Stress & UV-induced Squamous Cell Carcinoma

压力

• 批准号: 7761690
• 负责人: FIRDAUS S DHABHAR
• 金额: $ 24.46万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761690
• 关键词: Acute; Adverse effects; Affect; American; Animals; Anxiety; Behavior; Behavioral; Biological; Cancer Patient; Carcinogens; Cell Count; Cellular Immunity; Cessation of life; Chronic; Chronic stress; Circadian Dysregulation; Clinical Treatment; Corticosterone; DNA Adduction; DNA Damage; Data; Development; Disease; Equilibrium; Goals; Immunity; Immunosuppressive Agents; Immunotherapy; Incidence; Individual; Infectious Agent; Infiltration; Inflammation; Inflammatory; Interferons; Interleukin-2; Knowledge; Langerhans cell; Lead; Leukocyte Trafficking; Leukocytes; Life; Light; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Nature; Pathology; Phase; Predisposition; Production; Psychological Stress; Resistance; Sentinel Lymph Node; Skin; Skin Cancer; Skin Carcinoma; Squamous cell carcinoma; Stress; Sunlight; T cell response; T-Lymphocyte; TP53 gene; UV Radiation Exposure; Ultraviolet B Radiation; Ultraviolet Rays; acute stress; cytokine; hypothalamic-pituitary-adrenal axis; immune function; immunogenic; indexing; mortality; oxidative DNA damage; research study; response; stressor; trafficking; tumor; tumor progression; ultraviolet

DESCRIPTION (provided by applicant): The primary goal of the studies proposed here is to examine the effects of acute (skin immunoenhancing) versus chronic (skin immunosuppressive) stress on the emergence, progression or regression of skin cancer. We will use a murine model of ultraviolet B radiation (UVB) induced squamous cell carcinoma (SCC). SCCs afflict over 200,000 Americans per year and cause approximately 2,000 deaths per year. An examination of the effects of stress on SCC is warranted given the rising incidence of skin cancer and the ubiquitous nature of psychological stress. However, no study has examined the relationship between stress and SCC. Five key findings support such an examination: First, acute stress has been shown to enhance skin cell mediated immunity (CMI). A stress-induced trafficking of leukocytes to the skin, and increased pro-inflammatory and Th1 cytokines mediate this immunoenhancement. Second, in contrast to acute stress, chronic stress significantly suppresses skin CMI by decreasing leukocyte mobilization and T cell numbers. Importantly. SCCs are antigenic tumors that are eliminated by anti-tumor T cell immunity and hence may be affected by stressors that modulate CMI. Third, preliminary results suggest that acute stress suppresses the emergence of UVB induced SCC. Acute stress induced trafficking of T cells to skin may mediate this effect. Fourth, preliminary data show that chronic stress increases the emergence & progression of UVB induced SCC. Suppression of IFN-y production and inhibition of tumor infiltration by T cells may mediate susceptibility. Fifth, preliminary data show that baseline anxiety status predicts susceptibility to SCC. In light of these findings, we propose experiments that will accomplish the following specific aims: Aim 1: Elucidate mechanisms by which acute or chronic stress affect tumor emergence, progression or regression following repeated UVB exposure. Aim 2: Elucidate the effects of acute vs. chronic stress on DNA damage & inflammation following single UVB exposure. Aim 3: Determine whether specific phases of UV induced pathology are accompanied by dysregulation of the circadian corticosterone rhythm (such dysregulation increases mortality in cancer patients) and identify potential cytokine mediators of dysregulation. Aim 4: Determine whether differences in anxiety-related behavior can predict susceptibility to SCC and identify potential biological mediators. Our overarching hypothesis is that acute stress may enhance resistance to SCC through increased Th1 cyotkine action & leukocyte infiltration into SCC and sentinel lymph nodes, while chronic stress will increase susceptibility by suppressing leukocyte infiltration and altering the Th2-Th2 balance in favor of Th2 cytokines within and around SCC and in sentinel lymph nodes. These findings are likely to be generalizable to other cancers that are naturally antigenic or induced to be antigenic via tumor immunotherapy. The knowledge gained from these studies may lead to development of clinical treatments using behavioral and/or pharmacological manipulations to enhance endogenous anti-tumor responses or counter factors that favor tumor progression. These studies are important in light of increasing morbidity and mortality associated with skin cancer, the ubiquitous nature of stress, and our preliminary findings on the effects of stress on SCC.

描述（由申请人提供）：这里提出的研究的主要目标是检查急性（皮肤免疫增强）与慢性（皮肤免疫抑制）应激对皮肤癌发生，进展或消退的影响。我们将使用紫外线B辐射（UVB）诱导的小鼠鳞状细胞癌（SCC）模型。SCCs每年折磨着20多万美国人，每年造成大约2000人死亡。鉴于皮肤癌发病率的上升和无处不在的心理压力，有必要对压力对SCC的影响进行检查。然而，没有研究检查压力和SCC之间的关系。五个关键发现支持这样的检查：首先，急性应激已被证明可以增强皮肤细胞介导免疫（CMI）。应激诱导的白细胞运输到皮肤，促炎和Th1细胞因子的增加介导了这种免疫增强。其次，与急性应激相反，慢性应激通过减少白细胞动员和T细胞数量显著抑制皮肤CMI。重要的是。SCCs是抗原肿瘤，可被抗肿瘤T细胞免疫消除，因此可能受到调节CMI的应激源的影响。第三，初步结果表明急性应激抑制UVB诱导的鳞状细胞癌的发生。急性应激诱导的T细胞转运到皮肤可能介导了这种作用。第四，初步数据显示，慢性应激增加了UVB诱导的SCC的发生和发展。抑制IFN-y的产生和抑制T细胞的肿瘤浸润可能介导易感性。第五，初步数据显示，基线焦虑状态可预测SCC易感性。根据这些发现，我们提出了将实现以下具体目标的实验：目的1：阐明急性或慢性应激对重复UVB暴露后肿瘤出现、进展或消退的影响机制。目的2：阐明急性和慢性应激对单次UVB暴露后DNA损伤和炎症的影响。目的3：确定紫外线诱导的病理的特定阶段是否伴随着昼夜皮质酮节律的失调（这种失调会增加癌症患者的死亡率），并确定失调的潜在细胞因子介质。目的4：确定焦虑相关行为的差异是否可以预测SCC易感性，并确定潜在的生物介质。我们的总体假设是，急性应激可能通过增加Th1细胞因子的作用和白细胞浸润到SCC和前哨淋巴结来增强对SCC的抵抗力，而慢性应激会通过抑制白细胞浸润和改变Th2-Th2平衡来增加易感性，从而有利于SCC内部和周围以及前哨淋巴结的Th2细胞因子。这些发现很可能推广到其他自然抗原性或通过肿瘤免疫治疗诱导抗原性的癌症。从这些研究中获得的知识可能会导致临床治疗的发展，使用行为和/或药理操作来增强内源性抗肿瘤反应或对抗有利于肿瘤进展的因素。鉴于与皮肤癌相关的发病率和死亡率不断上升，压力无处不在，以及我们对压力对SCC影响的初步发现，这些研究是重要的。

项目成果

High-anxious individuals show increased chronic stress burden, decreased protective immunity, and increased cancer progression in a mouse model of squamous cell carcinoma.

• DOI: 10.1371/journal.pone.0033069
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Dhabhar FS;Saul AN;Holmes TH;Daugherty C;Neri E;Tillie JM;Kusewitt D;Oberyszyn TM
• 通讯作者: Oberyszyn TM