Hormone-induced inflammation and prostate cancer

描述（由申请人提供）：性激素环境、组织氧化状态和炎症的年龄依赖性改变被认为是人类前列腺癌（PCa）的内源性危险因素。用睾酮(T)和雌二醇-17 β (E2)治疗Noble大鼠（人pca相关模型）16周后，可诱导大鼠侧前列腺（LPs）的上皮发育不良，这是一种类似于人前列腺上皮内瘤变（PIN）的增生性病变，但在腹侧前列腺（VPs）没有发生。LP发育不良经常伴有炎症，与人类增生性炎症性萎缩（PIA）相似，PIA被认为是PIN和PCa的前兆。长期用T治疗的大鼠在100%的治疗大鼠的LPs中只引起PCa。T治疗还会引起高泌乳素血症，从而诱发LP炎症。在发育不良的LPs中发现了明显的氧化应激（OS）和硝化应激（NS）相关损伤，环氧化酶-2 (COX-2)， NAD(P)H氧化酶（NOXs）和NO合成酶（NOSs）的异常表达以及抗氧化防御的破坏。我们在这里假设，t支持的E2作用通过诱导慢性OS/NS直接促进大鼠LP的早期肿瘤发展，最终导致肿瘤发生。此外，e2诱导的高泌乳素血症激活组织炎症反应，造成额外的OS/NS损伤，从而加剧了这一过程。提出了三个目标。目的1 -确定T+ E2诱导的LP发育不良是否伴有直接在前列腺上皮室诱导OS/NS，并且该过程是否因炎症的存在而加剧。激光捕获显微镜将用于在有或无炎症证据的区域取样正常上皮和发育不良上皮及其邻近基质，以评估激素诱导与炎症介导的OS/ ns相关变化。将评估五种类型的生物标志物：1)OS/NS生成/防御途径的破坏，2)OS/NS诱导的脂质，DNA和蛋白质损伤，3)T+E2诱导的癌基因表达改变，4)细胞增殖和凋亡失衡，5)通过COX和/或lypoxygenase （LOX）途径产生炎症介质。目的2：确定塞来昔布（一种特异性COX-2抑制剂）和zileuton（一种5-LOX抑制剂）联合治疗是否能消除或减轻T+E2治疗大鼠LPs中的炎症和/或不典型增生，以及这种作用是否与OS/ ns相关生物标志物的减少有关。目的3 -利用LP器官培养系统，我们将进一步阐明E2、T、DHT和PRL在没有炎症或系统性混杂因素的情况下的直接促癌作用。目的4：确定年龄的增长是否使大鼠前列腺更容易受到激素诱导的炎症和/或癌变的影响。我们的研究结果应该有助于解释人类前列腺炎症和癌变之间的关系，这是一个激烈争论的话题。

DESCRIPTION (provided by applicant): Age-dependent alterations in sex hormone milieu, tissue oxidant status, and inflammation are purported endogenous risk factors of human prostate cancer (PCa). Treatment of Noble rats, a human PCa-relevant model, with testosterone (T) and estradiol-17beta (E2) for 16 weeks induced epithelial dysplasia, a proliferative lesion that resembles human prostatic intraepithelial neoplasia (PIN), in the lateral prostates (LPs), but not in the ventral prostate (VPs) of treated rats. The LP dyslasia is frequently attended by inflammation and resembles the human proliferative inflammatory atrophy (PIA), a putative precursor to PIN and PCa. Longer treatment of rats with T causes PCa exclusively in the LPs of 100 percent of the treated rats. T treatment also causes hyperprolactinemia, which induces inflammation in the LP. Marked oxidative stress (OS)- and nitrative stress (NS)-related damages, aberrant expression of cyclooxygenase-2 (COX-2), NAD(P)H oxidases (NOXs), and NO synthases (NOSs), as well as disruption of anti-oxidant defenses were noted in the dysplastic LPs. We here hypothesize that T-supported E2 action contributes to early neoplastic development directly in rat LP by induction of chronic OS/NS that ultimately leads to tumorigenesis. Moreover, the, E2-induced hyperprolactinemia activates tissue inflammatory responses that inflict additional OS/NS damages, thus exacerbating the process. Three aims are proposed. Aim I- To determine if T+ E2 induced LP dysplasia is accompanied by induction of OS/NS directly in the prostatic epithelial compartment and that this process is exacerbated by the presence of inflammation. Laser-capture-microscopy will be used to sample normal and dysplastic epithelia, and their adjacent stroma, in areas with and without evidence of inflammation, to assess the hormone- induced versus inflammation-mediated OS/NS-associated changes. Five types of biomarkers will be evaluated: 1) disruption of OS/NS generation/defense pathways, 2) OS/NS-induced lipid, DNA and protein damages, 3) altered expression of T+E2 induced oncogenes, 4) imbalances in cell proliferation and apoptosis, 5) production of inflammation mediators via COX and/or lypoxygenase (LOX) pathways. Aim 2 - To determine if combined celecoxib (a specific COX-2 inhibitor) and zileuton (a 5-LOX inhibitor) treatment negates or diminishes inflammation and/or dysplasia in the LPs of T+E2 treated rats and if this effect is attended by diminution of OS/NS-associated biomarkers. Aim 3 - Using a LP organ culture system, we will further elucidate the direct cancer-promoting actions of E2, T, DHT, and PRL, in the absence of inflammation or systemic confounding factors. Aim 4-To determine whether advancement of age renders the rat prostate more susceptible to hormone-induced inflammation and/or carcinogenesis. Results from our studies should help explicate the relation between inflammation and carcinogenesis in the human prostate, a topic of intense debate.