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，其特征是神经内分泌标志物的表达。mcc具有侵袭和转移的高倾向；然而，MCC的病因和细胞起源仍不清楚。此外，在过去十年中，MCC病例的发病率增加了两倍，不到一半的MCC患者在发现淋巴结累及后存活一年。人类流行病学数据表明，暴露于紫外线辐射是MCC发展的一个主要危险因素。此外，一种新的人类多瘤病毒，默克尔细胞多瘤病毒（MCPyV），在80%的人皮肤MCC中被发现，这表明大T抗原转化可能在MCC的发病机制中起致病作用。尽管取得了这一进展，但我们对引起MCC的靶细胞生物学的严重缺乏了解，严重阻碍了对这种病变的因果因素的定义。本提案中概述的研究是基于我们最近在皮肤表皮中发现的离散的上皮角质形成细胞群，它们作为祖细胞储存库负责维持正常的默克尔细胞谱系。这种祖细胞群居住在毛状皮肤的触摸圆顶中，并且在维持正常默克尔细胞周转方面具有独特的能力。我们的初步研究表明，这些触顶祖细胞也可能是MCC的靶细胞。为了评估这一点，我们基于我们的初步研究结果建立了一种新的MCC转基因小鼠模型，我们将使用该模型来验证以下假设：i)触摸穹窿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T抗原表达的结合足以导致默克尔细胞癌变。我们确定MCC关键病理成分的能力将为这些致命癌症的有效治疗策略的发展提供重大飞跃。