Stem Cells in the Exocrine Pancreas during Homeostasis, Injury, and Cancer

SIMPLE SUMMARY: Pancreatic cancer is one of the most lethal malignancies. Hence, improved therapies are urgently needed. Recent research indicates that pancreatic cancers depend on cancer stem cells (CSCs) for tumor expansion, metastasis, and therapy resistance. However, the exact functionality of pancreatic CSCs is still unclear. CSCs have much in common with normal pancreatic stem cells that have been better, albeit still incompletely, characterized. In this literature review, we address how pancreatic stem cells influence growth, homeostasis, regeneration, and cancer. Furthermore, we outline which intrinsic and extrinsic factors regulate stem cell functionality during these different processes to explore potential novel targets for treating pancreatic cancer. ABSTRACT: Cell generation and renewal are essential processes to develop, maintain, and regenerate tissues. New cells can be generated from immature cell types, such as stem-like cells, or originate from more differentiated pre-existing cells that self-renew or transdifferentiate. The adult pancreas is a dormant organ with limited regeneration capacity, which complicates studying these processes. As a result, there is still discussion about the existence of stem cells in the adult pancreas. Interestingly, in contrast to the classical stem cell concept, stem cell properties seem to be plastic, and, in circumstances of injury, differentiated cells can revert back to a more immature cellular state. Importantly, deregulation of the balance between cellular proliferation and differentiation can lead to disease initiation, in particular to cancer formation. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of only ~9%. Unfortunately, metastasis formation often occurs prior to diagnosis, and most tumors are resistant to current treatment strategies. It has been proposed that a specific subpopulation of cells, i.e., cancer stem cells (CSCs), are responsible for tumor expansion, metastasis formation, and therapy resistance. Understanding the underlying mechanisms of pancreatic stem cells during homeostasis and injury might lead to new insights to understand the role of CSCs in PDAC. Therefore, in this review, we present an overview of the current literature regarding the stem cell dynamics in the pancreas during health and disease. Furthermore, we highlight the influence of the tumor microenvironment on the growth behavior of PDAC.