title: Endothelial cells enhance prostate cancer metastasis via IL-6→androgen receptor→TGF-β→MMP-9 signals.
abstract: 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.
authors.affiliation: George Whipple Lab for Cancer Research, Department of Pathology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Xiaohai
authors.initials: X
authors.lastname: Wang
authors.forename: Soo Ok
authors.initials: SO
authors.lastname: Lee
authors.forename: Shujie
authors.initials: S
authors.lastname: Xia
authors.forename: Qi
authors.initials: Q
authors.lastname: Jiang
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D015850:Interleukin-6; D011944:Receptors, Androgen; D016212:Transforming Growth Factor beta; D020780:Matrix Metalloproteinase 9
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