Modulation of cancer prevention by social stress

社会压力对癌症预防的调节

• 批准号: 7809021
• 负责人: Hildegard M. Schuller
• 金额: $ 50万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7809021
• 关键词: Address; Adenocarcinoma; Adenocarcinoma Cell; Adenylate Cyclase; Adrenergic Agents; Adverse effects; African American; Agonist; Aminobutyric Acids; Antineoplastic Agents; Area; Behavior; Behavioral; Breast; Cell Line; Cells; Chronic; Clinical Trials; Colon Adenocarcinoma; Colon Carcinoma; Cyclic AMP; Data; Development; Disease; Effectiveness; Epidermal Growth Factor; Epinephrine; Failure; Foundations; Glucocorticoids; Hand; Health behavior; Histopathology; Hormones; Human; Human Cell Line; Hydrocortisone; Immunohistochemistry; In Vitro; Incidence; Laboratory Animals; Lead; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of ovary; Measurement; Mus; Mutation; Neurotransmitters; Nicotine; Nicotinic Receptors; Non-Steroidal Anti-Inflammatory Agents; Norepinephrine; Nude Mice; Ovary; PTGS2 gene; Pancreatic Ductal Adenocarcinoma; Physiological; Preclinical Testing; Prevention; Prevention strategy; Prevention therapy; Preventive; Production; Prostate; Psychological Stress; Reporting; Role; Signal Transduction; Stomach; Stress; System; Testing; Time; Vascular Endothelial Growth Factors; Western Blotting; Xenograft procedure; adrenergic; base; beta-adrenergic receptor; cancer cell; cancer prevention; celecoxib; dietary supplements; drug testing; gamma-Aminobutyric Acid; improved; in vivo; inhibitor/antagonist; low socioeconomic status; lung cancer prevention; molecular marker; mortality; non-genomic; novel; receptor; response; social stress; tumor progression

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (01) Behavior, Behavioral Change, and Prevention and the specific Challenge Topic, 01-CA-103: The Role of Health Behaviors in Cancer Prevention. Chronic psychological stress and the resulting systemic increase in stress neurotransmitters noradrenaline and adrenaline and the glucocorticoid stress hormone cortisol enhance vulnerability to numerous diseases. However, the effects of stress on the prevention of cancer has not been studied to date. We have shown that two of the most common and most deadly cancers, small airway-derived pulmonary adenocarcinoma (PAC) and pancreatic ductal adenocarcinoma (PDAC) are stimulated in vitro and in vivo by cAMP-dependent signaling downstream of beta-adrenergic receptors (b-ARs) and that glucocorticoids stimulate these cells by increasing cAMP signaling. These findings suggest that a stress-related increase in noradrenaline and adrenaline (that are agonists for b-ARs) and cortisol will stimulate the development and progression of these cancers, thus counteracting the effects of cancer preventive agents. The disappointing and as yet poorly understood disconnect between promising results of preclinical testing and failure of these agents in clinical trials may thus be caused by the absence of stress in carefully maintained systems for the testing of anti- cancer drugs in vitro and in laboratory animals. On the other hand, we have shown in PAC and PDAC cells in vitro that the stimulating cAMP signaling downstream of b-ARs is inhibited by the neurotransmitter g- aminobutyric acid (GABA) that inhibits the activation of adenylyl cyclase. In addition, we have shown in mouse xenografts from PDAC and PAC that GABA reverses the cancer promoting effects of nicotine, which include a nicotinic receptor-induced systemic increase in noradrenaline and adrenaline. Based on these data we will test the hypotheses in xenografts of two human PAC and two PDAC cell that the development and progression of PAC and PDAC is stimulated by psychological stress, decreases the responsiveness to cancer prevention by a non-steroidal anti-inflammatory agent, and that treatment with GABA reverses these effects. We will use nude mice subjected to chronic social stress and assess the impact of this condition on cancer prevention by daily measurements of xenograft size as well as the quantitative determination of molecular markers by real-time PCR and Western blotting accompanied by histopathology and immunohistochemistry. Specific Aim 1: To test the hypothesis that psychological stress stimulates the development and progression of PDAC and PAC. Specific Aim 2: To test the hypothesis that psychological stress reduces the cancer preventive effects of the COX-2 inhibitor celecoxib on PDAC and PAC xenografts. Specific Aim 3: To test the hypothesis that treatment with GABA reverses the effects of psychological stress in mice without celecoxib prevention. Specific Aim 4: To test the hypothesis that GABA reverses the adverse effects of psychological stress on cancer prevention with celecoxib. Data generated by this 2-year project have a high chance to significantly improve the effectiveness of PAC and PDAC prevention and also provide a foundation for improved prevention of cancer of the colon, prostate, breast, stomach and ovary, all of which are stimulated by beta-adrenergic signaling. This application addresses broad Challenge Area (01) Behavior, Behavioral Change, and Prevention and the specific Challenge Topic, 01-CA-103: The Role of Health Behaviors in Cancer Prevention. Chronic psychological stress and the resulting systemic increase in stress neurotransmitters noradrenaline and adrenaline and the glucocorticoid stress hormone cortisol enhance vulnerability to numerous diseases. Low socioeconomic status, which creates chronic psychological stress and is particularly prevalent in African Americans, is associated with a significantly higher incidence and mortality of all cancers. However, the negative modulation of cancer prevention by psychological stress has not been studied to date and no information exists as to how such negative effects can be overcome. The current project will test the hypotheses in mice with xenografts of cell lines from human lung adenocarcinomas and pancreatic ductal adenocarcinomas that the development and progression of these cancers is stimulated by psychological stress, decreases the responsiveness to cancer prevention by a non steroidal anti-inflammatory agent, and that treatment with gamma-aminobutyric acid (GABA) reverses these effects. Data generated by this 2-year project will rapidly improve the prevention of lung cancer and panreatic cancer and lay the foundation for the rapid development of more successful prevention and therapy of cancer of the colon, prostate, breast, stomach and ovary.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (01) 行为、行为改变和预防以及具体的挑战主题 01-CA-103：健康行为在癌症预防中的作用。慢性心理压力以及由此导致的应激神经递质去甲肾上腺素和肾上腺素以及糖皮质激素应激激素皮质醇的全身增加增加了对多种疾病的脆弱性。然而，迄今为止尚未研究压力对预防癌症的影响。我们已经证明，两种最常见和最致命的癌症，小气道源性肺腺癌 (PAC) 和胰腺导管腺癌 (PDAC) 在体外和体内均受到 β-肾上腺素能受体下游 cAMP 依赖性信号的刺激（b -ARs）并且糖皮质激素通过增加 cAMP 信号传导来刺激这些细胞。这些发现表明，与压力相关的去甲肾上腺素和肾上腺素（b-AR 激动剂）和皮质醇的增加将刺激这些癌症的发生和进展，从而抵消癌症预防药物的作用。因此，临床前测试的有希望的结果与这些药物在临床试验中的失败之间令人失望且至今知之甚少的脱节可能是由于在体外和实验动物中精心维护的抗癌药物测试系统中缺乏压力造成的。另一方面，我们在体外 PAC 和 PDAC 细胞中证明，b-AR 下游的刺激性 cAMP 信号传导受到神经递质 g-氨基丁酸 (GABA) 的抑制，GABA 会抑制腺苷酸环化酶的激活。此外，我们在 PDAC 和 PAC 的小鼠异种移植物中发现，GABA 可以逆转尼古丁的促癌作用，其中包括烟碱受体诱导的去甲肾上腺素和肾上腺素的全身增加。基于这些数据，我们将在两个人类 PAC 和两个 PDAC 细胞的异种移植物中测试假设，即 PAC 和 PDAC 的发育和进展受到心理压力的刺激，降低了非甾体抗炎药对癌症预防的反应性， GABA 治疗可以逆转这些影响。我们将使用承受慢性社会压力的裸鼠，通过每日测量异种移植物大小以及通过实时PCR和蛋白质印迹定量测定分子标记并结合组织病理学和免疫组织化学来评估这种情况对癌症预防的影响。具体目标 1：检验心理压力刺激 PDAC 和 PAC 发生和进展的假设。具体目标 2：检验心理压力会降低 COX-2 抑制剂塞来昔布对 PDAC 和 PAC 异种移植物的癌症预防作用的假设。具体目标 3：检验以下假设：GABA 治疗可逆转未接受塞来昔布预防的小鼠心理压力的影响。具体目标 4：检验 GABA 可逆转心理压力对塞来昔布预防癌症的不利影响的假设。这个为期两年的项目产生的数据很有可能显着提高 PAC 和 PDAC 预防的有效性，并为改善结肠癌、前列腺癌、乳腺癌、胃癌和卵巢癌的预防奠定基础，所有这些都受到β-肾上腺素能信号传导。该应用程序涉及广泛的挑战领域 (01) 行为、行为改变和预防以及具体的挑战主题 01-CA-103：健康行为在癌症预防中的作用。慢性心理压力以及由此导致的应激神经递质去甲肾上腺素和肾上腺素以及糖皮质激素应激激素皮质醇的全身增加增加了对多种疾病的脆弱性。社会经济地位低下会造成长期心理压力，在非裔美国人中尤其普遍，与所有癌症的发病率和死亡率显着升高有关。然而，迄今为止尚未研究心理压力对癌症预防的负面影响，也没有关于如何克服这种负面影响的信息。目前的项目将在小鼠中测试来自人类肺腺癌和胰腺导管腺癌细胞系异种移植物的假设，即这些癌症的发生和进展受到心理压力的刺激，降低了非甾体抗炎药对癌症预防的反应，而用 γ-氨基丁酸 (GABA) 治疗可以逆转这些影响。这个为期两年的项目产生的数据将迅速改善肺癌和胰腺癌的预防，并为快速发展更成功的结肠癌、前列腺癌、乳腺癌、胃癌和卵巢癌的预防和治疗奠定基础。