Hormone-induced inflammation and prostate cancer

激素引起的炎症和前列腺癌

• 批准号: 7618496
• 负责人: Shuk-Mei Ho
• 金额: $ 26.46万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7618496
• 关键词: 17p; 3-nitrotyrosine; 4 hydroxynonenal; 8-hydroxy-2' -deoxyguanosine; Age; Aging; Animals; Antioxidants; Apoptosis; Area; Atrophic; Biological Markers; Categories; Cell Death; Cell Proliferation; Chronic; Coxibs; DNA; Data; Deoxyguanosine; Development; Dinoprostone; Dysplasia; Enzymes; Epithelial; Epithelium; Estradiol; FOSL2 gene; GADD45; Gene Expression; Gene Expression Profile; Generations; Genes; Gland; Gonadal Steroid Hormones; Hormones; Human; Hyperprolactinemia; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intraepithelial Neoplasia; Lasers; Lateral; Lesion; Leukotriene B4; Leukotrienes; Lipid Peroxidation; Lipids; Lobe; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Microscopy; Modeling; Neoplasms; Neoplastic Cell Transformation; Nitric Oxide Synthase; Oncogenes; Oncogenic; Organ Culture Techniques; Oxidants; Oxidases; Oxidative Stress; Oxidative Stress Induction; Pathway interactions; Process; Production; Prostaglandins; Prostate; Prostatic; Prostatic Epithelium; Prostatic Intraepithelial Neoplasias; Proteins; Rattus; Reactive Nitrogen Species; Reactive Oxygen Species; Research Personnel; Risk Factors; STAT3 gene; Sampling; Stress; Superoxide Dismutase; System; Testing; Testosterone; Tissues; Zileuton; adduct; age related; base; carcinogenesis; catalase; celecoxib; cyclooxygenase 2; early onset; glutathione peroxidase; in vivo; inhibitor/antagonist; neoplastic; nitration; tumorigenesis; young adult

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.

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-17β (E2) 治疗 Noble 大鼠（一种人类 PCa 相关模型）16 周，可诱导外侧前列腺 (LP) 上皮发育不良，这是一种类似于人前列腺上皮内瘤变 (PIN) 的增殖性病变），但在治疗大鼠的腹侧前列腺（VP）中却没有。 LP 发育不良经常伴有炎症，类似于人类增殖性炎症萎缩 (PIA)，PIA 是 PIN 和 PCa 的假定前体。对大鼠进行 T 治疗较长时间后，100% 的接受治疗的大鼠的 LP 中都会出现 PCa。 T 治疗还会引起高泌乳素血症，从而诱发 LP 炎症。明显的氧化应激 (OS) 和硝化应激 (NS) 相关损伤、环氧合酶 2 (COX-2)、NAD(P)H 氧化酶 (NOX) 和 NO 合酶 (NOS) 的异常表达以及破坏在发育异常的 LP 中发现了抗氧化防御能力。我们在此假设 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 诱导的高催乳素血症会激活组织炎症反应，造成额外的 OS/NS 损伤，从而加剧这一过程。提出了三个目标。目的 I-确定 T+ E2 诱导的 LP 发育不良是否伴有直接在前列腺上皮区室中诱导 OS/NS，并且该过程因炎症的存在而加剧。激光捕获显微镜将用于在有或没有炎症证据的区域对正常和发育不良的上皮及其邻近基质进行取样，以评估激素诱导的与炎症介导的 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 诱导癌基因的表达改变，4) 细胞失衡增殖和凋亡，5) 通过 COX 和/或脂肪加氧酶 (LOX) 途径产生炎症介质。目标 2 - 确定塞来考昔（一种特定的 COX-2 抑制剂）和齐留通（一种 5-LOX 抑制剂）联合治疗是否可以消除或减轻 T+E2 治疗大鼠腰椎间盘突出症的炎症和/或发育不良，以及这种作用是否由以下因素引起： OS/NS 相关生物标志物减少。目标 3 - 使用 LP 器官培养系统，我们将在没有炎症或全身混杂因素的情况下进一步阐明 E2、T、DHT 和 PRL 的直接促癌作用。目标 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致癌之间的关系，这是一个激烈争论的话题。