When cancers spread, tumor cells can act like the siege towers of old, rumbling alongside healthy cells and projecting nanoscale intercellular membrane bridges, through which microRNAs course, like troops streaming across a gangplank, ready to wreak havoc on healthy cells, altering their molecular processes, effectively taking them over. But if these membrane bridges could be warded off, healthy cells might be spared metastatic conversion.
This possibility emerged from a study conducted by researchers at Brigham and Women’s Hospital (BWH). 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. Then the researchers found that the molecular profiles of some of the normal, endothelial cells had been changed. The researchers hypothesized that microRNAs were being transferred over the bridges into the endothelial cells. Upon closer examination, the researchers found that the transformed endothelial cells now harbored two microRNAs that have previously been implicated in metastasis.
Having exposed this metastatic mechanism, the researchers considered how they might defeat it. They opted for a pharmacological intervention, the deployment of chemical compounds to prevent the formation of nanoscale bridges. Ultimately, they hoped to disrupt communication between the tumor cells and the endothelial cells.
The outcome of this approach was described December 16 in the journal Nature Communications, in an article entitled, “Physical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype.” This article detailed how the BWH researchers tested their approach in their laboratory model and also in a mouse model.
The upregulation of markers that is associated with pathological endothelium, and that appears to result from the communication between the tumor cell and the endothelium, “is reversed by pharmacological inhibition of these nanoscale conduits,” the authors wrote. In particular, the authors found 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.
“Metastasis remains a final frontier in the search for a cure for cancer,” said Shiladitya Sengupta, Ph.D., 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,” added Elazer Edelman, M.D., Ph.D., of BWH's cardiovascular division in the department of medicine.
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,” concluded Dr. Sengupta. “We plan to continue searching for and evaluating treatments that take aim at these conduits.”