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.
Highlights
Lung cancer is a primary cause of cancer-associated morbidity and mortality, with over 1 million deaths from the disease worldwide per year[1]
In a second set of experiments, MFs were cultured alone, with mouse recombinant TGF-β (mrTGF-β) (2 ng/mL), with caner condition-medium or co-cultured with CMT/LLC cells. mIL-6 concentration in supernatant was measured by enzyme-linked immunosorbent assay (ELISA) (C–F) and mIL-6 protein in MFs was assessed by Western blots (G,H). mrTGF-β, lung cancer cells and cancer-CM enhanced expression of mIL-6 in MFs. n = 6 wells/group; *Compared to MF group, p < 0.05; #Compared to normal medium (NM) group, p < 0.05
Pro-inflammatory cytokine signaling through JAK/STAT3 could be critical for the interactions between lung cancer cells and stromal cells in the transformation of lung cancer cells to take on stromal cell properties, which promote progression of lung cancer and result in poor prognosis[14]
Summary
Lung cancer is a primary cause of cancer-associated morbidity and mortality, with over 1 million deaths from the disease worldwide per year[1]. It is known that the interaction between MFs and lung cancer cells influences the formation and progression of lung cancer development[3,4,5]. Changes in signaling via another pro-inflammatory cytokine, transforming growth factor-β (TGF-β), are closely linked to various activities related to cancer onset and migration[8,9,10]. Signaling pathways regulated by TGF-β in lung cancer cells include Wnt/β-catenin, MAPK, and JAK/STAT3 signaling[11]. Pro-inflammatory cytokine signaling through JAK/STAT3 could be critical for the interactions between lung cancer cells and stromal cells in the transformation of lung cancer cells to take on stromal cell properties, which promote progression of lung cancer and result in poor prognosis[14]
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