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
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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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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DOI: https://doi.org/10.1038/onc.2016.76
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