Androgen-Regulated SPARCL1 in the Tumor Microenvironment Inhibits Metastatic Progression.
Androgen-Regulated SPARCL1 in the Tumor Microenvironment Inhibits Metastatic Progression.
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DOI：
10.1158/0008-5472.can-15-0024
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发表时间：
2015-10-15
期刊：
影响因子：
11.2
通讯作者：
Schaeffer EM
中科院分区：
文献类型：
--
作者：
Hurley PJ;Hughes RM;Simons BW;Huang J;Miller RM;Shinder B;Haffner MC;Esopi D;Kimura Y;Jabbari J;Ross AE;Erho N;Vergara IA;Faraj SF;Davicioni E;Netto GJ;Yegnasubramanian S;An SS;Schaeffer EM
前列腺癌是男性癌症死亡的主要原因，因为癌症的亚群进展到转移。前列腺癌被认为与雄激素受体（AR）信号有关，但AR在前列腺中调节的变化促进了转移，但人们对其知之甚少。我们之前注意到，在雄激素诱导的前列腺生长的侵袭阶段，分泌蛋白、酸性和富含半胱氨酸样1 （SPARCL1）的表达显著减少，这表明这可能是一种由AR控制的新型侵袭程序。本文中，我们在基于患者的数据中表明，SPARCL1的丢失与AR扩增或过表达同时发生。在机制上，我们证明了雄激素诱导的AR激活和SPARCL1位点结合通过表观遗传机制直接抑制SPARCL1的表达，并且这些事件可以通过AR拮抗剂或HDAC抑制剂在药理学上减弱。我们利用Hi-Myc前列腺癌模型发现，在Hi-Myc/Sparcl1−/−小鼠中，Sparcl1具有抑制肿瘤形成的功能。此外，Myc-CaP原位同种异体移植物的转移进展在肿瘤微环境中受到SPARCL1的限制。具体来说，我们发现SPARCL1既能与细胞外基质（ECM）中的胶原蛋白结合，又能与细胞骨架结合。SPARCL1直接抑制局灶黏附的组装，从而限制细胞牵引力的传递。我们的研究结果为ar调节的前列腺上皮运动提供了新的见解，并提供了一个新的框架，即ECM微环境中的SPARCL1通过调节前列腺癌转移性侵袭所需的物理力网络的启动来限制肿瘤进展。
Prostate cancer is a leading cause of cancer death in men due to the subset of cancers that progress to metastasis. Prostate cancers are thought to be hardwired to androgen receptor (AR) signaling, but AR-regulated changes in the prostate that facilitate metastasis remain poorly understood. We previously noted a marked reduction in Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) expression during invasive phases of androgen-induced prostate growth, suggesting that this may be a novel invasive program governed by AR. Herein, we show that SPARCL1 loss occurs concurrently with AR amplification or overexpression in patient based data. Mechanistically, we demonstrate that SPARCL1 expression is directly suppressed by androgen-induced AR activation and binding at the SPARCL1 locus via an epigenetic mechanism, and these events can be pharmacologically attenuated with either AR antagonists or HDAC inhibitors. We establish using the Hi-Myc model of prostate cancer that in Hi-Myc/Sparcl1−/− mice, SPARCL1 functions to suppress cancer formation. Moreover, metastatic progression of Myc-CaP orthotopic allografts is restricted by SPARCL1 in the tumor microenvironment. Specifically, we show that SPARCL1 both tethers to collagen in the extracellular matrix (ECM) and binds to the cell's cytoskeleton. SPARCL1 directly inhibits the assembly of focal adhesions thereby constraining the transmission of cell traction forces. Our findings establish a new insight into AR-regulated prostate epithelial movement and provide a novel framework whereby, SPARCL1 in the ECM microenvironment restricts tumor progression by regulating the initiation of the network of physical forces that may be required for metastatic-invasion of prostate cancer.