Mast cells and immunosuppression in skin cancer

皮肤癌中的肥大细胞和免疫抑制

• 批准号: 8529528
• 负责人: TRACI A WILGUS
• 金额: $ 18.68万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-13 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529528
• 关键词: Affect; Allergic Reaction; Behavior; Case Study; Cell Count; Cell Proliferation; Cell Survival; Cells; Characteristics; Chronic; Clinical; Cyclosporine; Data; Dermal; Detection; Development; Distant; Drug Exposure; Exposure to; General Population; Graft Rejection; Growth and Development function; High Prevalence; Human; Immune response; Immune system; Immunocompetent; Immunosuppression; Immunosuppressive Agents; In Vitro; Inbred HRS Mice; Incidence; Inflammatory; Laboratories; Lesion; Malignant Neoplasms; Malignant Squamous Cell; Mediating; Mus; Neoplasm Metastasis; Organ; Organ Transplantation; Patients; Pharmaceutical Preparations; Population; Populations at Risk; Pre-Clinical Model; Prevalence; Property; Publishing; Rest; Risk; Risk Factors; Role; Sampling; Site; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Skin Neoplasms; Solid; Squamous cell carcinoma; T-Lymphocyte; Testing; The Sun; Transplant Recipients; Ultraviolet Rays; Work; cancer diagnosis; cancer risk; carcinogenesis; cell type; cytokine; high risk; immune function; in vitro testing; irradiation; mast cell; mouse model; neoplastic cell; prevent; research study; response; tumor; tumor progression

DESCRIPTION (provided by applicant): Non-melanoma skin cancers (NMSCs), which include basal and squamous cell carcinomas, are the most commonly diagnosed cancers. The incidence of these cancers is increasing at an alarming rate in the general population and the risk is significantly higher in people that have received solid organ transplants. Transplant recipients have a 65-250 fold increased risk of developing NMSC compared to the rest of the population. Unfortunately, these patients develop a high number of NMSCs with a larger proportion of squamous cell carcinomas (SCCs), and the tumors that arise tend to be highly aggressive and metastasize more frequently. The reason for this abnormally high prevalence in SCC in transplant patients is not clear; however, suppression of the immune system, which can diminish the detection and destruction of tumor cells, is thought to be important. Transplant patients have reduced immune function due to the immunosuppressive drugs they must take to maintain tolerance and prevent rejection of the transplanted organ. In addition, exposure to ultraviolet light (UV) from the sun, regarded as the largest risk factor and etiologic agent of NMSC, also suppresses the immune system. The immunosuppressive drugs and the immunosuppressive effects of cumulative UV exposure likely work in concert to increase the NMSC risk in transplant recipients. Recent studies have demonstrated that cyclosporine A, an immunosuppressive drug commonly taken by transplant patients, alters skin carcinogenesis. In mouse models, exposure to UV followed by systemic treatment with cyclosporine results in larger tumors and a higher percentage of malignant SCCs than control mice. In addition to affecting characteristics of the tumors, our preliminary data indicate that the number of dermal mast cells increases significantly in cyclosporine-treated mice compared to vehicle controls after chronic UV irradiation. Mast cells have recently been shown to be critical regulators of the immunosuppressive effects of UV; however, the importance of the immunosuppressive effects of mast cells on skin carcinogenesis after chronic UV exposure is not known. The central hypothesis of the proposed studies is that CsA enhances skin carcinogenesis by stimulating immunosuppressive properties of dermal mast cells. To test this hypothesis, the following specific aims will be carried out: Aim 1 - Examine the importance of mast cells to CsA-mediated tumor progression; Aim 2 - Determine direct effects of CsA on dermal mast cells. The results of these experiments will generate new information about the contribution of mast cells to the development and growth of UV-induced skin tumors both in a normal setting and in the presence of immunosuppressive drugs.

描述（由申请人提供）：包括基础和鳞状细胞癌在内的非黑色素瘤皮肤癌（NMSC）是最常见的癌症。这些癌症的发病率正在以惊人的速度增加，并且接受固体器官移植的人的风险明显更高。与其他人口相比，移植受者的患者的发展风险增加了65-250倍。不幸的是，这些患者会出现大量的NMSC，其中鳞状细胞癌（SCC）比例较大，并且出现的肿瘤往往具有高度的攻击性，并且更频繁地转移。在移植患者中，SCC异常患病率异常的原因尚不清楚。然而，认为可以减少肿瘤细胞的检测和破坏的免疫系统的抑制是重要的。移植患者由于必须服用的免疫抑制药物来维持耐受性并防止移植器官排斥，因此免疫功能降低。此外，被视为NMSC的最大危险因素和病因学药物的太阳暴露于紫外线（UV）也抑制了免疫系统。累积紫外线暴露的免疫抑制药物和免疫抑制作用可能会协同起作用，以增加移植受者的NMSC风险。最近的研究表明，环孢素A（一种通常由移植患者服用的免疫抑制药物）改变了皮肤致癌作用。在小鼠模型中，与对照小鼠相比，接触紫外线然后进行全身治疗会导致更大的肿瘤和更高的恶性SCC。除了影响肿瘤的特征外，我们的初步数据表明，与慢性紫外线照射后的媒介物对照相比，在环孢菌素处理的小鼠中，皮肤肥大细胞的数量显着增加。最近已证明肥大细胞是紫外线免疫抑制作用的关键调节剂。然而，尚不清楚肥大细胞对慢性紫外线暴露后皮肤致癌作用的免疫抑制作用的重要性。 提出的研究的中心假设是，CSA通过刺激皮肤肥大细胞的免疫抑制特性来增强皮肤致癌。为了检验该假设，将执行以下特定目的：目标1-检查肥大细胞对CSA介导的肿瘤进展的重要性； AIM 2-确定CSA对皮肤肥大细胞的直接影响。这些实验的结果将生成有关肥大细胞在正常环境和存在免疫抑制药物的情况下对肥大细胞对紫外线诱导的皮肤肿瘤发育和生长的贡献的新信息。