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Crosstalk between bone marrow-derived myofibroblasts and gastric cancer cells regulates cancer stemness and promotes tumorigenesis

Oncogene volume 35, pages 5388–5399 (2016)Cite this article

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Abstract

Bone marrow-derived cells have important roles in cancer development and progression. Our previous studies demonstrated that murine bone marrow-derived myofibroblasts (BMFs) enhanced tumor growth. In this study, we investigated the mechanisms of BMF actions. We found that co-injection of BMFs with gastric cancer cells markedly promoted tumorigenesis. Co-cultured BMFs or BMF-conditioned medium (BMF-CM) induced the formation of spheres, which expressed stem cell signatures and exhibited features of self-renewal, epithelial-to-mesenchymal transition and tumor initiation. Furthermore, CD44+ fractions in spheres were able to initiate tumorigenesis and re-establish tumors in serially passaged xenografts. In co-culture systems, BMFs secreted high levels of murine interleukin-6 (IL-6) and hepatocyte growth factor (HGF), whereas cancer cells produced high level of transformation growth factor-β1 (TGF-β1). BMF-CM and IL-6 activated BMFs to produce mHGF, which activated signal transducer and activator of transcription 3 (STAT3) and upregulated TGF-β1 in human cancer cells. In return, cancer cell-CM stimulated BMFs to produce IL-6, which was inhibited by anti-TGF-β1 neutralizing antibody. Blockade of HGF/Met, Janus kinase 2 (JAK2)/STAT3 and TGF-β1 signaling by specific inhibitors inhibited BMF-induced sphere formation. STAT3 knockdown in cancer cells also inhibited BMF-induced sphere formation and tumorigenesis. Moreover, TGF-β1 overexpression in cancer cells was co-related with IL-6 and HGF overexpression in stromal cells in human gastric cancer tissues. Our results show that BMF-derived IL-6/HGF and cancer cell-derived TGF-β1 mediate the interactions between BMFs and gastric cancer cells, which regulate cancer stemness and promote tumorigenesis. Targeting inhibition of the interactions between BMFs and cancer cells may be a new strategy for cancer therapy.

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Accession codes

Accessions

Gene Expression Omnibus

Abbreviations

BMFs:

bone marrow-derived myofibroblasts

BMF-CM:

BMF-conditioned medium

Co-culture-CM:

co-culture medium of BMFs and cancer cells

IL-6:

interleukin-6

JAK2:

Janus kinase 2

STAT3:

signal transducer and activator of transcription 3

HGF:

hepatocyte growth factor

MSCs:

mesenchymal stem cells

EGF:

epidermal growth factor

TGF-β:

transformation growth factor-β

CSCs:

cancer stem cells

CSC-LCs:

CSC-like cells

FACS:

flow cytometry

ELISA:

enzyme-linked immunosorbent assays.

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Acknowledgements

The project was supported by NIH R21CA149865, NSFC 81172159, NSFC 81272403, NSFC 81472727, NSFC 91029718, NSFC 91429307 and NIH RO1 CA133021; Shanghai Education Committee Key Discipline and Specialty Foundation (J50208), Science and Technology Commission of Shanghai Municipality (15JC1403100). National Laboratory of Oncogene and Cancer-related Genes foundation (90-15-05).

Author contributions

Liming Zhu and Xiaojiao Cheng conducted most of experiments, acquired data and drafted manuscript; Jindong Shi performed animal experiments; Jiacheng Lin performed animal experiments and immunofluorescence staining, analyzed data and revised the manuscripts; Huanyu Jin conducted animal experiments and ELISA; Anna B Liu performed H&E and immunochemical staining; Hyunseung Pyo cultured cells and wrote manuscript; Jing Ye technical assistance; Yanbo Zhu conducted tissue array assay of human gastric cancer tissues; Hong Wang helped to establish stable cell lines; Haoyan Chen and Jingyan Fang conducted TCGA data analysis; Li Cai conducted bioinformatics analysis of microarray data; Timothy C Wang helped to analyze data and revised manuscript; Chung S Yang designed experiments, analyzed data, obtained funding and wrote the manuscript; Shui Ping Tu designed this study and conducted experiments, analyzed data, obtained funding and wrote the manuscript.

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Author notes

  1. L Zhu and X Cheng: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

    L Zhu, X Cheng, J Lin, G Chen & S P Tu

  2. Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

    L Zhu, J Shi, G Chen, H Jin, A B Liu, H Pyo, H Wang, C S Yang & S P Tu

  3. Department of Emergency Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

    J Ye

  4. Department of Pathology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

    Y Zhu

  5. Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

    H Chen & J Fang

  6. Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

    L Cai

  7. Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    T C Wang

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Corresponding authors

Correspondence to C S Yang or S P Tu.

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The authors declare no conflict of interest.

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Zhu, L., Cheng, X., Shi, J. et al. Crosstalk between bone marrow-derived myofibroblasts and gastric cancer cells regulates cancer stemness and promotes tumorigenesis. Oncogene 35, 5388–5399 (2016). https://doi.org/10.1038/onc.2016.76

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