Mast cells and immunosuppression in skin cancer

皮肤癌中的肥大细胞和免疫抑制

基本信息

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
项目类别：
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

项目摘要

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）：非黑色素瘤皮肤癌（NMSC），包括基底细胞癌和鳞状细胞癌，是最常诊断的癌症。这些癌症的发病率在普通人群中以惊人的速度增加，并且接受实体器官移植的人的风险明显更高。与其他人群相比，移植受者患 NMSC 的风险增加 65-250 倍。不幸的是，这些患者会产生大量的 NMSC，其中鳞状细胞癌 (SCC) 的比例较大，而且产生的肿瘤往往具有高度侵袭性且更频繁地转移。移植患者鳞状细胞癌患病率异常高的原因尚不清楚；然而，抑制免疫系统被认为很重要，这可以减少肿瘤细胞的检测和破坏。移植患者的免疫功能下降，因为他们必须服用免疫抑制药物来维持耐受性并防止移植器官的排斥反应。此外，暴露于太阳紫外线 (UV) 被视为 NMSC 的最大危险因素和病因，也会抑制免疫系统。免疫抑制药物和累积紫外线暴露的免疫抑制作用可能协同作用，增加移植受者的 NMSC 风险。最近的研究表明，移植患者常用的免疫抑制药物环孢菌素 A 可以改变皮肤癌的发生。在小鼠模型中，暴露于紫外线后用环孢素进行全身治疗会导致比对照小鼠更大的肿瘤和更高比例的恶性鳞状细胞癌。除了影响肿瘤的特征外，我们的初步数据表明，与载体对照相比，在慢性紫外线照射后，环孢素治疗的小鼠的真皮肥大细胞数量显着增加。肥大细胞最近被证明是紫外线免疫抑制作用的关键调节者。然而，肥大细胞的免疫抑制作用对长期紫外线照射后皮肤癌发生的重要性尚不清楚。拟议研究的中心假设是 CsA 通过刺激真皮肥大细胞的免疫抑制特性来增强皮肤癌的发生。为了检验这一假设，将实现以下具体目标：目标 1 - 检查肥大细胞对 CsA 介导的肿瘤进展的重要性；目标 2 - 确定 CsA 对真皮肥大细胞的直接影响。这些实验的结果将产生关于肥大细胞在正常环境和免疫抑制药物存在下对紫外线诱导的皮肤肿瘤的发生和生长的贡献的新信息。