Modulation of cancer prevention by social stress

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。慢性心理应激以及由此引起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性增加增加了许多疾病的易感性。然而，到目前为止，人们还没有研究压力对癌症预防的影响。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)在体外和体内都受到β-肾上腺素能受体(b-ARs)下游cAMP依赖信号的刺激，糖皮质激素通过增加cAMP信号来刺激这些细胞。这些发现表明，与压力相关的去甲肾上腺素和肾上腺素(这是b-ars的激动剂)和皮质醇的增加将刺激这些癌症的发展和进展，从而抵消癌症预防药物的效果。临床前试验的令人失望的结果和这些药物在临床试验中的失败之间令人失望而又鲜为人知的脱节可能是由于在体外和在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，我们在体外的PAC和PDAC细胞中发现，刺激b-Ars下游的cAMP信号被神经递质g-氨基丁酸(GABA)抑制，后者抑制腺苷环化酶的激活。此外，我们在PDAC和PAC的小鼠移植瘤中表明，GABA逆转尼古丁的促癌作用，包括尼古丁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PAC和两个PDAC细胞的异种移植中测试假设，即PAC和PDAC的发展和进展受到心理应激的刺激，降低了对非类固醇抗炎剂预防癌症的反应性，而GABA治疗逆转了这些作用。我们将使用处于慢性社会压力下的裸鼠，通过每天测量移植瘤大小，以及实时定量聚合酶链式反应和免疫印迹结合组织病理学和免疫组织化学的分子标志物定量测定，来评估这种情况对癌症预防的影响。具体目的1：检验心理应激刺激PDAC和PAC发生发展的假设。具体目的2：验证心理应激降低COX-2抑制剂塞来昔布对PDAC和PAC异种移植肿瘤预防作用的假说。具体目标3：验证假设，即在没有塞来昔布预防的情况下，用GABA治疗可以逆转小鼠心理应激的影响。具体目标4：验证GABA逆转心理应激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著提高PAC和PDAC预防的有效性，还为改善对结肠癌、前列腺癌、乳腺癌、胃癌和卵巢癌的预防奠定了基础，所有这些癌症都是由β-肾上腺素能信号刺激的。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。慢性心理应激以及由此引起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性增加增加了许多疾病的易感性。低社会经济地位造成慢性心理压力，在非裔美国人中尤为普遍，与所有癌症的发病率和死亡率显著上升有关。然而，到目前为止，心理压力对癌症预防的负面调节作用还没有被研究过，也没有关于如何克服这种负面影响的信息。目前的项目将在移植了人肺腺癌和胰腺导管腺癌细胞系的小鼠身上测试假设，即这些癌症的发生和进展是由心理应激刺激的，降低了对非类固醇抗炎剂预防癌症的反应性，并且伽马氨基丁酸(GABA)治疗逆转了这些影响。这一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，并为更成功地预防和治疗结肠癌、前列腺癌、乳腺癌、胃癌和卵巢癌的快速发展奠定基础。

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.