Abstract
The IL-6/STAT3/NF-κB positive feedback loop links inflammation to cancer and maintains cells at a transformed state. Similarly, cancer-associated myofibroblats remains active even in absence of cancer cells. However, the molecular basis of this sustained active state remains elusive. We have shown here that breast cancer cells and IL-6 persistently activate breast stromal fibroblasts through the stimulation of the positive IL-6/STAT3/NF-κB feedback loop. Transient neutralization of IL-6 in culture inhibited this signaling circuit and reverted myofibrobalsts to a normalized state, suggesting the implication of the IL-6 autocrine feedback loop as well. Importantly, the IL-6/STAT3/NF-κB pro-inflammatory circuit was also active in cancer-associated fibroblasts isolated from breast cancer patients. Transient inhibition of STAT3 by specific siRNA in active fibroblasts persistently reduced the level of the RNA binding protein AUF1, blocked the loop and normalized these cells. Moreover, we present clear evidence that AUF1 is also part of this positive feedback loop. Interestingly, treatment of breast myofibroblasts with caffeine, which has been previously shown to persistently inhibit active breast stromal fibroblasts, blocked the positive feedback loop through potent and sustained inhibition of STAT3, AKT, lin28B and AUF1. These results indicate that the IL-6/STAT3/NF-κB positive feedback loop includes AUF1 and is responsible for the sustained active status of cancer-associated fibroblasts. We have also shown that normalizing myofibroblasts, which could be of great therapeutic value, is possible through the inhibition of this procarcinogenic circuit.
Highlights
During the last two decades evidence has accumulated that cancer-associated fibroblasts (CAFs), which constitute a major portion of the reactive breast stromal cells, actively participate in tumor growth, invasion and metastasis [1,2,3]
MDA-serum-free conditioned medium (SFCM) was replaced with complete medium (CpM) and cells were reincubated for 48 h, and these cells were split and reincubated for another 48 h (Split)
MDA-SFCM down-regulated p16 and p21 while it increased the levels of Stromal-derived factor-1 (SDF-1), IL-6, α-SMA and TGF-β1 as compared to serum-free medium (SFM) and MCF10A-SFCM (Figure 1A)
Summary
During the last two decades evidence has accumulated that cancer-associated fibroblasts (CAFs), which constitute a major portion of the reactive breast stromal cells, actively participate in tumor growth, invasion and metastasis [1,2,3]. A large amount of data has emerged showing cancer-promoting function of these cells, which escort tumor cells through all the carcinogenesis steps This involves many signaling proteins that transmit the message in both directions, allowing cooperative crosstalk between cancer cells and their stroma, which influences the clinical course of the disease [4,5,6]. The active status of cancer-associated fibroblasts persists even when these cells are separated from cancer cells and after prolonged cell culture in vitro [8, 9]. This could result from genetic and/or epigenetic changes [10]. Caffeine increased the expression of the tumor suppressor proteins p16, p21 and p53, and repressed the expression/secretion of various procarcinogenic cytokines such as SDF1, IL-6 and TGF-β1 in active breast fibroblasts [15]
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