing through lymphatic vessels. The team determined the route the cells followed by tying off the lymphatic vessels, leaving one knee lymph node and then injecting it with labeled cells. The tumor cells still metastasized to the lungs, indicating that “there is a shortcut” to the bloodstream, says Kerjaschki.

What the studies reveal, says Padera, is that “in mouse models, cancer cells can spread from the lymph nodes.” He and Kerjaschki note that researchers need to confirm that metastasis occurs this way in humans, so it's too early to draw any clinical lessons from the results.

The hypothesis that cancer cells metastasize via the lymph nodes dates to the 1890s, but “this is the first time that anyone has proven definitively” that this movement occurs, says S. David Nathanson, MD, of the Henry Ford Health System in Detroit, MI. If researchers could determine why some tumor cells are prone to leave the lymph nodes, they might be able to predict which patients are at risk for metastasis, he says.

However, Iris Nagtegaal, MD, PhD, of Radboud University Medical Center in Nijmegen, the Netherlands, questions the relevance of the findings for human cancer. “They use nice techniques to visualize the possibilities, but I'm not sure it's beyond theoretical,” she says. –Mitch Leslie