Nerve-signaling protein guides metastasis of pancreatic cancer, researchers found

By John Murphy, MDLinx
Published January 6, 2016

Key Takeaways

Sailors once used semaphore to signal other ships at sea. Similarly, semaphorins are proteins that work as signaling guides in the development of neurons, as well as new blood vessels. Scientists have now identified a molecular partnership—between semaphorin 3D (Sema3D) and the protein annexin A2 (AnxA2)—that might explain how cancer cells metastasize in pancreatic ductal adenocarcinoma (PDA).

The researchers showed that patients whose primary PDA tumors have abundant Sema3D also have widely metastatic disease and decreased survival compared with patients whose tumors have low Sema3D. In addition, annexin A2 has been linked to poor survival rates in these cancers.

In their study, published in the August 4, 2015 issue of Science Signaling, researchers at Johns Hopkins Kimmel Cancer Center in Baltimore, MD, showed that AnxA2 incites pancreatic cancer cells to secrete Sema3D. Once outside the cells, Sema3D joins with another molecule—plexin D1 (PlxnD1)—to fuel metastasis.

In experiments with mice that lacked AnxA2, the researchers calculated a 70-fold drop in the amount of Sema3D secreted from mouse pancreatic cancer cells. Out of 23 annexin-free mice, none of the animals developed visible metastatic tumors. By contrast, 16 out of 17 mice whose cells did produce AnxA2 developed metastatic tumors in the liver, lungs, or abdominal cavity.

In a second round of experiments using human tissue from patients with PDA (which accounts for more than 90% of pancreatic cancers), the researchers also tracked down a link between the abundance of Sema3D in those tissues and the progression of metastatic pancreatic cancer. They found that Sema3D 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. However, in patients who died after minimal cancer spread, Sema3D was abundant in the main tumor tissue of only 3 of 13 (23%) patients.

The presence of Sema3D also seemed to be associated with the recurrence of pancreatic cancer in patients whose primary tumors were surgically removed, the scientists noted. 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 with only 4 of 15 patients (27%) who lived disease-free for more than 2 years after surgery.

Thus, AnxA2 and Sema3D may be new therapeutic targets and prognostic markers of metastatic PDA, the researchers concluded. They are currently pursuing three possible ideas. “We are planning clinical trials with a recently developed vaccine to target annexin A2,” said Dr. Zheng, associate professor of oncology and surgery at the Johns Hopkins University School of Medicine in Baltimore, MD. “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.”

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