THBS4/integrin α2 axis mediates BM-MSCs to promote angiogenesis in gastric cancer associated with chronic Helicobacter pylori infection

LingNan He,HuiYing Shi,HaiLing Yao,YuRui Zhang,WeiJun Wang,Chen Jiang,Rong Lin,Wei Qian

doi:10.18632/aging.203334

Abstract

Background: BM-MSCs contribute to Helicobacter pylori (H. pylori)-induced gastric cancer, but their mechanism is still unclear. The aim of our study was to investigate the specific role and mechanism of BM-MSCs in H. pylori-induced gastric cancer.Main methods: Mice received total bone marrow transplants and were then infected with H. pylori. BM-MSCs were extracted and transplanted into the gastric serosal layer of mice chronically infected with H. pylori. Hematoxylin and eosin staining, immunohistochemistry staining and immunofluorescence were performed to detect tumor growth and angiogenesis in mouse stomach tissues. Chicken chorioallantoic membrane assays, xenograft tumor models, and human umbilical vein endothelial cell tube formation assays were used for in vivo and in vitro angiogenesis studies. THBS4 was screened from RNA-seq analysis of gastric tissues of BM-MSCs transplanted into H. pylori-infected mice.Results: BM-MSCs can migrate to the site of chronic mucosal injury and promote tumor angiogenesis associated with chronic H. pylori infection. Migration of BM-MSCs to the site of chronic mucosal injury induced the upregulation of THBS4, which was also evident in human gastric cancer and correlated with increased blood vessel formation and worse outcome. The THBS4/integrin α2 axis promoted angiogenesis by facilitating the PI3K/AKT pathway in endothelial cells.Conclusions: Our results revealed a novel proangiogenic effect of BM-MSCs in the chronic H. pylori infection microenvironment, primarily mediated by the THBS4/integrin α2 axis, which activates the PI3K/AKT pathway in endothelial cells and eventually induces the formation of new tumor vessels.

Highlights

Gastric cancer (GC) is the fifth most common cancer and the third most common cause of cancer death globally [1]
Hematoxylin and eosin (HE) staining revealed that in mice chronically infected with H. pylori, transplantation and engraftment of Bone marrow-derived mesenchymal stem cells (BM-MSCs) led to increased dysplasia and to gastric carcinoma (Figure 1E, 1F)
These findings indicate that bone marrow (BM)-MSC engraftment alters the tumor microenvironment of GC induced by chronic H. pylori infection-related inflammation and contributes to tumor tumorigenicity and angiogenesis

Summary

Introduction

Gastric cancer (GC) is the fifth most common cancer and the third most common cause of cancer death globally [1]. Recent studies on GC demonstrated that cancer stem cells (CSCs) exist in GC These cells could originate from bone marrow-derived cells (BMDCs) [4, 5]. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are among the BMDCs that have been shown to be recruited to GC and to promote tumor growth [6,7,8]. Migration of BM-MSCs to the site of chronic mucosal injury induced the upregulation of THBS4, which was evident in human gastric cancer and correlated with increased blood vessel formation and worse outcome. Conclusions: Our results revealed a novel proangiogenic effect of BM-MSCs in the chronic H. pylori infection microenvironment, primarily mediated by the THBS4/integrin α2 axis, which activates the PI3K/AKT pathway in endothelial cells and eventually induces the formation of new tumor vessels

Objectives

Methods

Results

Conclusion