Currently, two major paradigms have been proposed to explain the metastatic process. The first, or classical model, sees metastasis as the final step in a progressive sequence in which tumors acquire mutations that promote invasive behavior and dissemination late in tumor evolution. The alternative model envisions metastasis as an inherent feature of a tumor very early in its natural history.
This model is consistent with recent investigations in the field of breast cancer that suggest that cellular dissemination leading to metastasis (or metastatic seeding) may occur prior to the formation of an identifiable primary tumor among cells that would not meet a standard definition of cancer.
Recently, this alternative model has evoked the concept that pancreatic cancer cells precede the formation of tumors. Among the mysteries of pancreatic adenocarcinoma is that while it is often discovered after the cancer has matured and metastasized, it is rarely found in its nascent stages.
To examine the early events leading to pancreatic tumor formation, a team of researchers at Penn Medicine led by Ben Z. Stanger, MD, and Andrew Rhim, MD, developed a sensitive lineage-labeling system to tag (detect and isolate) cells of pancreatic epithelial origin during stochastic tumor progression in a mouse model.
An advantage of the labeling system was that it allowed the team to determine the kinetics of the epithelial-to-mesenchymal transition (EMT) and hematogenous dissemination during the natural evolution of pancreatic ductal adenocarcinoma (PDAC). It has been proposed that carcinoma cells undergo EMT, losing epithelial characteristics and acquiring invasive properties and stem-like features in the process.
The Penn team discovered that tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial to mesenchymal transition (EMT).
Circulating pancreatic cells maintained a mesenchymal phenotype, exhibited stem cell properties, and seeded the liver. EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells. Conversely, treatment with the immunosuppressive agent dexamethasone abolished dissemination. These results provide insight into the earliest events of cellular invasion in situ and suggest that inflammation enhances cancer progression in part by facilitating EMT and entry into the circulation.
This study was published in Cell.
Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert
M, Beatty GL, Rustgi AK, Vonderheide RH, Leach SD, Stanger BZ. EMT and
dissemination precede pancreatic tumor formation. Cell. 2012 Jan 20;148(1-2):349-61.