Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer

Abstract

Activated pancreatic stellate cells (PSCs) are the main effector cells in the process of fibrosis, a major pathological feature in pancreatic diseases that including chronic pancreatitis and pancreatic cancer. During tumorigenesis, quiescent PSCs change into an active myofibroblast-like phenotype which could create a favorable tumor microenvironment and facilitate cancer progression by increasing proliferation, invasiveness and inducing treatment resistance of pancreatic cancer cells. Many cellular signals are revealed contributing to the activation of PSCs, such as transforming growth factor-β, platelet derived growth factor, mitogen-activated protein kinase (MAPK), Smads, nuclear factor-κB (NF-κB) pathways and so on. Therefore, investigating the role of these factors and signaling pathways in PSCs activation will promote the development of PSCs-specific therapeutic strategies that may provide novel options for pancreatic cancer therapy. In this review, we systematically summarize the current knowledge about PSCs activation-associated stimulating factors and signaling pathways and hope to provide new strategies for the treatment of pancreatic diseases.

Keywords: chronic pancreatitis; fibrosis; pancreatic cancer; pancreatic stellate cells; signaling pathway.

Figure 1

The activation and deactivation of PSCs. PSCs are activated by profibrogenic mediators, such as ethanol, high glucose and cytokines. And persisting of PSCs activation under pathological conditions results in pancreatic fibrosis.

Figure 2

Signal transduction pathways in PSCs activation. PSCs can be activated by MAPK, Rho/ROCK, NF-κB, PI3K/AKT, JAK/STAT, and sonic hedgehog-Gli1 pathway. Smads pathway play a dual role in this process. And PPAR-γ pathway will inhibit the activation of PSCs.