Researchers Identify Nerve-Guiding Protein That May Be Associated With Pancreatic Cancer Metastasis
Scientists at the Johns Hopkins Kimmel Cancer Center 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 and were published by Foley et al in Science Signaling.
Annexin A2
One of the molecular partners is annexin A2, a protein that scientists say was already linked to poor survival rates in pancreatic cancer. Lei Zheng, MD, PhD, Associate Professor of Oncology and Surgery, and his colleagues 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 axons of nerve cells as they grow and develop.
In experiments with mice, 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 of 17 mice that produced annexin A2 in their cells developed metastatic tumors in the liver, lungs, or abdominal cavity.
Sema3D Levels
In a second group of experiments using human tissue from patients with pancreatic ductal adenocarcinoma, Dr. Zheng and colleagues also tracked down a link between the abundance of Sema3D in those tissues and the progression of metastatic pancreatic cancer.
The team reported that Sema3D was abundant in the main tumor tissue of only 3 of 13 (23%) patients who died after minimal cancer spread. However, 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 said. Sema3D was abundant in the primary tumors of 15 of 20 patients (75%) who lived free of the cancer for less than 1 year after their surgery, compared with only 4 of 15 (27%) patients who lived disease-free for more than 2 years after surgery.
With their new data, 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 Dr. Zheng. “At the same time, we are also developing a therapeutic antibody targeting annexin A2, as well as looking for a small molecule that would inhibit Sema3D.”
Dr. Zheng and colleagues emphasized they don't know precisely how 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. This neural highway might be especially important in pancreatic cancer, they said, because it grows fewer blood vessels that can carry cancer cells to the rest of the body.
It's also unclear at this point, said Dr. Zheng, exactly how annexin A2 encourages pancreatic cancer cells to release Sema3D, but it’s suspected annexin A2 shelters and guides the protein as it makes its way toward an exit at the cell surface. Or, they speculated, it may help enclose Sema3D in tiny molecular vesicles before the cell secretes it.
Dr. Zheng and colleagues became interested in annexin A2's exact role in cancer spread after noting a curious effect in a trial of the pancreatic cancer vaccine GVAX, first developed by Johns Hopkins researchers.
In a 2011 vaccine trial of patients whose primary pancreatic tumors were surgically removed, “we found antibodies against annexin A2 in those who had received the vaccine and who also had demonstrated long-term, disease-free survival after receiving the vaccines,” explained Dr. Zheng. “This suggested to us that we should study annexin's role in pancreatic cancer progression.”
The research was supported by the National Cancer Institute, the Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins, the Lefkofsky Family Foundation, and the Lustgarten Foundation.
Drs. Jaffee and Zheng hold a patent on annexin A2 as a target for cancer therapy, and Dr. Zheng has a pending patent on annexin A2 as an immunologic target (U.S. Patent Application No.14/249,534).
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
