Stress & UV-induced Squamous Cell Carcinoma

描述（由申请人提供）：本文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）应激对皮肤癌出现、进展或消退的影响。我们将使用紫外线B辐射（UVB）诱导的鳞状细胞癌（SCC）的小鼠模型。SCC每年折磨超过200，000名美国人，并且每年导致大约2，000人死亡。鉴于皮肤癌发病率的上升和心理压力的普遍存在，有必要对压力对SCC的影响进行检查。然而，没有研究探讨压力和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的免疫力（CMI）。应激诱导的白细胞向皮肤的运输，以及促炎和Th 1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细胞数量来显著抑制皮肤CMI。重要的是。SCC是通过抗肿瘤T细胞免疫消除的抗原性肿瘤，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SCC的出现。急性应激诱导的T细胞向皮肤的运输可能介导这种效应。第四，初步数据显示，慢性应激增加UVB诱导的SCC的出现和进展。IFN-γ产生的抑制和T细胞对肿瘤浸润的抑制可介导易感性。第五，初步数据显示，基线焦虑状态预测SCC的易感性。根据这些发现，我们提出了将实现以下具体目标的实验：目标1：阐明急性或慢性应激影响肿瘤出现，反复UVB暴露后的进展或消退的机制。目的2：阐明急性与慢性应激对单次UVB暴露后DNA损伤和炎症的影响。目标3：确定紫外线诱导的病理学的特定阶段是否伴随着昼夜皮质酮节律的失调（这种失调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的易感性，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Th 1细胞因子作用和白细胞浸润到SCC和前哨淋巴结中来增强对SCC的抵抗力，而慢性应激将通过抑制白细胞浸润和改变SCC内和周围以及前哨淋巴结中有利于Th 2细胞因子的Th 2-Th 2平衡来增加易感性。这些发现很可能推广到其他天然抗原性或通过肿瘤免疫疗法诱导抗原性的癌症。从这些研究中获得的知识可能导致开发使用行为和/或药理学操作的临床治疗，以增强内源性抗肿瘤应答或有利于肿瘤进展的对抗因子。这些研究是重要的，因为皮肤癌的发病率和死亡率不断增加，压力无处不在，我们的初步研究结果对SCC的压力的影响。

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.