A stroma targeted therapy enhances castration effects in a transplantable rat prostate cancer model
A stroma targeted therapy enhances castration effects in a transplantable rat prostate cancer model
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DOI：
10.1002/pros.20657
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发表时间：
2007-11-01
期刊：
影响因子：
2.8
通讯作者：
Bergh, Anders
中科院分区：
文献类型：
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作者：
Johansson, Anna;Jones, Jonathan;Bergh, Anders
背景。阉割导致正常前列腺的严重退化。这个过程是由前列腺基质和脉管系统的作用启动的。然而，雄激素敏感性前列腺肿瘤的去势诱导消退不太明显，并且假设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索基质和血管效应的重要性，以及是否可以通过针对肿瘤基质的同步治疗来增强去势效应。方法。使用患有 Dunning PAP 和 H 肿瘤的大鼠，通过体视学方法、免疫组织化学和蛋白质印迹，我们研究了去势后 7 和 28 天以及添加基质靶向治疗后的肿瘤反应。 结果。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，Dunning 肿瘤下调癌性上皮中的 AR，但不下调周围基质中的 AR。正如在 VP 中观察到的，去势后，血管生成素、tie 2 和 PDGF-R 等血管调节剂在基质中并未减少，从而创造了一个防止血管复旧的环境。当同时抑制tie 2受体和PDGF-Rβ的肿瘤基质靶向治疗添加到去势时，与单独去势相比，它导致血管密度降低、肿瘤细胞凋亡增加和肿瘤生长减少。结论。高度分化的雄激素敏感邓宁肿瘤中的间质显然对雄激素不敏感。如果针对这种无反应的基质，可以增强阉割的效果。
BACKGROUND. 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.METHODS. 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.RESULTS. 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-R were not decreased in the strorna 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-R beta simultaneously was added to castration it resulted in a decreased vascular density, increased tumor cell apoptosis and decreased tumor growth compared to castration alone.CONCLUSIONS. 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.