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Sci Rep. 2017 Aug 17;7(1):8660. doi: 10.1038/s41598-017-09020-8.

Targeted blockade of TGF-β and IL-6/JAK2/STAT3 pathways inhibits lung cancer growth promoted by bone marrow-derived myofibroblasts.

Author information

1
Department of Respiratory Medicine, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China.
2
Department of Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China.
3
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
4
Department of Gastroenterology, Ruijin Hospital North, Shanghai Jiaotong University School of Medicine, Shanghai, 201821, China.
5
Departments of Respiratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
6
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA.
7
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. tushuiping@yahoo.com.
8
Department of Gastroenterology, Ruijin Hospital North, Shanghai Jiaotong University School of Medicine, Shanghai, 201821, China. tushuiping@yahoo.com.
9
Department of Respiratory Medicine, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China. jiezjlxh@163.com.

Abstract

To investigate the role of TGF-β and IL-6 in myofibroblasts (MFs) - lung cancer cell interactions, lung cancer cells (Lewis and CTM-167 cell lines) were stimulated by IL-6, MF-conditioned medium (MF-CM) or MFs, with or without TGF-β signaling inhibitor - SB431542 and/or JAK2/STAT3 inhibitor - JSI-124. MFs were stimulated by TGF-β, cancer cell-CM or cancer cells, with or without SB431542 and JSI-124. Cell proliferation, the levels of cytokines, expression of mRNA and protein were determined. Mice bearing xenograft tumors were intraperitoneally treated with SB431542 or JSI-124 and monitored for up to 45 days. In co-culture systems, MFs secreted high levels of IL-6, while cancer cells produced high levels of TGF-β. Recombinant IL-6 and MF-CM activated STAT3 and upregulated TGF-β in cancer cells. In contrast, cancer cell-CM or TGF-β stimulated MFs to produce IL-6. Blockade of JAK2/STAT3 and TGF-β signaling by specific inhibitors significantly inhibited cell proliferation in vitro and tumor growth in vivo of lung cancer cells. Our study demontrated that the TGF-β and IL-6/JAK2/STAT3 signaling pathways form a positive feedback signaling loop that mediated the interactions between MFs and lung cancer cells. Targeted inhibiton of this signaling loop could be a new approach for lung cancer prevention and therapy.

PMID:
28819126
PMCID:
PMC5561133
DOI:
10.1038/s41598-017-09020-8
[Indexed for MEDLINE]
Free PMC Article

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