Fresh Insight into Pancreatic Cancer Progression
The study, funded by the National Institutes of Health, The Pancreatic Cancer Action Network and by The Irvington Institute Postdoctoral Fellowship Program of the Cancer Research Institute, appears in the June 12 issue of Cancer Cell.
Pancreatic cancer is known for its aggressive nature. Only four percent of patients survive past five years from the time of diagnosis, and currently available therapies are largely ineffective.
"It is extremely important that we learn how the advancement of pancreatic cancer is being regulated in an effort to interrupt the progression of the disease," said senior author Dafna Bar-Sagi, PhD, senior vice president and vice dean for Science and chief scientific officer at NYU School of Medicine.
Using mouse models of pancreatic cancer, Dr. Bar-Sagi and colleagues found that a mutation of the KRAS gene, present in 95 percent of all pancreatic cancers, triggers the expression of a protein called GM-CSF. The tumor-derived GM-CSF then directs accumulation of myeloid-derived suppressor cells in the area surrounding the tumor. These cells suppress the body's natural immune defense reaction to growing tumor cells. In this way, pancreatic cancer cells escape being seen by the body's immune system and are free to grow and divide. Establishment of an immunosuppressive environment around pancreatic cancer cells, therefore, prevents their prompt rejection by the immune system.
By blocking production of GM-CSF in pancreatic cancer cells, the researchers found that they were able to disrupt accumulation of myeloid-derived suppressor cells, liberating the tumor-killing immune response. "Our study suggests a therapeutic strategy for harnessing the anti-tumor potential of the immune system," Dr. Bar-Sagi explained.
"Our findings should be applicable to a significant proportion of human pancreatic cancer cases, as the vast majority of human pancreatic cancer samples that we tested express the GM-CSF protein prominently," Dr. Bar-Sagi added. The researchers are hopeful that their findings will open new doors in therapeutic research, eventually leading to new drug therapies that block the production or function of the GM-CSF protein to allow anti-tumor immune cells to attack the cancer cells and halt tumor development.
Although the study focuses on pancreatic cancer, KRAS mutations are prevalent in a number of other cancers, including colon and lung cancer. "From a research standpoint, the contribution of KRAS mutation to the production of GM-CSF is a very exciting find, as it may have important implications for the therapeutic management of other cancers, as well," Dr. Bar-Sagi said.