Mast cells and immunosuppression in skin cancer

描述(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，是最常见的诊断癌症。在普通人群中，这些癌症的发病率正在以惊人的速度增加，在接受过实体器官移植的人中，风险明显更高。与其他人群相比，移植受者患NMSC的风险增加了65-250倍。不幸的是，这些患者形成了大量的NMSCs和更大比例的鳞状细胞癌(SCCs)，并且出现的肿瘤往往具有高度侵袭性和更频繁的转移。移植患者鳞癌发病率异常高的原因尚不清楚，但免疫系统的抑制被认为是重要的，免疫系统可以减少对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和防止移植器官的排斥反应。此外，暴露于太阳的紫外线(UV)被认为是NMSC的最大危险因素和病原体，也抑制了免疫系统。免疫抑制药物和累积紫外线暴露的免疫抑制效应可能协同作用增加移植受者的NMSC风险。最近的研究表明，环孢素A，一种移植患者常用的免疫抑制药物，可以改变皮肤癌的发生。在小鼠模型中，暴露在紫外线下，然后用环孢菌素进行全身治疗，会导致更大的肿瘤和更高比例的恶性SCC。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，环孢素治疗的小鼠真皮肥大细胞的数量比赋形剂对照组显著增加。近来，肥大细胞被证明是紫外线免疫抑制作用的关键调节细胞；然而，肥大细胞的免疫抑制作用在慢性紫外线照射后的皮肤癌发生中的重要性尚不清楚。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而增强皮肤癌的发生。为了验证这一假设，将执行以下特定目标：目标1-检查肥大细胞在CsA介导的肿瘤进展中的重要性；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紫外线诱导的皮肤肿瘤的发展和生长中的作用的新信息，无论是在正常情况下还是在免疫抑制药物存在的情况下。 公共卫生相关性：非黑色素瘤皮肤癌(NMSC)是普通人群中诊断出的最常见的癌症类型，美国每年报告的新病例超过100万例。对于接受过实体器官移植的患者来说，NMSC是一个更大的问题，因为他们患NMSC的风险要高得多，而且他们会患上侵袭性癌症，更有可能扩散到远处。在这项申请中提出的研究将检查肥大细胞，一种免疫系统的细胞，参与皮肤癌的发展。来自这些研究的信息可以提供信息，从而找到更好的预防和治疗皮肤癌的方法。

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. PUBLIC HEALTH RELEVANCE: Non-melanoma skin cancer (NMSC) is the most common type of cancer diagnosed in the general population, with over a million new cases reported in the U.S. every year. NMSC is an even bigger problem for patients that have received solid organ transplants, because they are at a much higher risk of developing NMSC and they develop aggressive cancers that are more likely to spread to distant sites. The studies proposed in this application will examine the involvement of mast cells, a cell of the immune system, on skin cancer development. The information resulting from these studies could provide information leading to better ways of preventing and treating skin cancer.