Abstract
BackgroundThe causative role of the pro-inflammatory cytokine IL-6 in prostate cancer progression has been well established at molecular level. However, whether and how IL-6 may play a role in prostate cancer risk and development is not well defined. One limitation factor to acquiring this knowledge is the lack of appropriate animal models.MethodsWe generated a novel line of prostate-specific IL-6 transgenic mouse model. We compared the prostate pathology, tumorigenic signaling components, and prostate tumor microenvironment of the IL-6 transgenic mice with wild type littermates.ResultsWith this model, we demonstrate that IL-6 induces prostate neoplasm autonomously. We further demonstrate that transgenic expression of IL-6 in the prostate activates oncogenic pathways, induces autocrine IL-6 secretion and steadily-state of STAT3 activation in the prostate tissue, upregulates paracrine insulin-like growth factor (IGF) signaling axis, reprograms prostate oncogenic gene expression, and more intriguingly, amplifies inflammation in the prostate and peri-prostatic adipose tissue.ConclusionsThe pro-inflammatory IL-6 is autonomous oncogene for the prostate. IL-6 induces prostate oncogenesis through amplifying local inflammation. We also presented a valuable animal model to study inflammation and prostate cancer development.
Highlights
The causative role of the pro-inflammatory cytokine IL-6 in prostate cancer progression has been well established at molecular level
We demonstrated that enforced expression of IL-6 in the prostate activated signal transduction and activator of transcription 3 (STAT3) pathway in the epithelium and stroma, induced an IL-6 autocrine and insulin-like growth factor (IGF) paracrine loop, reprogrammed prostate oncogenic gene expression, and amplified pro-tumorigenic inflammation in the prostate tissue microenvironment and peri-prostatic adipose tissue
IL-6 transgene induces early prostate neoplastic transformation Previously, we described that IL-6 facilitated prostate tumorigenesis and progression through autocrine IL-6 loop and re-programming oncogenic transcriptional profiles using oncogene-immortalized benign prostate epithelial cell lines [14]
Summary
The causative role of the pro-inflammatory cytokine IL-6 in prostate cancer progression has been well established at molecular level. Emerging evidence indicated that the pro-inflammatory cytokine IL-6 may play a causative role in prostate cancer progression [1]. Elevation of serum levels of IL-6 or activation of IL-6 signaling pathways in the tumor tissue correlates with the shortened overall survival and time to progression in prostate cancer [8,9,10,11,12,13]. IL-6, a multi-functional cytokine that can be produced by various cell types, including immune/inflammatory cells (monocytes, macrophages, B cells, T cells, nature killer cells), fibroblasts, keratinocytes, endothelial cells, and tumor cells, plays a pivotal role in controlling cell differentiation and cancer cell survival [15, 16].
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