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Bone marrow-derived mesenchymal stem cells increase drug resistance in CD133-expressing gastric cancer cells by regulating the PI3K/AKT pathway

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Tumor Biology

Abstract

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are recruited to primary tumours to compose the tumour microenvironment. In various cancers, CD133-positive cells have been shown to possess cancer stem cell properties that confer chemoresistance. This study aimed to investigate the role of BM-MSCs in the anti-tumour drug resistance of CD133-expressing gastric cancer cells and explore the underlying mechanisms that governing this role. We found that CD133+ gastric cancer cells displayed more resistance to chemotherapeutics than CD133− cells. In addition, BM-MSCs increased the anti-apoptotic abilities and chemoresistance of CD133+ cells via upregulation of Bcl-2 and downregulation of BAX. Mechanistically, BM-MSCs triggered activation of the PI3K/Akt signalling cascade in CD133+ cells. Blocking the PI3K/Akt pathway inhibited the promotion of chemoresistance. Furthermore, BM-MSCs enhanced the drug resistance of CD133-overexpressing cells in vitro and in vivo, but not that of CD133-knockdown cells, which demonstrated the contribution of CD133 to this process. In conclusion, we demonstrated that BM-MSCs increased the anti-apoptotic abilities and drug resistance of CD133-expressing cells via activation of the PI3K/Akt pathway following Bcl-2 upregulation and BAX downregulation, in which CD133 played a significant role. Targeting this route may help improve the efficacy of chemotherapy in gastric cancer.

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Abbreviations

BM-MSCs:

Bone marrow-derived mesenchymal stem cells

CSCs:

Cancer stem cells

GC:

Gastric cancer

GCCs:

Gastric cancer cells

MCS:

Magnetic cell sorting

IC50:

Half-maximal inhibitory concentration

DDP:

Cisplatin

q-PCR:

Real-time quantitative PCR.

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Acknowledgments

This research was supported by grants from the Health Bureau of Shanghai (grant no. 20134393 for BJJ) and the Research Funds of Shanghai Jiao Tong University School of Medicine (grant no. 13XJ10028 for BJJ). All authors appreciate the flow cytometry technical support assistance of Dr. Zhu-ying Guo. All authors read and approved the final manuscript for publication.

Authors’ contributions

NJ contributed to the study design, intellectual content, literature research, experimental studies, data acquisition, data analysis, statistical analysis and manuscript preparation. JWY, JGW, XCN and SLW contributed to the literature research, study design and data analysis. NJ, JWY, JGW, SLW assisted with the pathological and immunohistochemical analyses. JGW asisted with the RT-PCR analysis. XCN, SLW assisted with technique support in the laboratory. BJJ contributed to grant acquisition for this study. BJJ ensured the integrity of the entire study, study concepts, study design and manuscript review. All authors read and approved the final manuscript for publication.

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Authors and Affiliations

  1. Department of General Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Mohe Rd 280, Shanghai, 201900, People’s Republic of China

    Nuo Ji, Ji-Wei Yu, Xiao-Chun Ni, Ju-Gang Wu, Shou-Lian Wang & Bo-Jian Jiang

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  1. Nuo Ji
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  2. Ji-Wei Yu
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Correspondence to Bo-Jian Jiang.

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Ethics approval

Animal studies were approved by the animal ethics committee of our hospital and all animal procedures were performed in accordance with institutional guidelines.

In our study, all experimental procedures were conducted in accordance with our institutional guidelines for the care and use of laboratory animals and conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All animal experiments were performed according to protocols that were approved by our animal care and use committee.

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The authors declare that they have no competing interests.

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Nuo Ji and Ji-Wei Yu contributed equally to this article.

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Ji, N., Yu, JW., Ni, XC. et al. Bone marrow-derived mesenchymal stem cells increase drug resistance in CD133-expressing gastric cancer cells by regulating the PI3K/AKT pathway. Tumor Biol. 37, 14637–14651 (2016). https://doi.org/10.1007/s13277-016-5319-0

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