Role of ultraviolet radiation in Merkel cell carcinogenesis

紫外线辐射在默克尔细胞癌变中的作用

• 批准号: 8255458
• 负责人: DAVID M OWENS
• 金额: $ 28.18万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-08 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255458
• 关键词: Acute; Biology; CD 200; Cell Lineage; Cells; Chronic; Cutaneous; Data; Detection; Development; Elements; Epidemiology; Epidermis; Epithelial; Etiology; Exhibits; Exposure to; Genes; Homeostasis; Human; Immunosuppression; Incidence; Internal Ribosome Entry Site; Laboratories; Large T Antigen; Lesion; Lymph Node Involvement; Malignant Neoplasms; Merkel Cells; Merkel cell carcinoma; Modeling; Mus; Neoplasm Metastasis; Neoplastic Merkel Cell; Neurosecretory Systems; Oncogene Proteins; Pathogenesis; Patients; Play; Polyomavirus; Polyomavirus Infections; Population; Risk Factors; Role; Skin; Skin Cancer; Solar Energy; Stem cells; Sunlight; Tamoxifen; Testing; Therapeutic; Touch sensation; Transgenic Mice; UV Radiation Exposure; Ultraviolet Rays; Viral Oncogene; Work; base; carcinogenesis; design; keratinocyte; mortality; mouse model; novel; progenitor; public health relevance; response

DESCRIPTION (provided by applicant): Merkel cell carcinoma (MCC) is a rare but highly aggressive form of skin cancer that features the expression of neuroendocrine markers. MCCs characteristically exhibit a high propensity for invasion and metastasis; however, the etiology and cellular origin of MCC remain unknown. Moreover, the incidence of MCC cases has tripled over the last decade with less than half of MCC patients surviving one year following detection of lymph node involvement. Human epidemiological data indicates that exposure to ultraviolet radiation is a major risk factor for MCC development. In addition, a novel human polyomavirus, Merkel cell polyomavirus (MCPyV), was identified in 80% of human cutaneous MCC suggesting that large T antigen transformation may play a causative role in the pathogenesis of MCC. Despite this progress, our severe lack of understanding of the biology of the target cells that give rise to MCC significantly hinders efforts to define the causal elements of this lesion. The studies outlined in this proposal are based on our recent discovery of a discrete population of epithelial keratinocytes in the epidermis of skin that serve as the progenitor cell reservoir responsible for sustaining the normal Merkel cell lineage. This progenitor cell population resides in touch domes in the hairy skin and is unique in its capacity to maintain normal Merkel cell turnover. Our preliminary studies suggest that these touch dome progenitors may also be a target cell for MCC. To assess this, we have generated a novel transgenic mouse model for MCC based on our preliminary findings and we will employ this model to test the hypothesis that i) touch dome progenitor cells are the cells of origin for normal and neoplastic Merkel cells and ii) that ultraviolet radiation in combination with large T antigen expression is sufficient for Merkel cell carcinogenesis. Our ability to pinpoint the critical pathological components of MCC will provide a significant leap forward in the development of effective therapeutic strategies for these fatal cancers. PUBLIC HEALTH RELEVANCE: Chronic exposure to sunlight is the underlying cause of 90% of skin cancers. This proposal is designed to better understand exactly how solar radiation influences the development of a highly aggressive form of skin cancer called Merkel cell carcinoma. In particular, we will assess the role of two significant risk factors for Merkel cell carcinoma in humans, ultraviolet radiation and viral oncogenes, on the formation Merkel cell carcinoma in a newly develop experimental mouse model.

描述（由申请人提供）：默克尔细胞癌（MCC）是一种罕见但高度侵袭性的皮肤癌，其特征是表达神经内分泌标记物。 MCC 的特点是表现出高度的侵袭和转移倾向；然而，MCC 的病因学和细胞起源仍不清楚。此外，MCC 病例的发病率在过去十年中增加了两倍，只有不到一半的 MCC 患者在检测到淋巴结受累后一年内存活。人类流行病学数据表明，暴露于紫外线辐射是 MCC 发生的主要危险因素。此外，在 80% 的人类皮肤 MCC 中发现了一种新型人类多瘤病毒——默克尔细胞多瘤病毒 (MCPyV)，表明大 T 抗原转化可能在 MCC 的发病机制中发挥致病作用。尽管取得了这一进展，但我们对引起 MCC 的靶细胞生物学严重缺乏了解，严重阻碍了确定这种病变的因果因素的努力。本提案中概述的研究基于我们最近在皮肤表皮中发现的离散上皮角质形成细胞群，这些细胞作为负责维持正常默克尔细胞谱系的祖细胞库。这种祖细胞群存在于多毛皮肤的接触圆顶中，其维持默克尔细胞正常更新的能力是独一无二的。我们的初步研究表明，这些触摸圆顶祖细胞也可能是 MCC 的靶细胞。为了评估这一点，我们根据我们的初步发现建立了一种新型的 MCC 转基因小鼠模型，我们将利用该模型来检验以下假设：i) 触摸穹顶祖细胞是正常和肿瘤默克尔细胞的起源细胞，ii)紫外线辐射与大量 T 抗原表达相结合足以导致默克尔细胞癌变。我们查明 MCC 关键病理成分的能力将为开发这些致命癌症的有效治疗策略带来重大飞跃。 公共卫生相关性：长期暴露在阳光下是 90% 皮肤癌的根本原因。该提案旨在更好地了解太阳辐射如何影响一种高度侵袭性皮肤癌（称为默克尔细胞癌）的发展。特别是，我们将评估人类默克尔细胞癌的两个重要危险因素，紫外线辐射和病毒癌基因，在新开发的实验小鼠模型中默克尔细胞癌形成的作用。