Tumor-Educated Neutrophils Activate Mesenchymal Stem Cells to Promote Gastric Cancer Growth and Metastasis.

Jiahui Zhang,Xu Zhang,Yinghong Shi,Runbi Ji,Wei Li,Hui Shi,Cheng Ji,Zheying Mao,Wenrong Xu,Hui Qian

doi:10.3389/fcell.2020.00788

Abstract

In response to tumor signals, mesenchymal stem cells (MSCs) are recruited to tumor sites and activated to promote tumor progression. Emerging evidences suggest that in addition to tumor cells, non-tumor cells in tumor microenvironment could also interact with MSCs to regulate their phenotype and function. However, the mechanism for MSCs regulation in gastric cancer has not been fully understood. In this study, we reported that tumor-educated neutrophils (TENs) induced the transformation of MSCs into cancer-associated fibroblasts (CAFs) which in turn remarkably facilitated gastric cancer growth and metastasis. Mechanistic study showed that TENs exerted their effects by secreting inflammatory factors including IL-17, IL-23 and TNF-α, which triggered the activation of AKT and p38 pathways in MSCs. Pre-treatment with neutralizing antibodies to these inflammatory factors or pathway inhibitors reversed TENs-induced transformation of MSCs to CAFs. Taken together, these data suggest that TENs promote gastric cancer progression through the regulation of MSCs/CAFs transformation.

Highlights

Gastric cancer (GC) is one of the most common malignant tumors worldwide
The results of western blot showed that treatment with CM from tumor-educated neutrophils (TENs) induced the expression of cancerassociated fibroblasts (CAFs) markers, including fibroblast activating protein (FAP) and α-smooth muscle actin (α-SMA), in mesenchymal stem cells (MSCs) (Figure 1A)
TEN-CM-treated MSCs showed increased expression of FAP, α-SMA, MMP9, IL6, TGF-β, and VEGF genes (Figure 1F). These results indicate that TEN-CM could induce MSCs to differentiate into CAFs and promote its proliferation and migration in vitro

Summary

Introduction

Gastric cancer (GC) is one of the most common malignant tumors worldwide. the recent advances in curative resection and targeted therapy, the overall survival rate of patients with GC is still poor with a 5-year survival rate of 20–40% (Bray et al, 2018). Recent studies demonstrate that the interactions between GC cells, immune cells, and stromal cells orchestrate a unique microenvironment that promotes tumor growth, metastasis, therapy resistance, and recurrence (Hanahan and Weinberg, 2011; Quail and Joyce, 2013). The studies over the past decade have revealed an important role of neutrophils in the pathogenesis of many cancers (Swierczak et al, 2015; Liang and Ferrara, 2016; Powell and Huttenlocher, 2016). Neutrophils infiltrating within tumor stroma were educated by signals from tumors to promote tumor growth and metastasis, enhance angiogenesis, and mediate immunosuppression through multiple mechanisms

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