Endothelial Cells Enhance Prostate Cancer Metastasis via IL-6→Androgen Receptor→TGF-β→MMP-9 Signals

Abstract

While the potential roles of endothelial cells (ECs) in the microvascules of prostate cancer (PCa) during angiogenesis have been documented, their direct impacts on the PCa metastasis remain unclear. We found that the CD31-positive and CD34-positive ECs are increased in PCa compared to the normal tissues and these ECs cells were decreased upon castration, gradually recovered with time, and become increased after PCa progresses into the castration resistant stage, suggesting a potential linkage of these ECs with androgen deprivation therapy. The in vitro invasion assays demonstrated that the co-culture of ECs with PCa cells significantly enhanced the invasion ability of the PCa cells. Mechanism dissection found that co-culture of PCa cells with ECs led to increased IL-6 secretion from ECs, which might result in down-regulation of AR signaling in PCa cells, and then the activation of TGF-β/MMP9 signaling. The consequences of the IL-6→androgen receptor→TGFβ→MMP9 signaling pathway might then trigger the increased invasion of PCa cells. Blocking the IL-6→androgen receptor→TGFβ→MMP9 signaling pathway either by IL-6 antibody, AR-siRNA, or TGF-β1 inhibitor all interrupted the ability of ECs to influence PCa invasion. These results, for the first time, revealed the important roles of ECs within the PCa microenvironment to promote the PCa metastasis, and provide new potential targets of IL-6→androgen receptor→TGFβ→MMP9 signals to battle the PCa metastasis.

T-box Transcription Factor Brachyury Is Associated with Prostate Cancer Progression and Aggressiveness

“…In prostate cancer, the activation and secretion to the extracellular environment of soluble factors that mediate the cross-talk between tumor cells and tumor stroma, such as interleukins and growth factors, has been reported to play a role in tumor progression (13,14,(38)(39)(40). Our analysis confirm a previously result that demonstrated that Brachyury increases the expression and secretion of TGFb1 in a prostate cell line (13).…”

Noncoding RNAs that associate with YB-1 alter proliferation in prostate cancer cells

“…IL-6, a cytokine that can be both pro-and antiinflammatory, plays an important role in the metastasis of prostate cancer (Shariat et al 2002). Endothelial cells have been shown to excrete IL-6 resulting in a decrease in androgen receptor activity leading to increased invasion of the epithelial cells (Wang et al 2013). In HER2 positive breast cancer, IL-6 expression is increased as well (Hartman et al 2011).…”

Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

“…We recently learned from a study by Wang et al (2013) that endothelial cells within the prostate are increased following ADT. These cells secrete interleukin 6 (IL6), which activates PI3K/AKT signal transduction to suppress AR transactivation (Yang et al 2003).…”