Activation of mesenchymal stem cells by macrophages prompts human gastric cancer growth through NF-κB pathway

Tingting Yang; Xu Zhang; Mei Wang; Jie Zhang; Feng Huang; Jie Cai; Qiang Zhang; Fei Mao; Wei Zhu; Hui Qian; Wenrong Xu

doi:10.1371/journal.pone.0097569

Activation of mesenchymal stem cells by macrophages prompts human gastric cancer growth through NF-κB pathway

PLoS One. 2014 May 13;9(5):e97569. doi: 10.1371/journal.pone.0097569. eCollection 2014.

Authors

Tingting Yang¹, Xu Zhang¹, Mei Wang¹, Jie Zhang¹, Feng Huang¹, Jie Cai¹, Qiang Zhang¹, Fei Mao¹, Wei Zhu¹, Hui Qian¹, Wenrong Xu²

Affiliations

¹ School of Medical Science and Laboratory Medicine, Jiangsu University Zhenjiang, Jiangsu, China.
² School of Medical Science and Laboratory Medicine, Jiangsu University Zhenjiang, Jiangsu, China; The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.

Abstract

Accumulating evidence indicate that macrophages activate mesenchymal stem cells (MSCs) to acquire pro-inflammatory phenotype. However, the role of MSCs activated by macrophages in gastric cancer remains largely unknown. In this study, we found that MSCs were activated by macrophages to produce increased levels of inflammatory cytokines. Cell colony formation and transwell migration assays revealed that supernatants from the activated MSCs could promote both gastric epithelial cell and gastric cancer cell proliferation and migration. In addition, the expression of epithelial-mesenchymal transition (EMT), angiogenesis, and stemness-related genes was increased in activated MSCs. The phosphorylated forms of NF-κB, ERK and STAT3 in gastric cells were increased by active MSCs. Inhibition of NF-κB activation by PDTC blocked the effect of activated MSCs on gastric cancer cells. Co-injection of activated MSCs with gastric cancer cells could accelerate gastric cancer growth. Moreover, human peripheral blood monocytes derived macrophages also activated MSCs to prompt gastric cancer cell proliferation and migration. Taken together, our findings suggest that MSCs activated by macrophage acquire pro-inflammatory phenotype and prompt gastric cancer growth in an NF-κB-dependent manner, which provides new evidence for the modulation of MSCs by tumor microenvironment and further insight to the role of stromal cells in gastric carcinogenesis and cancer progression.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analysis of Variance
Animals
Blotting, Western
Cell Line, Tumor
Cell Movement / physiology
Cell Proliferation
Cytokines / metabolism*
Epithelial-Mesenchymal Transition / genetics
Gene Expression Regulation, Neoplastic / physiology*
Humans
Immunohistochemistry
Macrophages / metabolism*
Mesenchymal Stem Cells / metabolism*
Mice
Mice, Inbred BALB C
NF-kappa B / metabolism*
Neovascularization, Pathologic / genetics
Real-Time Polymerase Chain Reaction
Stomach Neoplasms / metabolism
Stomach Neoplasms / physiopathology*
Tumor Stem Cell Assay

Substances

Cytokines
NF-kappa B

Grants and funding

This work was supported by the Major Research Plan of the National Natural Science Foundation of China (Grant No. 91129718), the National Natural Science Foundation of China (Grant no. 81302119, 81201660, 81071421), Jiangsu Province for Outstanding Sci-tech Innovation Team in Colleges and Universities (Grant no. SJK2013-10), Jiangsu Province’s Project of Scientific and Technological Innovation and Achievements Transformation (Grant no.BL2012055), Jiangsu Province’s Outstanding Medical Academic Leader and Sci-tech Innovation Team Program (Grant no.LJ201117), the Natural Science Foundation of the Jiangsu Province (Grant no.BK2012709, BK20130540), Doctoral Program Foundation of State Education Ministry (Grant no. 20113227110011), Jiangsu Province for Natural Scicence Research in Colleges and Universities (13KJB320001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.