Crosstalk between bone marrow-derived myofibroblasts and gastric cancer cells regulates cancer stemness and promotes tumorigenesis.
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.
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA.
Liming
L
Zhu
Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 200127, China.
Xiaojiao
X
Cheng
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA.
Jindong
J
Shi
Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 200127, China.
Lin
L
Jiacheng
Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 200127, China.|Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA.
Gang
G
Chen
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA.
Huanyu
H
Jin
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA.
Anna B
AB
Liu
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA.
Hyunseung
H
Pyo
Emergency Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, 200025, China.
Jing
J
Ye
Department of Pathology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, 200025, China.
Yanbo
Y
Zhu
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA.
Hong
H
Wang
Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 200232, China.
Haoyan
H
Chen
Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 200232, China.
Jingyuan
J
Fang
Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Li
L
Cai
Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
Timothy C
TC
Wang
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA.
Chung S
CS
Yang
Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 200127, China.|Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA.
Shui Ping
SP
Tu
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D053614:Janus Kinase 2 / Q000235:genetics; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000235:genetics; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
D017077:Culture Media, Conditioned; C553307:HGF protein, mouse; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2