Stress & UV-induced Squamous Cell Carcinoma

描述(申请人提供)：这里提出的研究的主要目标是检验急性(皮肤免疫增强)和慢性(皮肤免疫抑制)应激对皮肤癌的出现、进展或消退的影响。我们将使用紫外线B辐射(UVB)诱导的小鼠鳞状细胞癌(SCC)模型。SCCS每年困扰着20多万美国人，每年造成约2,000人死亡。鉴于皮肤癌发病率的上升和心理压力的无处不在的性质，有必要检查压力对鳞状细胞癌的影响。然而，还没有研究探讨压力和鳞癌之间的关系。五个关键发现支持这样的检查：第一，急性应激已被证明可以增强皮肤细胞介导的免疫(CMI)。应激诱导的白细胞向皮肤的运输，以及增加的促炎和Th1细胞因子介导了这种免疫增强。第二，与急性应激相比，慢性应激通过减少白细胞动员和T细胞数量而显著抑制皮肤CMI。重要的是。SCC是一种抗原性肿瘤，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，急性应激抑制了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了这一效应。第四，初步数据表明，慢性应激增加了UVB诱导的鳞状细胞癌的发生和发展。抑制干扰素-γ的产生和T细胞对肿瘤的侵袭可能参与了易感性的调节。第五，初步数据显示，基线焦虑状态预测鳞状细胞癌的易感性。根据这些发现，我们建议进行实验，以实现以下特定目标：目的1：阐明急性或慢性应激对反复UVB暴露后肿瘤的出现、进展或退化的影响机制。目的2：探讨急性应激与慢性应激对UVB单次照射后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(这种失调增加了癌症患者的死亡率)，并确定了调节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鳞状细胞癌的易感性，并确定潜在的生物介质。我们的主要假设是，急性应激可能通过增加Th1细胞因子的作用和白细胞渗入SCC和前哨淋巴结来增强对SCC的抵抗力，而慢性应激则通过抑制白细胞渗透和改变Th2-Th2平衡来增加对SCC的易感性，有利于SCC及其周围和前哨淋巴结中的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/或药物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的增加，应激的普遍性质，以及我们关于应激对鳞状细胞癌影响的初步发现，这些研究是重要的。

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.