Boston, MA-- Metastasis - or the spread of cancer from one part of the body to other parts - accounts for more than 90 percent of cancer-related deaths. Although the cells that seed metastasis and the sites that they tend to travel to have been increasingly studied over the years, little has been known about how cancer migrates from a primary site, such as breast tissue, to a secondary site, such as the brain or bone marrow. A study by researchers from Brigham and Women's Hospital (BWH), published in Nature Communications, offers a new view of how cancer cells extend their reach, co-opting and transforming normal cells through "metastatic hijacking." The researchers also find that in pre-clinical models, pharmacological intervention can prevent this hijacking from occurring, pointing to new therapeutic targets for preventing cancer cells from spreading.
"Metastasis remains a final frontier in the search for a cure for cancer," said Shiladitya Sengupta, MS, PhD, of BWH's Bioengineering Division in the Department of Medicine and corresponding author of the study. "For the past five years we have studied how cancer travels to other parts of the body, and what we find is that communication is key."
"By working together, our labs have been able to gain greater insights into cell-cell communication in tumor states, which will shed new light on cancer as a disease and the promise and potential of emerging innovative therapies," said Elazer Edelman, MD, PhD, of BWH's Cardiovascular Division in the Department of Medicine.
Sengupta, Edelman and colleagues began with a simple experiment. In the lab, they constructed a three-dimensional tumor matrix, complete with endothelial cells, and added metastatic breast cancer cells. They observed that instead of adhering to themselves to form a sphere, the metastatic breast cancer cells spread out along the model's blood vessels. Using a scanning electron microscope, the researchers detected long, thin tubes extending outward from the cells - nanoscale bridges that connected the cancer cells to normal tissue. The researchers found that the molecular profiles of some of the normal, endothelial cells had been changed, and hypothesized that microRNAs were being transferred over the bridges into the endothelial cells. Upon closer examination, they found that the transformed endothelial cells now harbored two microRNAs that have previously been implicated in metastasis.
The researchers then used chemical compounds to prevent the nanoscale bridges from forming, disrupting communication between the tumor cells and endothelium. They did so in the laboratory constructed model and also in a mouse model, finding that pharmacological agents, including docetaxel, which is used to treat metastatic breast cancer, decreased the number of nanoscale bridges formed by the cells. In mice pre-treated with the pharmacological agents, the researchers observed a significant decrease in metastatic tumor burden.
In future studies, the researchers will look to see if ATPase inhibitors - drugs that have been studied for treating HIV-AIDS - may also be effective at preventing the bridges from forming and inhibiting metastasis.
"Our study opens up new avenues for exploration and suggests that these nanoscale membrane bridges may represent new therapeutics in managing metastatic breast cancer," said Sengupta. "We plan to continue searching for and evaluating treatments that take aim at these conduits."
Other researchers who contributed to this work include Yamicia Connor, Sarah Tekleab, Shyama Nandakumar, Cherelle Walls, Yonatan Tekleab, Amjad Husain, Or Gadish, Venkata Sabbisetti, Shelley Kaushik, Seema Sehrawat, Ashish Kulkarni, Harold Dvorak and Bruce Zetter. This work was supported by the NIH (1R01CA135242-01A2), a Department of Defense Breast Cancer Research Program Breakthrough Award (W81XWH-14-1-0168) an American Lung Association Innovator Award and the National Institute of General Medical Sciences (T32GM007753).
Paper cited: Connor Y et al. "Physical nanoscale conduit-mediated communication between tumor cells and endothelium modulates endothelial phenotype." Nature Communications DOI: 10.1038/NCOMMS9671.
Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 4.2 million annual patient visits, nearly 46,000 inpatient stays and employs nearly 16,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 1,000 physician-investigators and renowned biomedical scientists and faculty supported by nearly $600 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH continually pushes the boundaries of medicine, including building on its legacy in transplantation by performing a partial face transplant in 2009 and the nation's first full face transplant in 2011. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative as well as the TIMI Study Group, one of the premier cardiovascular clinical trials groups. For more information, resources and to follow us on social media, please visit BWH's online newsroom.