Although the potential roles of endothelial cells in the microvascules of
prostate cancer during angiogenesis have been documented, their direct impacts on the
prostate cancer metastasis remain unclear. We found that the CD31-positive and CD34-positive endothelial cells are increased in
prostate cancer compared with the normal tissues and that these endothelial cells were decreased upon
castration, gradually recovered with time, and increased after
prostate cancer progressed into the
castration-resistant stage, suggesting a potential linkage of these endothelial cells with
androgen deprivation
therapy. The in vitro invasion assays showed that the coculture of endothelial cells with
prostate cancer cells significantly enhanced the invasion ability of the
prostate cancer cells. Mechanism dissection found that coculture of
prostate cancer cells with endothelial cells led to increased
interleukin (IL)-6 secretion from endothelial cells, which may result in downregulation of
androgen receptor (AR) signaling in
prostate cancer cells and then the activation of TGF-β/
matrix metalloproteinase-9 (MMP-9) signaling. The consequences of the IL-6→AR→TGFβ→MMP-9 signaling pathway might then trigger the increased invasion of
prostate cancer cells. Blocking the IL-6→AR→TGFβ→MMP-9 signaling pathway either by
IL-6 antibody, AR-
siRNA, or TGF-β1 inhibitor all interrupted the ability of endothelial cells to influence
prostate cancer invasion. These results, for the first time, revealed the important roles of endothelial cells within the
prostate cancer microenvironment to promote the
prostate cancer metastasis and provide new potential targets of IL-6→AR→TGFβ→MMP-9 signals to battle the
prostate cancer metastasis.