The relationship between pancreatic cancer and inflammation has long been recognized. There have been many studies carried out to reveal the underlying mechanisms that contribute to tumorigenesis induced by inflammation, but the reasons behind this connection have remained unclear. Now, a new mouse study by researchers at the University of Texas MD Anderson Cancer Center has shed light on the long-established link.
The new findings are published in the journal Science, in a paper titled, “Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis.”
The researchers discovered that pancreatic cells display an adaptive response to repeated inflammatory episodes that initially protects against tissue damage but can promote tumor formation in the presence of mutant KRAS. KRAS mutations are present in approximately 25% of tumors, making them one of the most common gene mutations linked to cancer.
“The association between tumors and inflammation is a long-established clinical observation,” the researchers wrote. “Although many studies have demonstrated that the inflammatory microenvironment can promote tumor growth through the activation of survival and proliferation programs in cancer cells, the reason why inflammation, an evolutionarily conserved response to damage aimed at reestablishing tissue integrity upon injury, might be integral to tumorigenesis remains unknown.”
The researchers sought to determine the effects of inflammation on normal pancreatic epithelial cells in different mouse models.
“We discovered that a single transient inflammatory event induced long-term transcriptomic and epigenetic reprogramming of epithelial cells that cooperated with oncogenic KRAS to promote pancreatic tumors long after the inflammation was resolved,” said corresponding author Andrea Viale, MD, assistant professor of genomic medicine. “In the setting of repeated pancreatitis, KRAS mutations can be acquired early on to limit tissue damage, suggesting the existence of a strong evolutionary pressure to select mutated cells and providing a possible explanation for the nearly universal presence of mutant KRAS in pancreatic cancers.”
Deep molecular analysis of epithelial cells following a single inflammatory event demonstrated substantial reprogramming of gene expression and epigenetic regulation that persisted long after recovery of the tissue damage, a process the researchers termed “epithelial memory.” This cellular reprogramming activated pathways related to cell survival, proliferation, and embryonic development, which are similar to pathways active during cancer development.
“We are working to better understand how cells maintain the epithelial memory we observed, but our data suggest that KRAS initially has a beneficial role during pancreatitis,” said I-Lin Ho, PhD student, the University of Texas MD Anderson Cancer Center. “There may be a similar phenomenon in other cancers with universal driver mutations, where there is a strong pressure to select those mutations based on some purpose unrelated to cancer development.”
“We have uncovered a new physiologic role of somatic mutations in preserving tissue homeostasis during repeated damages,” concluded the researchers. “We propose that KRAS mutations, independent from the eventual contribution to tumorigenesis, may be beneficial and under strong positive selection in the context of recurrent pancreatitis, perhaps representing a nearly universal event in the development of pancreatic cancer.”