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

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.

IL‐6 promotes metastasis of non‐small‐cell lung cancer by up‐regulating TIM‐4 via NF‐κB

“…In addition to NF-κB, STAT3 is another key factor in IL-6 signalling pathway, 34,35 and it has been documented that IL-6 promoted lung cancer development and progression by activating STAT3. 36,37 Another study found that IL-6 could induce immunosuppressive factor PD-L1 expression on peripheral myeloid cells through STAT3-dependent mechanism. 38 However, we did not observe the significant change of IL-6-inducing elevated TIM-4 expression in STAT3 inhibitor treatment group.…”

RNAi screening identifies a mechanosensitive ROCK-JAK2-STAT3 network central to myofibroblast activation

“…This decision was influenced by the ambiguous nature of the existing data linking STAT3 to fibroblast activation and fibrosis. Although a limited number of studies have implicated STAT3 signaling in fibroblast activation and/or fibrosis in models of kidney, liver, dermal and cardiac scarring and fibrosis (Chakraborty et al, 2017;Dai et al, 2013;Khan et al, 2012;Pang et al, 2010;Ray et al, 2013;Shi et al, 2017;Su et al, 2015;Xu et al, 2014;Zepp et al, 2017), others have suggested protective (Mair et al, 2010;Yu et al, 2015), wound healing (Pickert et al, 2009) or regenerative roles for STAT3 (Jacoby et al, 2003;Moh et al, 2007), likely reflecting context-and cell type-specific roles for STAT3. Moreover, because STAT3 is a major downstream mediator of interleukin (IL-6) and associated family members and plays a prominent role in immune cell signaling and autoimmunity (Milner et al, 2015;Radojcic et al, 2010), it has been challenging to dissociate the effects of STAT3 in mouse models and human disease from alterations in inflammatory state and immune cell function.…”

Glutaminolysis is required for transforming growth factor-β1–induced myofibroblast differentiation and activation

“…However, TGF-␤1 has also been reported to stimulate alternative pathways to SMAD during differentiation such as the p38 MAPK pathway. To determine whether TGF-␤1 up-regulates GLS1 expression through its binding to TGF-␤ type I receptor activin receptor-like kinase ALK5 (32), we analyzed the effect of a specific inhibitor (SB431542) of the ALK5 receptor on TGF-␤1-induced GLS1 (33,34). The blockade of ALK5 with SB431542 prevented the up-regulation of both KGA and GAC protein and mRNA expression in myofibroblasts compared with controls (TGF-␤1-treated lung fibroblasts treated with vehicle) ( Fig.…”