Thrombospondin-1 regulates the normal prostate in vivo through angiogenesis and TGF-β activation
Thrombospondin-1 regulates the normal prostate in vivo through angiogenesis and TGF-β activation
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DOI：
10.1038/labinvest.2010.90
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发表时间：
2010-07-01
影响因子：
5
通讯作者：
Doll, Jennifer A.
中科院分区：
文献类型：
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作者：
Fitchev, Philip P.;Wcislak, Susan M.;Doll, Jennifer A.
啮齿动物的去势实验表明，基质脉管系统对于雄激素介导的前列腺生长调节至关重要。然而，血管生成抑制剂，例如血小板反应蛋白-1 (TSP-1)，在此过程中的作用尚不清楚。 TSP-1 是一种多功能糖蛋白，可作为有效的血管生成抑制剂和某些组织中潜在转化生长因子-β (TGF-β) 的体内激活剂。基于这些观察，我们假设 TSP-1 调节雄激素撤退诱导的前列腺退化，并且该过程不仅通过抗血管生成活性介导，而且还通过 TGF-β 激活介导。为了测试这一点，我们评估了体外用雄激素和缺氧处理的人前列腺上皮细胞和基质细胞的血管生成活性。对 TSP-1 敲除小鼠进行表征以研究 TSP-1 的体内功能。在体外，我们发现雄激素和缺氧对 TSP-1 和血管生成活性有差异性调节。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，同时抑制上皮活性。因此，在体内，净血管生成活性必须反映细胞相互作用。而且，我们发现，在常氧条件下生长的上皮细胞的条件培养基刺激了基质细胞的血管生成活性，并且如果上皮细胞在缺氧条件下生长，则基质活性进一步增加。然而，TSP-1 水平没有变化。在体内，小鼠模型中 TSP-1 的缺失会导致 3 个月大时的前列腺上皮增生，且仅产生适度的基质效应。雄激素抑制 TSP-1，因为在正常小鼠前列腺和人类前列腺癌组织中，去势后表达增加。此外，TSP-1 表达与小鼠组织中 TGF-β 激活的增加相对应，特别是在基质室中。这些数据表明 TSP-1 通过血管生成抑制和潜在 TGF-β 激活在前列腺上皮和基质生长调节中发挥关键作用。因此，肿瘤发生过程中 TSP-1 的丢失将消除癌症进展的两个障碍。实验室调查 (2010) 90, 1078-1090; doi：10.1038/labinvest.2010.90； 2010 年 5 月 10 日在线发布
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. Laboratory Investigation (2010) 90, 1078-1090; doi:10.1038/labinvest.2010.90; published online 10 May 2010