Scientists have identified a molecular partnership in pancreatic cancer cells that might help to explain how the disease metastasizes, in some cases. Their findings reveal urgently needed new targets to treat pancreatic cancer, which strikes nearly 50,000 people in the United States each year and has only a 5% survival rate 5 years after diagnosis. The findings were published in Science Signaling (2015; doi:10.1126/scisignal.aaa5823).
One of the molecular partners is annexin A2, a protein that scientists say was already linked to poor survival rates in these cancers. Lei Zheng, MD, PhD, and his colleagues at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, showed that annexin A2 helps usher a protein called Sema3D out of pancreatic cancer cells. Once outside the cells, Sema3D joins with another molecule to fuel the cancer’s spread. Sema3D is a protein that guides the projecting arms of nerve cells (axons) as the nerve cells grow and develop.
In experiments with mice, the researchers calculated a 70-fold drop in the amount of Sema3D secreted from mouse pancreatic cancer cells in animals that lacked annexin A2. In an experiment involving 23 mice, none of the annexin-free animals developed visible metastatic tumors. By contrast, 16 out of 17 mice that produced annexin A2 in their cells developed metastatic tumors in the liver, lungs, or abdominal cavity.
In a second group of experiments using human tissue from patients with pancreatic ductal adenocarcinoma, which accounts for more than 90% of pancreatic cancers, Zheng and his colleagues also tracked down a link between the abundance of Sema3D in those tissues and the progression of metastatic pancreatic cancer.
The team reports that Sema3D was abundant in the main tumor tissue of only three of 13 (23%) patients who died after minimal cancer spread. But it was abundant in the main tumors of 14 of 22 (64%) patients who died with widely metastatic cancer, and also in the metastatic tumors of 17 of 23 (74%) patients.
The presence of Sema3D also seems to be associated with the recurrence of pancreatic cancer in patients whose primary tumors were surgically removed, the scientists say. Sema3D was abundant in the primary tumors of 15 of 20 patients (75%) who lived free of the cancer for less than a year after their surgery, compared to only 4 of 15 (27%) patients who lived disease-free for more than 2 years after surgery.
With their new data in hand, the researchers are pursuing three possible therapeutic targets to stop pancreatic cancer metastasis driven by annexin A2 and Sema3D.
“We are planning clinical trials with a recently developed vaccine to target annexin A2,” said Zheng, an associate professor of oncology and surgery at the Johns Hopkins University School of Medicine. “But at the same time, we are also developing a therapeutic antibody targeting annexin A2, and we are looking for a small molecule that would inhibit Sema3D.”
Zheng and colleagues emphasize they do not know precisely how the Sema3D encourages the spread of pancreatic cancer, but they think it may help cancer cells surround and track nerves to travel away from the main tumor.