Department of Surgery, NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA.
Lab Invest. 2010 Jul;90(7):1078-90. doi: 10.1038/labinvest.2010.90. Epub 2010 May 10.
Castration experiments in rodents show that the stromal vasculature is critical to the androgen-mediated prostate growth regulation. However, the role of angiogenesis inhibitors, such as thrombospondin-1 (TSP-1), in this process is unclear. TSP-1 is a multifunctional glycoprotein that can function as a potent angiogenesis inhibitor and an in vivo activator of latent transforming growth factor-beta (TGF-beta) in some tissues. On the basis of these observations, we hypothesized that TSP-1 regulated androgen withdrawal-induced prostate regression and that this process was mediated not only through antiangiogenic activity but also through TGF-beta activation. To test this, we evaluated angiogenic activity in human prostate epithelial and stromal cells treated with androgens and hypoxia in vitro. TSP-1 knockout mice were characterized to investigate the in vivo functions of TSP-1. In vitro, we found that androgens and hypoxia differentially regulated TSP-1 and angiogenic activity. Androgens stimulated normal epithelial cell, but inhibited normal stromal cell, angiogenic activity. Conversely, hypoxia stimulated stromal while inhibiting epithelial activity. Thus, in vivo, net angiogenic activity must reflect cellular interactions. And, we found that media conditioned by epithelial cells grown under normoxic conditions stimulated stromal cell angiogenic activity, and if epithelial cells were grown under hypoxic conditions, stromal activity was further increased. TSP-1 levels, however, were unchanged. In vivo, TSP-1 loss in a mouse model led to prostate epithelial hyperplasia by 3 months of age with only a modest stromal effect. Androgens suppressed TSP-1 as expression increased after castration both in normal mouse prostate and in human prostate cancer tissues. In addition, TSP-1 expression corresponded to increased TGF-beta activation in mouse tissues, specifically in the stromal compartment. These data show a critical role for TSP-1 in prostate epithelial and stromal growth regulation through angiogenic inhibition and activation of latent TGF-beta. Therefore, loss of TSP-1 during tumorigenesis would eliminate two barriers to cancer progression.
去势实验鼠表明基质脉管系统对于雄激素介导的前列腺生长调控至关重要。然而，血管生成抑制剂如血小板反应蛋白-1（TSP-1）在这一过程中的作用尚不清楚。TSP-1 是一种多功能糖蛋白，在某些组织中可作为有效的血管生成抑制剂和潜伏转化生长因子-β（TGF-β）的体内激活剂。基于这些观察，我们假设 TSP-1 调节雄激素剥夺诱导的前列腺退化，这个过程不仅通过抗血管生成活性，而且还通过 TGF-β激活来介导。为了验证这一点，我们评估了雄激素和缺氧体外处理人前列腺上皮细胞和基质细胞的血管生成活性。我们对 TSP-1 基因敲除小鼠进行了特征分析，以研究 TSP-1 在体内的功能。在体外，我们发现雄激素和缺氧可差异调节 TSP-1 和血管生成活性。雄激素刺激正常上皮细胞，但抑制正常基质细胞的血管生成活性。相反，缺氧刺激基质细胞而抑制上皮细胞活性。因此，在体内，净血管生成活性必须反映细胞间的相互作用。并且，我们发现正常条件下培养的上皮细胞产生的条件培养基可刺激基质细胞的血管生成活性，如果上皮细胞在缺氧条件下培养，基质细胞的活性会进一步增强。然而，TSP-1 水平没有变化。在体内，TSP-1 缺失导致 3 月龄的小鼠模型前列腺上皮细胞增生，仅对基质细胞有轻微影响。雄激素抑制 TSP-1 的表达，因为在正常小鼠前列腺和人前列腺癌组织中，去势后 TSP-1 的表达增加。此外，TSP-1 的表达与 TGF-β的激活相对应，在小鼠组织中，特别是在基质区室中。这些数据表明 TSP-1 在前列腺上皮和基质生长调控中起着关键作用，通过血管生成抑制和潜伏 TGF-β的激活。因此，在肿瘤发生过程中 TSP-1 的缺失将消除癌症进展的两个障碍。
