Hormone-induced inflammation and prostate cancer

激素引起的炎症和前列腺癌

• 批准号: 7426315
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7426315
• 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; DNA Damage; Data; Deoxyguanosine; Development; Dinoprostone; Disruption; Dysplasia; Elevation; Enzymes; Epithelial; Epithelium; Estradiol; FOSL2 gene; Gene Expression; Gene Expression Profile; Generations; Genes; Gland; Gonadal Steroid Hormones; Growth; 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; NAD(P)H oxidase; Neoplasms; Neoplastic Cell Transformation; Nitric Oxide Synthase; Oncogenes; Oncogenic; Organ Culture Techniques; Oxidants; Oxidative Stress; Oxidative Stress Induction; PRL gene; Pathway interactions; Process; Production; Prolactin; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Prostate; Prostatic; Prostatic Epithelium; Prostatic Intraepithelial Neoplasias; Proteins; Rattus; Reactive Nitrogen Species; Reactive Oxygen Species; Research Personnel; Risk Factors; STAT3 gene; Sampling; Stanolone; Stress; Superoxide Dismutase; System; Testing; Testosterone; Tissues; Week; Zileuton; adduct; age related; base; carcinogenesis; catalase; celecoxib; cyclooxygenase 1; 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，组织氧化剂状态和炎症的年龄依赖性改变是人类前列腺癌（PCA）的内源性危险因素。贵族大鼠是一种与人类PCA相关的模型，具有睾丸激素（T）和雌二醇-17beta（E2）16周诱导上皮性发育不良，这种增殖性病变类似于人类前列腺内上皮内肿瘤（PIN），但在后期的前列腺（lps），但在vertrate（lps）中，vertrate（lps）。 LP肿瘤经常通过炎症来参加，类似于人类增殖性炎症性萎缩（PIA），这是PIN和PCA的假定前体。用T的大鼠治疗更长的治疗在100％治疗的大鼠的LP中引起PCA。 T治疗还会引起高乳酸血症，从而诱导LP炎症。明显的氧化应激（OS）和硝化应激（NS）相关的损伤，环氧合酶-2（COX-2）的异常表达，NAD（P）H氧化酶（NOXS）以及无合酶（NOSS）（NOSS）以及抗氧化剂防御的抗氧化剂LPS中的抗氧化剂LPS。我们在这里假设T支持的E2作用通过诱导慢性OS/NS最终导致肿瘤发生的慢性OS/NS直接导致早期肿瘤发育。此外，E2诱导的高乳酸血症会激活组织炎症反应，从而造成其他OS/NS损害，从而加剧了该过程。提出了三个目标。目的I-确定T+ E2诱导的LP发育不良是否伴随着直接在前列腺上皮室中诱导OS/NS，并且由于存在炎症而加剧了此过程。激光捕获 - 显微镜将用于采样正常和发育不良的上皮症，及其相邻的基质，在有和没有炎症证据的区域，以评估激素诱导的与炎症介导的OS/NS相关的变化。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和蛋白质损害，3）T+E2诱导的Oncogenes的表达改变，4）细胞增殖中的不平衡，5）通过Cox和/或/或/或/或/或/或LOPCOX的产生（5）炎症途径（5）。目的2-确定塞来昔布（特定的COX-2抑制剂）和Zileuton（5-lox抑制剂）是否会否定或减少T+E2治疗大鼠LPS的炎症和/或异常增生，并且是否通过OS/NS与伴相关的生物标志物的OS/NS NS相关生物标志物的减小来表现出这种作用。 AIM 3-使用LP器官培养系统，我们将进一步阐明E2，T，DHT和PRL的直接促进癌症作用，而没有炎症或全身混杂因素。目标4确定年龄的发展是否会使大鼠前列腺更容易受到激素诱导的炎症和/或癌变。我们研究的结果应有助于阐明人类前列腺中炎症与癌变之间的关系，这是激烈争论的话题。