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

ABSTRACT: To investigate the role of TGF-? 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-? signaling inhibitor - SB431542 and/or JAK2/STAT3 inhibitor - JSI-124. MFs were stimulated by TGF-?, 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-?. Recombinant IL-6 and MF-CM activated STAT3 and upregulated TGF-? in cancer cells. In contrast, cancer cell-CM or TGF-? stimulated MFs to produce IL-6. Blockade of JAK2/STAT3 and TGF-? 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-? 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.

SUBMITTER: Shi J 

PROVIDER: S-EPMC5561133 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature