Endothelial cells enhance prostate cancer metastasis via IL6→androgen receptor→TGFβ→MMP9 signals
Menée in vitro, cette étude met en évidence un mécanisme par lequel les cellules endothéliales du microenvironnement tumoral favorisent le processus métastatique d'un cancer de la prostate
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.
http://mct.aacrjournals.org/content/early/2013/03/21/1535-7163.MCT-12-0895.abstract