Role of ultraviolet radiation in Merkel cell carcinogenesis

描述(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具有较高的侵袭和转移倾向；然而，MCC的病因和细胞起源尚不清楚。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患者在发现淋巴结受累后存活一年。人类流行病学数据表明，暴露于紫外线辐射是MCC发生的主要危险因素。此外，在80%的人皮肤MCC中发现了一种新的人类多瘤病毒--Merkel细胞多瘤病毒(MCPyV)，提示大T抗原转化可能在MCC的发病机制中起作用。尽管取得了这些进展，但我们严重缺乏对引起MCC的靶细胞生物学的了解，大大阻碍了确定这种损害的原因的努力。这项建议中概述的研究是基于我们最近发现的皮肤表皮中离散的上皮性角质形成细胞群体，这些细胞是维持正常默克尔细胞谱系的祖细胞储存库。这种祖细胞群体居住在毛茸茸的皮肤中的接触穹顶上，其独特的能力是维持正常的默克尔细胞周转。我们的初步研究表明，这些接触穹顶的祖细胞也可能是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个新的MCC转基因小鼠模型，并将使用该模型来检验以下假设：i)接触穹顶前体细胞是正常和肿瘤Merkel细胞的起源细胞，ii)紫外线辐射和大量T抗原的表达足以导致Merkel细胞癌变。我们能够准确定位MCC的关键病理成分，这将在开发这些致命癌症的有效治疗策略方面实现重大飞跃。 与公共健康相关：长期暴露在阳光下是90%皮肤癌的根本原因。这项建议旨在更准确地了解太阳辐射如何影响一种名为默克尔细胞癌的高度侵袭性皮肤癌的发展。特别是，我们将评估两个重要的人类默克尔细胞癌危险因素，紫外线辐射和病毒癌基因，在新开发的实验小鼠模型中形成默克尔细胞癌的作用。

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.