Heterogeneous Pancreatic Stellate Cells Are Powerful Contributors to the Malignant Progression of Pancreatic Cancer

Abstract

Pancreatic cancer is associated with highly malignant tumors and poor prognosis due to strong therapeutic resistance. Accumulating evidence shows that activated pancreatic stellate cells (PSC) play an important role in the malignant progression of pancreatic cancer. In recent years, the rapid development of single-cell sequencing technology has facilitated the analysis of PSC population heterogeneity, allowing for the elucidation of the relationship between different subsets of cells with tumor development and therapeutic resistance. Researchers have identified two spatially separated, functionally complementary, and reversible subtypes, namely myofibroblastic and inflammatory PSC. Myofibroblastic PSC produce large amounts of pro-fibroproliferative collagen fibers, whereas inflammatory PSC express large amounts of inflammatory cytokines. These distinct cell subtypes cooperate to create a microenvironment suitable for cancer cell survival. Therefore, further understanding of the differentiation of PSC and their distinct functions will provide insight into more effective treatment options for pancreatic cancer patients.

Senescent Human Pancreatic Stellate Cells Secrete CXCR2 Agonist CXCLs to Promote Proliferation and Migration of Human Pancreatic Cancer AsPC-1 and MIAPaCa-2 Cell Lines

“…Previous studies have shown the cancer-promoting roles of PSCs [ 5 ]. For example, interleukin-6 secreted from PSCs promotes cell proliferation, stemness, and drug resistance of pancreatic cancer cells [ 14 ]. Xu et al [ 50 ] reported that PSCs promote the epithelial–mesenchymal transition and drug resistance of pancreatic cancer cells via paracrine hepatocyte growth factor.…”

“…Importantly, the inhibitory effects of PSCs on pancreatic cancer have been reported [ 15 , 16 ]. The development of therapies targeting PSCs requires consideration of their heterogeneity [ 6 , 14 ]. Our study implies that senescent PSCs, which secrete various SASP factors despite having low α-SMA expression and anti-fibrotic effects, have features that are different from those of quiescent and activated PSCs.…”

“…Pancreatic stellate cells (PSCs), which were first identified and characterized in 1998, play a pivotal role in the development of desmoplastic stroma by producing large amounts of ECM proteins, such as collagen and fibronectin [ 5 , 9 , 10 ]. Moreover, PSCs directly promote cell proliferation and invasion, the epithelial–mesenchymal transition, and drug resistance in pancreatic cancer cells through the actions of cytokines, growth factors, and exosomes [ 5 , 11 , 12 , 13 , 14 ]. PSCs and desmoplastic stroma, the major components of the tumor microenvironment in pancreatic cancer, have attracted attention as therapeutic targets due to their cancer-promoting effects [ 7 ].…”

“…These findings indicate the existence of cancer-restraining PSCs and suggest that various phenotypes of PSCs are intermingled in the tumor microenvironment of pancreatic cancer. The development of novel therapies targeting PSCs requires consideration of their heterogeneity [ 6 , 14 ].…”

Editorial: Mechanisms of Inflammation and Fibrosis Interplays in the Digestive Diseases

“…In contrast, cancer-promoting subpopulations of PSCs also have been identified. Interestingly, these PSCs are further divided into myofibroblastic and inflammatory subtypes, which produce collagen fibers and inflammatory cytokines, respectively ( Zhang et al, 2021 ). These studies highlighted the heterogeneity of PSCs, cancer-promoting and cancer-inhibiting roles, which should be taken into consideration for therapeutic intervention.…”