BOSTON—Despite its pivotal role in cancer, the exact nature of how cancer migrates to secondary sites has remained unknown, until a recent study out of Brigham and Women's Hospital (BWH) shed some light on the mechanism of metastasis.
“Metastasis remains a final frontier in the search for a cure for cancer,” Dr. Shiladitya Sengupta of BWH’s Bioengineering Division in the Department of Medicine, corresponding author of the study, said in a press release. “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.”
“Traditionally what people have studied, they've looked at metastasis, but they've looked at that subset of cancer cells that metastasize out,” he explains. “Not all cancer cells in a tumor metastasize; there's a subset which actually tends to metastasize. So people have tried identifying that subset, you know, are there parameters that define those? And the second area of research has been why is it that, take for example, a breast cancer metastasizes to the bone, or to the liver, or to the brain? Why is it lung cancer metastasizes to the brain?'”
The best way to try and answer that question is to look at the pathway by which cancer metastasizes: the vascular system. In general, says Sengupta, people with cancer don't die from the primary tumor, they die as a result of that tumor metastasizing to a secondary site; metastasis is responsible for more than 90 percent of cancer-related deaths.
The traditional gold standard for studying tumors cells, says Sengupta, is what is known as a spheroid; when tumor cells are cultured on their own in a three-dimensional matrix, they collect to form spheres. However, when Sengupta, along with Dr. Elazer Edelman of BWH's Cardiovascular Division in the Department of Medicine, and colleagues created created a three-dimensional tumor matrix, complete with endothelial cells (the cells that comprise blood vessels), and added metastatic breast cancer cells, those cells reacted in a completely new manner.
“If you take a cancer cell and you grow it in a three-dimensional matrix, isolated from the tumor, they typically form these ball-like structures called spheroids. People have been using spheroids to study drug effects, that's been the gold standard for studying cancer biology,” says Sengupta. “In a tumor, you actually have these blood vessels too, and nobody had done work with these blood vessels next to a tumor in a spheroid. So what we thought is, 'why not add blood vessels to the three-dimensional matrix? And then we'll add these tumor cells, and they will form spheroids, and we'll see how the blood vessels are actually interacting with the spheroids.'”
But that was far from the case.
“What was very interesting is we didn't see a single spheroid form,” he continues. “Now, that's been the gold standard. Not a single spheroid formed when we introduced endothelial cells or blood vessels into that system. All the tumor cells were actually sitting on the blood vessels—they were completely aligned along the vascular network.”
The team used a scanning electron microscope to view the constructed matrix, and found long, thin tubes protruding from the cancer cells, nanoscale bridges that linked them to normal tissue. In addition, the molecular profiles of some of the normal endothelial cells had been changed, which the researchers hypothesized was due to microRNAs being transferred via the nanoscale bridges to the endothelial cells. When they examined the altered endothelial cells, the team found they harbored two microRNAs previously implicated in metastasis. Sengupta says that the cancer cells start sending out protrusions toward blood vessels as early as three hours into being placed in the model, and completely connect over a roughly 24-hour period. These same behaviors were also seen in melanoma and ovarian cancer cells.
Their next step consisted of using chemical compounds to block the nanoscale bridges from forming, in both their constructed model and a mouse model. What they found was that pharmacological agents, including docetaxel, decreased the number of nanoscale bridges formed by the cancer cells. In addition, in mice pretreated with the pharmacological agents, they saw a significant decrease in metastatic tumor burden.
Moving forward, Sengupta, Edelman and their colleagues will examine the potential of using ATPase inhibitors, which have traditionally been studied for the treatment of HIV/AIDS, to inhibit metastasis by preventing the formation of nanoscale bridges. The logic for this approach, says Sengupta, is that the process of sending out protrusions and forming the nanoscale bridges takes a great deal of energy, which means ATP, or adenosine triphosphate, the main source of energy for cells, must play a role somewhere in this process.
“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,” Edelman remarked in a press release.
This study appeared in Nature Communications under the title “Physical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype.”