Table 2.
PSCs mainly involved paracrine pathways and their functions
| Paracrine signaling | Mediator(s) | Description | Functional roles |
|---|---|---|---|
| Toll-like receptor (TLR) signaling | DAMPs in TME | TLR9 is activated both in PDA cells and PSCs | ·Pro-inflammatory effects [82] ·Up-regulated expression of PSCs-derived cytokines (e.g. CCL3, CCL11) [83] ·Recruitment of Treg cells in PDAC [83] |
| IL-6/JAK/STAT signaling | IL-6 | A versatile pathway in PSCs-PDA cells interactions | ·Inducing chemoresistance, fibrotic reaction [44, 46] ·Invasive TME remodeling [47] ·Affecting other cytokines production ·Recruitment of immunosuppressive cells [49] ·Enhancing tumor aggressiveness via PSCs-PDA cells crosstalk [44, 47] |
| Shh signaling | SHH protein | An altered signaling between PSCs and tumor cells | ·Sustaining PSCs activation and proliferation [51–55] ·Promoting vasculature and desmoplasia [52] ·Driving perineural invasion (PNI) and drug resistance [53–55] ·Tumor proliferation and progression [51, 53] |
| CXCL12 (SDF-1)/CXCR4 signaling | PSCs-derived SDF-1 (CXCL12) | It’s highly activated in PDAC, the elevated level is correlated with poor clinical outcomes | ·Causing low response to gemcitabine treatment [60] ·Promoting PDAC progression via enhanced proliferation, EMT, angiogenesis and metastasis [61] ·Inducing over-expressed MMPs, up-regulated invasiveness and migration of tumor cells [60, 62] ·Supporting immunosuppressive environment [64] ·A potential target for PDAC immunotherapy combined with CTLA-4 or PD-L1 checkpoint block [64] |
| MCP-1/CCR2 pathway | MCP-1 expressed in PSCs | An important cytokine signaling mediating PSCs activation and fibrogenic ECM | ·Serving as a novel component in PSC inflammatory and fibrogenic signaling [81] ·Mediating monocytes migration into pancreases and then differentiation into PSCs [81] ·Maintaining activated status of PSCs through autocrine manner [15] |
| Ets-2-dependent regulation | E26 oncogene homolog 2 (Ets-2) originated in PSCs | New functions unlocked about Est-2 signaling in TME of PDAC | ·Stromal Ets-2 regulates chemokines production and immune cells recruitment during PDAC ·Fibroblast Ets-2 deletion leads to an increased CD8+T-cell population, and decreased presence of regulatory T cells (Tregs), MDSCs [74] |
| Peroxisome proliferator activated receptor-γ signaling (PPAR-γ) | PPAR-γ ligands | A nuclear hormone receptor that is characterized as the master regulator for adiopogenic properties in PSCs | ·Maintenance of quiescent status of PSCs [15, 65] ·PPAR-γ ligand may enhance the phagocytic activity of PSCs, which is partially responsible for the inhibition of fibrogenesis [66] |
| Periostin pathway | periostin | A secretory protein mainly from PSCs, whose expression regulates behaviors of both PSCs and TME | ·Periostin secreted by PSCs creates a tumor-supportive microenvironment [67] ·PSCs remains via periostin autocrine loop [68] ·Biphasic effects on PDAC development: low concentration of periostin (to 150 ng/ml) drives mesenchymal-to-epithelial phenotypical transition while high concentration (1μg/ml) promoting cancer cell migration via Akt/PKB signaling pathway [69] |
| microRNAs (miRNAs) and exosomes | Various miRNAs and exosomes derived from PDA cells or PSCs | A recent hot spot, covering many aspects of TME remodeling, PSCs-tumor cells interactions | ·Controlling myofibroblast phenotype of PSCs [84] ·Promoting migration and proliferation of tumor cells [85, 87] ·Mediating metabolic reprogramming, TME remodeling and intracellular interplay [86] ·Delivering nutrients for cancer cells [84] |
| integrin | kindlin-2 | Newly identified signaling | ·Binding of kindlin-2 and integrin, promotes cytokines production in PSCs and further accelerating progression of pancreatic cancer [39] |
| galectin-1 | β-galactoside-binding protein expressed in activated PSCs | A heterotrimer protein strongly expressed in the stroma of PDAC | ·Promoting proliferation and chemokine synthesis of activated PSCs [70] ·Contributing to the immune escape by enhanced apoptosis and anergy of T cells [71, 72] ·Inducing SDF-1 secreted from PSCs; promoting PDAC metastasis [71, 72] |
| Vitamin D Receptor (VDR) pathway | Circulating Vitamin D | A promising target for PDAC treatment | ·Mediating PSCs phenotypical switch and stromal remodeling [58] ·Enhancing PDAC treatment [58, 108] |
| Growth factors | hepatocyte growth factor (HGF), Connective tissue growth factor (CCN2), others | “Multifunctional messengers” among all components in TME | ·Promoting growth, invasion, migration, and chemotherapy resistance of PDA cells [34] ·Modulator of metabolic crosstalk between tumor cells and stromal components [73] ·PSCs fibrogenic signaling [73] |
| Other signaling pathways | HIF-1α, ROS, NF-κB, TGF-β/Smad, VEGF, PDGF, GM-CSF and so on | Commonly present in numerous malignancies | ·TME remodeling; promoting proliferation, invasion, migration, chemotherapy resistance, angiogenesis, immune evasion and other behaviors of PDA cells [75–80] |
Notes: PSCs-related paracrine signaling pathways have been depicted above, including their biological roles, functional molecules and influences on PDAC behaviors