Non-melanoma skin cancer: A model for impact of aging on an environmental disease

非黑色素瘤皮肤癌（NMSC），包括基底细胞癌（BCC）和鳞状细胞癌 (SCC)是人类癌症中最常见的形式，在美国每种癌症的确诊病例超过500万例。 年NMSC的发病率在过去三十年中在美国增加了200%， 活到65岁的人至少会患一次皮肤癌。人们普遍认为， 紫外线辐射（UVR）和高龄是NMSC的主要危险因素。因此NMSC发病率是 75岁及以上的成年人比45岁以下的人更高。大约90%的NMSC在 人类与暴露于阳光衍生的紫外线辐射和太阳辐射的主要致癌成分有关。 紫外线包括UVB（290- 320 nm）和UVA（320- 400 nm）。小鼠模型，如SKH-1无毛小鼠， 使用模拟暴露于这些波长的实验平台进行了广泛的研究， 我们对紫外线辐射皮肤损伤在细胞和分子水平上的急性和慢性影响的理解。 然而，衰老本身的影响及其对UVR诱导的NMSC易感性的影响在很大程度上是未知的。 被研究界忽视，可能是由于老年动物的不可用以及高昂的成本 以及与圈养2岁或更大动物相关的时间。我们相信体内皮肤癌 在年轻小鼠中进行的研究不太可能解决环境诱导的人类 皮肤癌因此，我们对皮肤结构和功能的年龄相关变化严重缺乏了解， 它们对肿瘤易感性的影响代表了皮肤癌领域的一个关键空白。此UH 2/UH 3应用程序 旨在通过测试老年小鼠皮肤对UVR更敏感的假设来解决这一关键差距- 与年轻成人皮肤相比，诱导的皮肤损伤和NMSC。为了验证我们的假设，我们将使用SKH- 1和Ptch 1 +/-/SKH-1小鼠，它们是UVR诱导的SCC和BCC的良好建立的临床前模型， 分别在UH 2阶段，我们将建立年轻和老年SKH-1和Ptch 1 +/-/SKH-1的队列 用于UVR研究的小鼠以及UVR诱导的年轻人和老年人皮肤缺损的实验基准 老鼠皮在UH 3阶段，我们将进行慢性和急性UVR研究，以确定年龄是否 影响UVR诱导的皮肤缺损和NMSC的易感性。我们相信我们的SKH-1和Ptch 1 +/-/SKH- 1模型将牢固地建立老年小鼠中UVR诱导的NMSC研究的临床相关性，并影响 癌症领域，这表明需要将基于机制和治疗的研究转移到老年小鼠模型， 为了更接近人类暴露在阳光下的历史及其后果， 并更好地确定针对年龄相关NMSC的新型靶向疗法。

Non-melanoma skin cancers (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are the most common forms of human cancer with more than 5 million cases diagnosed in the US each year. The incidence of NMSC has increased 200% over the past three decades in the US and half of all adults who live to age 65 will develop skin cancer at least once. It is widely accepted that sunlight-derived ultraviolet radiation (UVR) and advanced age are the major risk factors for NMSC. Thus NMSC incidence is 50 to 300 times higher in adults aged 75 and older compared to those under 45 years of age. Approximately, 90% of NMSC in humans are associated with exposure to sunlight-derived UVR and the major carcinogenic components of solar UVR include UVB (290-320nm) and UVA (320-400nm). Mouse models such as SKH-1 hairless mice have been studied extensively using experimental platforms that mimic exposure to these wavelengths and have facilitated our understanding of the acute and chronic effects of UVR skin damage at the cellular and molecular level. However, the impact of aging per se and its influence on susceptibility to UVR-induced NMSC has been largely overlooked by the research community, likely due to the unavailability of older animals as well as the high costs and time associated with housing animals at ages of 2 years or greater. It is our belief that in vivo skin cancer studies conducted in young mice are unlikely to address the pathogenesis of environmentally-induced human skin cancer. As such, our severe lack of understanding of age-related alterations of skin structure and function and their impact on tumor susceptibility represents a key gap in the skin cancer field. This UH2/UH3 application aims to address this key gap by testing the hypothesis that Aged murine skin is more susceptible to UVR- induced skin damage and NMSC compared to young adult skin. To test our hypothesis, we will employ SKH- 1 and Ptch1+/-/SKH-1 mice, which are well established pre-clinical models for UVR-induced SCC and BCC, respectively. During the UH2 phase, we will establish cohorts of young and aged SKH-1 and Ptch1+/-/SKH-1 mice for UVR studies as well as experimental benchmarks for UVR-induced skin defects in young and aged mouse skin. During the UH3 phase, we will conduct chronic and acute UVR studies to determine whether age impacts susceptibility to UVR-induced skin defects and NMSC. It is our belief that our SKH-1 and Ptch1+/-/SKH- 1 models will firmly establish clinical relevance for UVR-induced NMSC studies in aged mice and impact the cancer field by signifying a need to shift mechanism- and therapeutic-based research to aged mouse models in order to more closely approximate the history of sun exposure and its consequences in the human population and to better identify novel targeted therapies for age-related NMSCs.