Abstract
Metastasis and tumor progression are the major cause of death in patients suffering from pancreatic ductal adenocarcinoma. Tumor growth and especially dissemination are typically associated with activation of an epithelial-to-mesenchymal transition (EMT) program. This phenotypic transition from an epithelial to a mesenchymal state promotes migration and survival both during development and in cancer progression. When re-activated in pathological contexts such as cancer, this type of developmental process confers additional stemness properties to specific subsets of cells. Cancer stem cells (CSCs) are a subpopulation of cancer cells with stem-like features that are responsible for the propagation of the tumor as well as therapy resistance and cancer relapse, but also for circulating tumor cell release and metastasis. In support of this concept, EMT transcription factors generate cells with stem cell properties and mediate chemoresistance. However, their role in pancreatic ductal adenocarcinoma metastasis remains controversial. As such, a better characterization of CSC populations will be crucial in future development of therapies targeting these cells. In this review, we will discuss the latest updates on the mechanisms common to pancreas development and CSC-mediated tumor progression.
Highlights
Division of Gynecological Oncology, Department of Obstetrics and Gynecology of the University of Ulm, 89081 Ulm, Germany
The epithelium is characterized by the expression of the transcription factors Pdx1, Ptf1a, and Sox9 [7,8,9]
The phenotypic changes associated with epithelial-to-mesenchymal transition (EMT) contribute to the appearance of Cancer stem cells (CSCs), plasticity, delamination, CTC generation, metastasis formation, and therapy resistance
Summary
The pancreas arises from the posterior foregut of the definitive endoderm [1] and first becomes evident around embryonic day E8.5 in mice and prior to 26 days of gestation in humans, with the emergence of dorsal and ventral buds, which fuse by E12.5 (Carnegie stage 18–20 in humans) [2,3]. Active cell proliferation and extensive branching morphogenesis expand the epithelium into the surrounding mesenchyme in a tree-like structure, increasing the size of the pancreatic buds [6] (Figure 1A). At this stage, the epithelium is characterized by the expression of the transcription factors Pdx, Ptf1a, and Sox9 [7,8,9]. Low Notch levels allow Ngn to rise in scattered epithelial cells, which the mesenchyme to coalesce and form the future islets [10]. Exocrine pancreas, which consists of acinar and ductal cells making up 96–99% of the total organ mass. Pancreatic intraepithelial neoplasia (PanINs) [11,12]
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