The invasion of cancer cells into the lymph vessels that connect the breast to surrounding lymph nodes is the first step leading to the metastasis, or spread, of cancer throughout the body. Metastasis is the primary cause of breast cancer deaths. Surprisingly little is known about the control of this process and how it might be interrupted to prolong the lives of women with breast cancer. In a study to be reported Sept. 10 in the Proceedings of the National Academy of Sciences Online Early Edition, researchers at Johns Hopkins describe their discovery of how a protein responsible for cell survival in low oxygen can trigger the spread of cancer cells into the lymphatic system in a mouse model of breast cancer.
The researchers knew that like all solid tumor cancers, breast cancer cells can grow so densely that they end up starved for oxygen. To survive, cancer cells trigger the growth of new blood vessels by activating a protein called hypoxia-inducible factor 1, or HIF-1. "We've known that increased levels of HIF-1 are associated with increased tumor vessels and with patient mortality," says Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of Medicine, director of the vascular program at Hopkins' Institute for Cell Engineering and a member of the McKusick-Nathans Institute of Genetic Medicine. "Now we've found that HIF-1 activity is directly responsible for the spread of breast cancer to the lymph vessels."
Working in mice injected with human breast cancer cells, which when left undisturbed grow into tumors that spread from the breast to the lungs, Semenza's team previously found that interfering with HIF-1 in these mice reduced growth of the primary tumor and prevented metastasis through blood vessels to the lung. "So of course we wanted to see whether blocking HIF-1 could affect lymph node metastasis as well," he says.
In new experiments, they injected mice with human breast cancer cells that were genetically engineered to knock down HIF-1 protein levels and, after 24 days, examined the mouse lymph nodes to see if the human breast cancer cells had spread. They found that compared to mice whose HIF-1 levels were left undisturbed, lymph nodes with knocked-down HIF-1 contained 76 percent fewer human breast cancer cells, supporting the idea that HIF-1 is somehow involved in the spread of breast cancer to lymph nodes.