Mast cells and immunosuppression in skin cancer

描述（由申请人提供）：非黑色素瘤皮肤癌（NMSCs），包括基底细胞癌和鳞状细胞癌，是最常诊断的癌症。在普通人群中，这些癌症的发病率正以惊人的速度增长，而在接受实体器官移植的人群中，风险明显更高。与其他人群相比，移植受者发生NMSC的风险增加了65-250倍。不幸的是，这些患者产生大量的NMSCs，鳞状细胞癌（SCCs）的比例更大，并且产生的肿瘤往往具有高度侵袭性和更频繁的转移。移植患者中SCC异常高患病率的原因尚不清楚；然而，抑制免疫系统可以减少对肿瘤细胞的检测和破坏，这被认为是重要的。移植患者由于必须服用免疫抑制药物来维持对移植器官的耐受性和防止排斥反应，免疫功能下降。此外，暴露于太阳紫外线（UV），被认为是NMSC的最大危险因素和病因，也抑制免疫系统。免疫抑制药物和累积紫外线暴露的免疫抑制作用可能共同增加移植受者的NMSC风险。最近的研究表明，环孢素A，一种常用于移植患者的免疫抑制药物，可以改变皮肤癌的发生。在小鼠模型中，暴露于紫外线下，然后用环孢素进行全身治疗，导致肿瘤变大，恶性SCCs的百分比高于对照小鼠。除了影响肿瘤的特征外，我们的初步数据表明，在慢性紫外线照射后，环孢素治疗的小鼠皮肤肥大细胞的数量比对照小鼠显著增加。肥大细胞最近被证明是紫外线免疫抑制作用的关键调节因子；然而，肥大细胞的免疫抑制作用在慢性紫外线照射后皮肤癌发生中的重要性尚不清楚。提出的研究的中心假设是CsA通过刺激真皮肥大细胞的免疫抑制特性来促进皮肤癌的发生。为了验证这一假设，将实施以下具体目标：目标1 -检查肥大细胞对csa介导的肿瘤进展的重要性；目的2 -确定CsA对真皮肥大细胞的直接作用。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展和生长的贡献的新信息。

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.