Endothelial cells enhance prostate cancer metastasis via IL-6→androgen receptor→TGF-β→MMP-9 signals.
Endothelial cells enhance prostate cancer metastasis via IL-6→androgen receptor→TGF-β→MMP-9 signals.
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DOI：
10.1158/1535-7163.mct-12-0895
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发表时间：
2013-06
影响因子：
5.7
通讯作者：
Chang C
中科院分区：
文献类型：
--
作者：
Wang X;Lee SO;Xia S;Jiang Q;Luo J;Li L;Yeh S;Chang C
虽然内皮细胞（EC）在前列腺癌（PCa）微血管生成过程中的潜在作用已被证明，但其对PCa转移的直接影响仍不清楚。我们发现，CD 31阳性和CD 34阳性EC在前列腺癌中增加，这些EC细胞在去势后减少，随着时间的推移逐渐恢复，并在前列腺癌进展到去势抵抗期后增加，这表明这些EC与雄激素剥夺治疗的潜在联系。体外侵袭实验表明，ECs与PCa细胞共培养可显著增强PCa细胞的侵袭能力。机制研究发现，PCa细胞与ECs共培养后，ECs分泌IL-6增加，可能导致PCa细胞AR信号下调，进而激活TGF-β/MMP 9信号。IL-6→雄激素受体→TGFβ→ MMP 9信号通路的结果可能触发PCa细胞的侵袭增加。用IL-6抗体、AR-siRNA或TGF-β1抑制剂阻断IL-6→雄激素受体→TGFβ→ MMP 9信号通路均能阻断EC影响PCa侵袭的能力。这些结果首次揭示了PCa微环境中ECs在促进PCa转移中的重要作用，并为IL-6→雄激素受体→TGFβ→ MMP 9信号通路提供了新的潜在靶点。
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.