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CANCER RESEARCH Surprise Route Found for Breast Cancer Spread Once breast cancer reaches marble size, there is a good chance it will shed cells that spread to the lymph nodes and other parts of the body. Even smaller breast tumors can metastasize. But researchers have been hard pressed to say how, exactly, this deadly exodus happens. Cancer cells are thought to enter the lymph nodes through the lymphatic system—a multipurpose welter of vessels—but how the cells actually make their way out of the primary tumor and into the lymphatic system has been an enduring puzzle. "This mechanism may provide new tools to improve our ability to distinguish cancers that have a better or worse prognosis with regard to metastasis. And it may open up a new way to treat cancer and to prevent metastasis by blocking this mechanism," says Michael Detmar, shown with Mihaela Skobe. Photo by Graham Ramsay In the February Nature Medicine, Massachusetts General Hospital researchers report that they have identified a new—and surprising—mechanism by which breast cancer cells may metastasize to the lymph nodes. Mihaela Skobe, HMS instructor in dermatology at MGH, Michael Detmar, and their colleagues report that the tumor cells appear to be leaving the tumor through a homegrown system of lymphatic vessels—one expressly cultivated by the tumor. By blocking this growth, the researchers say, it may be possible to prevent the spread of cancer cells from a primary tumor. "We have identified a mechanism of breast cancer metastasis," said Detmar, HMS associate professor of dermatology. "I wouldn't say it's the mechanism, because there may be several others. But this is certainly a major molecular mechanism of how breast cancer metastasizes to the lymph nodes." New Sight What is especially surprising about the discovery is that lymphatic vessels were not thought to exist in tumors. Part of the problem, said Detmar, is that until recently there has been no effective means of visualizing lymphatic vessels. Using a new method for imaging these vessels, he and Skobe observed vessel networks 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 a particular mouse tumor was highly correlated with the number of metastatic cells in the lymph nodes and lungs of the mouse, suggesting that the lymphatic vessels were providing a conduit for the flow of metastatic tumor cells. This correlation, if also true of humans, could be turned to a cancer patient's benefit, said 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 said. "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." Scientists have known for some time that tumors, in order to grow, put out a flurry of new blood vessels. Tumor cells have recently been spotted inside the walls of up to 15 percent of these blood vessels, leading researchers to suggest that these "mosaic" blood vessels might be an avenue for metastasis (Focus Jan. 26, 2001). But no one had observed lymphatic vessels inside a tumor, though they have observed the vessels growing at the tumor's periphery. Many assumed that the physical pressure inside a tumor is so great that it 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 said. "In fact, the dogma was that tumors do not have functioning lymphatic vessels." Blazing Trails To study the role of lymphatic vessels, Skobe, Detmar, and their colleagues 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 the protein VEGF-C, which triggers lymphatic vessel growth. The tumors were allowed to grow for 12 weeks. Using a newly discovered lymphatic vessel marker, LYVE-1, the researchers looked for signs of new vessel growth in the tumors. While all of the 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 outward. Suspecting that the tumor cells might be using the lymphatic highways to metastasize, the researchers examined the lymph nodes and lungs for signs of the green fluorescent cancer cells. Sure enough, the VEGF-C–expressing mice exhibited a much higher incidence of fluorescent cells in their lymph nodes. Even the lungs exhibited a greater influx of green 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," said Detmar. Tumor-grown lymphatic vessels may not be the only route by which tumor cells metastasize, he said. Tumor blood vessels could also be carrying cells from the primary tumor, and metastasis most likely occurs through both means. In fact, the growth of the two vessel types may be linked. There is evidence that the protein triggering blood vessel growth, VEGF, may also induce the production of VEGF-C, the protein that induces lymphatic vessel growth, though Detmar said more study will be needed to clarify the relationship. Meanwhile, he is hopeful that the new discovery will attract researchers to the once-neglected vessels. "People will probably look at lymphatic vessels in a different way—as a very active system that plays a major role in determining the fate of a tumor or of a patient by determining the rate of metastasis," he said. He and Skobe plan to explore the role of lymphatic vessels in different tumors, such as malignant melanomas and prostate and colon cancers, to see how much VEGF-C they produce and whether the number of lymphatic vessels within the tumors is correlated with the risk of metastasis. A better understanding of how VEGF-C triggers the growth of lymphatic vessels could lead to new approaches to treating and preventing cancer, said Detmar. "This could provide a new target for therapy," he said. "By blocking the interaction of VEGF-C with its receptor on the lymphatic system, we may be able to block metastasis from occurring." —Misia Landau