A study by Massachusetts General Hospital (MGH) investigators finds that, in mouse models, cancer cells from metastatic lymph nodes can escape into the circulation by invading nodal blood vessels, leading to the development of metastases in other parts of the body. Their report appearing in the March 23 issue of Science adds evidence to the debate regarding the role of lymph node metastases in the spread of cancer.
"When cancer cells spread in the body, often the first place they travel is the lymph node that drains the site of the primary tumor, but there has been controversy around the ability of cells from the lymph nodes to spread to organs such as the lung, liver, bone and brain -- sites where the spread of cancer is often fatal," says Timothy Padera, PhD, of the Steele Laboratories for Tumor Biology in the MGH Department of Radiation Oncology, senior author of the paper. "We directly showed that cancer cells that first spread to lymph nodes can invade blood vessels perfusing the nodes to become a source of tumors that grow in distant organs."
To investigate whether cancer cells from lymph node metastases can spread to other organs, the researchers labeled several different types of cancer cell -- mouse versions of breast cancer, melanoma and squamous cell carcinoma -- with a fluorescent protein that changes from green to red when exposed to a specific light. Primary tumors were generated by implanting the labeled cells into mice, and when lymph node metastases developed, metastatic cancer cells were converted from green to red fluorescence. Red cancer cells found in the circulation or elsewhere in the body could have come only from the metastatic lymph node and not the primary tumor.
The research team detected red circulating tumor cells in the animals' bloodstreams, indicating that cancer cells were being released from the metastatic lymph nodes. They also found red cancer cells in the animal's lungs, supporting the hypothesis that cells from lymph node metastases can form new metastatic colonies in the lungs or other organs. Close examination of metastatic lymph nodes from the mice in this study suggested that metastatic cells within lymph nodes move toward and into blood vessels by means of conduits through which immune cells travel through the nodes. Similarly, in lymph nodes from patients with head and neck cancer, tumor cells could be identified in lymph node blood vessels.
"If these data are confirmed in human patients, they would suggest that some lymph node metastases could be the source of fatal distant metastases and would need to be definitively treated," says Padera, who is an associate professor in Radiation Oncology at Harvard Medical School. "Defining the molecular control of how cancer cells within lymph nodes can invade lymph node blood vessels would enable the therapeutic targeting of that process, and characterizing the molecular profiles of the cells that escape the nodes could identify markers signifying which nodes are dangerous and need to be definitively treated to cure the patient."
Ethel R. Pereira, PhD, of the Steele Labs in the MGH Department of Radiation Oncology is lead author of the Science paper. Support for the study includes National Institutes of Health grants DP2 OD008780, R01 CA214913, and R01 HL128168; and National Cancer Institute Federal Share/MGH Proton Beam Income C06 CA059267.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $900 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2017 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."