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.

Keywords: antineoplastic protocols; fibrosis; inflammation; pancreatic neoplasms; pancreatic stellate cells.

FIGURE 1

Pancreatic cancer cells can send activation signals to quiescent pancreatic stellate cells (PSCs) via paracrine factors, resulting in the activation of PSCs and differentiation into multiple subsets that participate in the progression of pancreatic cancer. Transforming growth factor beta and Sonic hedgehog can promote the activation of PSCs to myofibroblastic PSCs. The cells of this subgroup mainly secrete collagen fibers and mediate environmental fibrosis and hypoxia. Interleukin-1 alpha can promote the differentiation of PSCs into inflammatory PSCs to induce the inflammatory response and interstitial hypertension. Inflammatory PSCs also induce immunosuppression by recruiting immunosuppressive cells; BAG: Bcl2‐associated athanogene; FAP: fibroblast activation protein; IL-6: Interleukin-6; LIF: leukemia inhibitory factor; PSC: pancreatic stellate cell; Shh: Sonic hedgehog; TGF-β: transforming growth factor beta.

FIGURE 2

Malignant pancreatic epithelial cells activate PSCs and secrete oncogenic factors that drive PSC differentiation into myofibroblastic and inflammatory PSC subtypes, and such heterogeneous PSCs reshape the tumor microenvironment and promote the development of pancreatic cancer.

FIGURE 3

Type 1 collagen (Col1) fibers are secreted by myofibroblastic pancreatic stellate cells (PSCs), which can promote multiple processes such as migration, proliferation, drug resistance, and stemness enhancement of pancreatic cancer cells, by binding to α1β2 integrins and discoidin domain receptors 1 (DDR1). In addition, when the E-cadherin-Col1 complex is destroyed, it will lead to the accumulation of ß-catenin in the nucleus, activate the oncogene c-myc, and eventually lead to the proliferation of pancreatic cancer cells; Col1: type 1 collagen; DDR1: Discoidin domain receptors one; EMT: epithelial mesenchymal transition; FAK: focal adhesion kinase; MET: metformin; HMGA2: high mobility group A2; MMPs: matrix metalloproteinases; MT1-MMP: membrane-type matrix metalloproteinase-1; SIP1: smad interacting protein one; TGF-βR: transforming growth factor beta receptor.

FIGURE 4

Schematic representation of the interaction between pancreatic cancer cells and inflammatory pancreatic stellate cells (PSCs). Secretion of interleukin (IL)-1α by pancreatic cancer cells stimulates activation of JAK-STAT3 signaling in quiescent PSCs, and leads to differentiation of inflammatory PSCs. Thereafter, inflammatory PSCs produce hyaluronic acid that then binds to cluster of differentiation (CD) 44 to activate AKT and ERK signaling pathways and promote the malignant process of pancreatic cancer. Additionally, inflammatory PSCs can also secrete large amounts of the cytokine IL-6, which activates JAK-STAT3 signaling pathways in cancer cells, promoting their proliferation and invasion. In addition, IL-6 also promotes the transcription of PD-L1 in antigen-presenting cells and cancer cells, leading to suppression of T-cell immunity; APC: antigen-presenting cell; ERK: extracellular regulated kinase; HA: hyaluronic acid; HAS: hyaluronan synthase; IL-1: Interleukin-1 IL-6: Interleukin-6; PD-1: programmed cell death one; PD-L1: protein programmed cell death one ligand one; PSC: pancreatic stellate cell.