Working with cancer cells from 55 patients, the Hopkins team found that a growth signal normally turned off in adult tissues is mistakenly turned back on after injury or inflammation of the pancreas. "We think reactivation may be a first step in initiating pancreatic cancer, well before the onset of any alterations to the pancreatic cells' genetic material," says Steven D. Leach, M.D., Paul K. Neumann Professor in Pancreatic Cancer at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and director of the study.
The Notch pathway, when functioning normally, regulates embryonic development in a wide variety of organisms, ranging from fruit flies to humans. In adult tissues, the pathway becomes dormant as cells become differentiated to perform specialized functions. But, when the pancreas is injured or diseased, Notch signaling may be reactivated in the adult pancreas, resulting in conversion of adult pancreas cells to cells similar to those seen in embryonic pancreas. These primitive cells accumulate in the epithelium, or lining, of the pancreas, setting the stage for the additional genetic changes that lead to cancer. "Using drugs to deactivate the Notch pathway could prevent these cancer-causing events from occurring," says Leach.
When the researchers evaluated the pancreatic cancer samples at the genetic level, little to no activity of the Notch pathway was observed in normal pancreatic cells, while increased activity was seen in cancer cells and cells in the inflamed pancreas. In addition, the investigators found that when Notch signaling was blocked in test tube studies, they were able to prevent the early cellular changes leading to pancreatic cancer.
The investigators are now attempting to block Notch signaling in mouse models in hopes of developing a strategy for human pancreatic cancer prevention. "Curing pancreatic cancer is difficult. Few patients survive past five years. Preventing it may be the best path to pursue," says Leach.
Pancreatic cancer has one of the lowest survival rates among all cancers. Each year, approximately 30,300 Americans are diagnosed with the disease, and nearly 30,000 die. Often unresponsive to conventional therapies, pancreatic cancer is the fourth leading cause of cancer death.
In addition to Leach, other investigators include Yoshiharu Miyamoto, Anirban Maitra, Bidyu Ghosh, Ulrich Zechner, Pedram Argani, Christine A. Iacobuzio-Donahue, Virote Sriuranpong, Tatsuya Iso, Ingrid M. Meszoely, Michael S. Wolfe, Ralph H. Hruban, Douglas W. Ball, and Roland M. Schmid.
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Journal
Cancer Cell