The IL-6–STAT3 axis mediates a reciprocal crosstalk between cancer-derived mesenchymal stem cells and neutrophils to synergistically prompt gastric cancer progression

Abstract

Emerging evidence indicate that mesenchymal stem cells (MSCs) affect tumor progression by reshaping the tumor microenvironment. Neutrophils are essential component of the tumor microenvironment and are critically involved in cancer progression. Whether the phenotype and function of neutrophils is influenced by MSCs is not well understood. Herein, we investigated the interaction between neutrophils and gastric cancer-derived MSCs (GC-MSCs) and explored the biological role of this interaction. We found that GC-MSCs induced the chemotaxis of neutrophils and protected them from spontaneous apoptosis. Neutrophils were activated by the conditioned medium from GC-MSCs with increased expression of IL-8, TNFα, CCL2, and oncostatin M (OSM). GC-MSCs-primed neutrophils augmented the migration of gastric cancer cells in a cell contact-dependent manner but had minimal effect on gastric cancer cell proliferation. In addition, GC-MSCs-primed neutrophils prompted endothelial cells to form tube-like structure in vitro. We demonstrated that GC-MSCs stimulated the activation of STAT3 and ERK1/2 pathways in neutrophils, which was essential for the functions of activated neutrophils. We further revealed that GC-MSCs-derived IL-6 was responsible for the protection and activation of neutrophils. In turn, GC-MSCs-primed neutrophils induced the differentiation of normal MSCs into cancer-associated fibroblasts (CAFs). Collectively, our results suggest that GC-MSCs regulate the chemotaxis, survival, activation, and function of neutrophils in gastric cancer via an IL-6–STAT3–ERK1/2 signaling cascade. The reciprocal interaction between GC-MSCs and neutrophils presents a novel mechanism for the role of MSCs in remodeling cancer niche and provides a potential target for gastric cancer therapy.

Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy

“…These findings suggest that the interaction of inflammatory cells and PSCs is bidirectional - targeting TANs reduces PSC activation, and in turn targeting PSCs reduces the recruitment of TANs, with both approaches reducing tumor growth. This is consistent with previous in vitro work demonstrating that neutrophils interact reciprocally with myofibroblasts and PSCs (57, 58). In conclusion, our work reveals a crosstalk between CAAs, TANs, and PSCs that promotes tumor progression in obese hosts, with IL-1β (secreted by all these cells) playing a major role in this cooperation (Fig.…”

Mesenchymal stromal cells inhibit murine syngeneic anti-tumor immune responses by attenuating inflammation and reorganizing the tumor microenvironment

“…Consistent with previous findings [15, 27-31], our data show that concurrent administration of MSCs enhanced growth of syngeneic Lewis Lung carcinoma, and that intratumoral Ad-FasL promoted rejection of the primary tumor and led to the generation of systemic, anti-tumor immunity [1]. Furthermore, our results indicate that tumor-specific T cells promoted significant infiltration of the tumor by host (recipient-derived) macrophages and other effector cells, and that the presence of exogenous MSCs, which are impervious to FasL-mediated signals, created a functional or anatomic barrier that diminished the capacity of T cells to recruit and activate such effector cells.…”

IL-6-stimulated CD11b+CD14+HLA-DR− myeloid-derived suppressor cells, are associated with progression and poor prognosis in squamous cell carcinoma of the esophagus

“…IL-6 is associated with tumor progression in vivo and in clinical patients for certain cancers [20, 25, 26]. To further investigate the potential correlation of IL-6 levels with esophageal tumor progression, we examined the levels of IL-6 in the PB samples from the 50 SCC patients and 12 healthy controls using ELISA.…”