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Table 2 PSCs mainly involved paracrine pathways and their functions

From: The critical roles of activated stellate cells-mediated paracrine signaling, metabolism and onco-immunology in pancreatic ductal adenocarcinoma

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 [51,52,53,54,55]

·Promoting vasculature and desmoplasia [52]

·Driving perineural invasion (PNI) and drug resistance [53,54,55]

·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 [75,76,77,78,79,80]

  1. Notes: PSCs-related paracrine signaling pathways have been depicted above, including their biological roles, functional molecules and influences on PDAC behaviors