Lineage tracking demonstrates early presence of pancreatic cancer cells in the bloodstream
Scientists have developed a fluorescent cell tagging system to demonstrate in a mouse model that pancreatic cancer cells begin to spread out and move to other tissue sites well before the initial tumor is clinically evident. A team at the University of Pennsylvania School of Medicine and Johns Hopkins University School of Medicine’s Sol Goldman Pancreatic Research Center, generated mice with pancreas-specific Kras and p53 mutations and added a fluorescent marker that would specifically identify pancreatic epithelial cells that had undergone epithelial-to-mesenchymal transition (EMT).
Studies in these animals first confirmed that EMT occurs in premalignant lesions before the appearance of cancerous pancreatic ductal adenocarcinoma (PDAC) cells and that even before any cancer or invasive behavior was evident by standard histology, individual pancreatic epithelium-derived cells had undergone EMT, traversed the basement membrane and dissociated from pancreatic epithelial structures, and were present in the circulation of mice. These circulating pancreatic cells (CPCs) from precancerous mice appeared to be phenotypically similar to those found in cancer-bearing PDAC mice and demonstrated similar survival and self-renewal properties.
Interestingly, the researchers found that EMT and invasiveness of pancreatic epithelial cells was accelerated under pancreatic inflammatory conditions, and inducing pancreatitis in mice increased the numbers of CPCs. In fact, both chemical and surgical methods for inducing pancreatitis resulted in an increase in EMT and CPC number. These findings, they say, have implications for the management of patients at high risk of pancreatic cancer, including those with hereditary pancreatitis or family members of patients with inherited pancreatic cancer.
Penn’s Ben Z. Stanger, Ph.D., and colleagues, report their results in Cell in a paper titled “EMT and Dissemination Precede Pancreatic Tumor Formation.” The authors state, “Our data support a model for pancreatic cancer progression in which the seeding of distant organs occurs before and in parallel to tumor formation at the primary site. Such an interpretation is especially applicable to PDAC, as the vast majority of patients with pancreatic cancer have metastatic disease at the time of diagnosis.”
The team admits that their studies don’t provide inconclusive evidence that CPCs from PanIN mice ultimately give rise to metastases. However, the data is strongly suggestive and supports a wealth of clinical and experimental data from other systems that is consistent with early spread. “If dissemination and seeding of pancreatic epithelial cells precede the detection of a tumor in humans, as they do in the mouse model, a window of opportunity may exist for prophylactic therapy in high-risk patients.”