Helicobacter pylori Infection-Induced Hepatoma-Derived Growth Factor Regulates the Differentiation of Human Mesenchymal Stem Cells to Myofibroblast-Like Cells.

Chung-Jung Liu,Ming-Hong Tai,Fang-Jung Yu,Chao-Hung Kuo,Wen-Hung Hsu,Shuchen Hsieh,Fu-Chen Kuo,Yao-Kuang Wang,Deng-Chyang Wu

doi:10.3390/cancers10120479

Abstract

Hepatoma-derived growth factor (HDGF) plays a critical role in tumor cell proliferation, anti-apoptosis, VEGF expression, lymph node metastasis and poor prognosis in human gastric cancer. Gastric cancer, as one of the most prevalent cancers worldwide, is the second leading cause of cancer-related mortality in the world for the prognosis of gastric cancer is generally poor, especially in patients with advanced stage. Helicobacter pylori (H. pylori) infection causes the chronic inflammation of stomach as well as the development of gastric cancer, with a three to six-fold increased risk of gastric cancer. Carcinoma-associated fibroblasts (CAFs) are myofibroblasts in tumor microenvironment, which possess various abilities to promote the progression of cancer by stimulating neoangiogenesis, proliferation, migration, invasion and therapy resistance of tumor cell. Mesenchymal stem cells (MSCs) are reported to promote tumor malignance through differentiation of MSCs toward CAFs. In the present study, we demonstrated that H. pylori infection promotes HDGF expression in human gastric cancer cells. HBMMSCs treated with HDGF assume properties of CAF-like myofibroblastic phenotypes, including expression of myofibroblast markers (α-smooth muscle actin (α-SMA), procollagen α1, tropomyoson I, desmin, fibroblast activation protein (FAP)), and fibroblast markers (prolyl-4-hydroxylase A1 (PHA1) and fibroblast specific protein-1 (FSP-1)/S100A4). HDGF recruits HBMMSCs, and then HBMMSCs further contributes to cell survival and invasive motility in human gastric cancer cells. Treatment of HDGF neutralizing antibody (HDGF-NAb) and serum significantly inhibit HDGF-regulated differentiation and recruitment of HBMMSCs. These findings suggest that HDGF might play a critical role in gastric cancer progress through stimulation of HBMMSCs differentiation to myofibroblast-like cells.

Highlights

Accumulating studies suggest that carcinoma-associated fibroblasts (CAFs) are involved in tumor development
We investigated the effect of H. pylori infection on Hepatoma-derived growth factor (HDGF) expression, the effect of HDGF on the differentiation of human bone marrow-derived mesenchymal stem cells (HBMMSCs) toward Carcinoma-associated fibroblasts (CAFs), the recruitment of HBMMSCs by HDGF, and further observed if the capacity of human gastric cancer cell survival and invasive motility is upregulated by HBMMSCs
The present study demonstrated HDGF increased myofibroblast markers, including α-smooth muscle actin (α-SMA), procollagen α1, tropomyoson I, desmin, fibroblast activation protein (FAP) (Figure 3A), and fibroblast markers, including prolyl-4hydroxylase A1 (PHA1) and fibroblast specific protein-1(FSP-1)/S100A4 (Figure 3B)

Summary

Introduction

Accumulating studies suggest that carcinoma-associated fibroblasts (CAFs) are involved in tumor development. Myofibroblasts in the tumor microenvironment ( called carcinoma-associated fibroblasts (CAFs) or cancer stroma) possess abilities to promote primary tumor growth and progression by inducing the processes of neoangiogenesis, tumor cell proliferation, survival, migration, invasion and therapy resistance [1,2]. CAFs isolated from gastric cancer may promote angiogenesis through high expression of galectin-1 [3]. CAFs contribute to gastric cancer cell invasion and peritoneal dissemination through epigenetic modulation and miR-200b repression [4]. FGF9 secreted from CAFs may be a possible mediator that promotes anti-apoptosis in gastric cancer cells [5]. CAFs might act as a therapeutic target for gastric cancer progression [6]

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