Johansson Anna, Jones Jonathan, Pietras Kristian, Kilter Sigrid, Skytt Asa, Rudolfsson Stina Häggström, Bergh Anders
Department of Medical Bioscience, Pathology, Umeå University, Sweden.
Prostate. 2007 Nov 1;67(15):1664-76. doi: 10.1002/pros.20657.
Castration results in a major involution of the normal prostate gland. This process is initiated by effects in the prostate stroma and vasculature. Castration-induced regression of androgen sensitive prostate tumors is however less prominent and hypothetically this could be related to a limited stromal/vascular response. We therefore used animal tumor models to explore the importance of stroma and vascular effects, and if castration effects could be enhanced by a simultaneous therapy targeting the tumor stroma.
Using rats with Dunning PAP and H tumors, stereological methods, immunohistochemistry, and Western blotting, we studied the tumor response 7 and 28 days after castration and after the addition of stroma targeted therapies.
In the normal ventral prostate (VP) nuclear androgen receptors (AR) were rapidly downregulated after castration. In contrast, the Dunning tumors downregulated the AR in the cancerous epithelium, but not in the surrounding stroma. Vascular regulators such as the angiopoietins, tie 2, and PDGF-Rbeta were not decreased in the stroma after castration, as observed in the VP, creating an environment that prevents vascular involution. When a tumor stroma targeted therapy inhibiting the tie 2 receptor and the PDGF-Rbeta simultaneously was added to castration it resulted in a decreased vascular density, increased tumor cell apoptosis and decreased tumor growth compared to castration alone.
The stroma in highly differentiated androgen sensitive Dunning tumors is apparently androgen insensitive. If this unresponsive stroma is targeted the effects of castration can be enhanced.
去势导致正常前列腺显著萎缩。这一过程由前列腺基质和脉管系统的变化引发。然而，去势诱导的雄激素敏感性前列腺肿瘤消退并不明显，据推测这可能与有限的基质/血管反应有关。因此，我们使用动物肿瘤模型来探究基质和血管效应的重要性，以及去势效应是否可通过同时靶向肿瘤基质的治疗得以增强。
利用患有邓宁PAP和H肿瘤的大鼠，采用体视学方法、免疫组织化学和蛋白质印迹法，我们研究了去势后以及添加基质靶向治疗7天和28天后的肿瘤反应。
在正常腹侧前列腺（VP）中，去势后核雄激素受体（AR）迅速下调。相比之下，邓宁肿瘤在癌上皮细胞中下调了AR，但在周围基质中未下调。与VP中观察到的情况不同，去势后基质中的血管调节因子如血管生成素、酪氨酸激酶2（Tie 2）和血小板衍生生长因子受体β（PDGF-Rβ）并未减少，从而形成了一个阻止血管萎缩的环境。当在去势治疗的同时添加一种同时抑制Tie 2受体和PDGF-Rβ的肿瘤基质靶向治疗时，与单纯去势相比，其导致血管密度降低、肿瘤细胞凋亡增加以及肿瘤生长减缓。
高分化雄激素敏感性邓宁肿瘤中的基质显然对雄激素不敏感。如果靶向这种无反应的基质，去势的效果可以增强。
