IL-6 secreted from senescent mesenchymal stem cells promotes proliferation and migration of breast cancer cells

Guo-Hu Di; Yang Liu; Ying Lu; Jin Liu; Chutse Wu; Hai-Feng Duan

doi:10.1371/journal.pone.0113572

IL-6 secreted from senescent mesenchymal stem cells promotes proliferation and migration of breast cancer cells

PLoS One. 2014 Nov 24;9(11):e113572. doi: 10.1371/journal.pone.0113572. eCollection 2014.

Authors

Guo-Hu Di¹, Yang Liu², Ying Lu³, Jin Liu², Chutse Wu², Hai-Feng Duan²

Affiliations

¹ Beijing Institute of Radiation Medicine (BIRM), No. 27, Taiping Road, Haidian District, Beijing 100850, China; State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, 5 Yan'erdao Road, Qingdao 266071, China.
² Beijing Institute of Radiation Medicine (BIRM), No. 27, Taiping Road, Haidian District, Beijing 100850, China.
³ The 307 Hospital, No. 8, Dongdajie Street, Fengtai District, Beijing 100071, China.

Abstract

Human mesenchymal stem cells (hMSCs) are currently investigated for a variety of therapeutic applications. However, MSCs isolated from primary tissue cannot meet clinical grade needs and should be expanded in vitro for several passages. Although hMSCs show low possibility for undergoing oncogenic transformation, they do, similar to other somatic cells, undergo cellular senescence and their therapeutic potential is diminished when cultured in vitro. However, the role of senescent MSCs in tumor progression remains largely elusive. In the current study, by establishing senescent human umbilical cord mesenchymal stem cells (s-UCMSCs) through the replicative senescence model and genotoxic stress induced premature senescence model, we show that s-UCMSCs significantly stimulate proliferation and migration of breast cancer cells in vitro and tumor progression in a co-transplant xenograft mouse model compared with 'young' counterparts (defined as MSCs at passage 5, in contrast to senescent MSCs at passage 45). In addition, we identified IL-6, a known pleiotropic cytokine, as a principal mediator for the tumor-promoting activity of s-UCMSCs by induction of STAT3 phosphorylation. Depletion of IL-6 from s-UCMSCs conditioned medium partially abrogated the stimulatory effect of s-UCMSCs on the proliferation and migration of breast tumor cells.

Publication types

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

MeSH terms

Animals
Blotting, Western
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Breast Neoplasms / therapy
Cell Line, Tumor
Cell Movement / drug effects*
Cell Proliferation / drug effects*
Cells, Cultured
Cellular Senescence / drug effects
Culture Media, Conditioned / metabolism
Culture Media, Conditioned / pharmacology
Endothelin-1 / metabolism
Female
Fetal Blood / cytology
Humans
Hydrogen Peroxide / pharmacology
Interleukin-6 / metabolism
Interleukin-6 / pharmacology*
MCF-7 Cells
Mesenchymal Stem Cell Transplantation / methods
Mesenchymal Stem Cells / cytology*
Mesenchymal Stem Cells / metabolism
Mice
Neovascularization, Pathologic / metabolism
Neovascularization, Pathologic / pathology
Oxidants / pharmacology
Phosphorylation / drug effects
STAT3 Transcription Factor / metabolism
Xenograft Model Antitumor Assays

Substances

Culture Media, Conditioned
Endothelin-1
Interleukin-6
Oxidants
STAT3 Transcription Factor
Hydrogen Peroxide

Grants and funding

This work was supported by the National Basic Research and Development of China (973 program) (Nos. 2010CB529903, 2010CB833600 and 2012CB518105); the National Science Foundation of China (Nos. 81201760, 30973670 and 3090592); and the Chinese National Science and Technology Major Project (Nos. 2012ZX09102301-001 and 2011ZX09102-001-30). The funders had no role in study design, data collectin and analysis, decision to publish, or preparation of the manuscript.