Researchers found that a couple of molecules that nerve cells use to grow during development could help explain why the most common pancreatic cancers are so difficult to contain and for patients to survive.
The molecules could be key to pancreatic cancer spread.
The findings could lead to new ways to prevent the spread, or metastasis, of pancreatic cancers as well as to treat the extreme pain that often accompanies them.
The research was led by Johns Hopkins Kimmel Cancer Center.
Pancreatic ductal adenocarcinoma (PDA) affects an estimated 57,000 Americans annually and kills about 45,000, according to the American Cancer Society.
It is the fourth leading cause of cancer death in the U.S. Its five-year, stage-combined survival rate of 9% is lower than that of any other cancer type in the nation.
The main reason for cancer’s poor prognosis is metastasis, the process by which cancers grow and spread to distant organs.
Many patients already have metastatic disease at diagnosis; those who don’t still typically die of metastatic disease even after the local disease has been ostensibly controlled by surgery and radiation.
Most cases of PDA are also marked by a process called perineural invasion (PNI), in which tumors grow into nearby nerves.
Although it’s been well established that PNI is an accurate sign of poor prognosis and decreased survival, why it occurs and whether it’s connected with metastasis has been unclear.
In the new study, the team used human and mouse cell lines to look closely at axon guidance proteins, a family of biochemical molecules frequently found to be genetically altered in PDA.
They focused further on two of these proteins: SEMA3D and its target, PLXND1.
Both are involved in growing the long extensions of nerve cells, called axons.
The team found when they used genetic tweaks to knock down the amount of SEMA3D that cancer cells produced, those cells lost approximately 30% of their capacity to invade nearby nerves compared with cancer cells that produced the normal amount of these protein molecules.
When the researchers injected the altered human pancreatic cancer cells into mice, they found a fourfold increase in nerves that grew into the tumors.
In addition, when the researchers genetically altered mice to reduce the amount of PLXND1 that their nerves produced, they made what they said was a stunning finding:
Not only did fewer nerves grow around tumor cells, but also the animals displayed a sharp decline in metastasis, suggesting that PNI is critical for metastatic PDA growth.
The researchers confirmed the critical role of these molecules in human PDA cells.
As a whole, the findings suggest that SEMA3D and PLXND1 play crucial roles in PNI and PDA metastasis.
The team says they may be able to develop medications that target these two molecules so as to reduce cancer-related pain.
The lead author of the study is Lei Zheng, M.D., Ph.D. The study was published in Gastroenterology.
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