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)和鳞癌 (SCC)是最常见的人类癌症，在美国每种癌症都有500多万例确诊病例 年。在过去的30年里，NMSC的发病率在美国和一半的成年人中增加了200% 活到65岁的人至少会得一次皮肤癌。人们普遍认为，太阳光产生的紫外线 辐射(UVR)和高龄是NMSC的主要危险因素。因此，NMSC的发病率是50到300倍 75岁及以上的成年人比45岁以下的成年人更高。大约90%的NMSC在 人类暴露于阳光产生的紫外线辐射和太阳的主要致癌成分有关 UVR包括UVB(290-320 nm)和UVA(320-400 nm)。SKH-1无毛小鼠等小鼠模型已经被 使用模拟暴露在这些波长下的实验平台进行了广泛的研究，并促进了 我们对UVR皮肤损伤的急性和慢性影响的细胞和分子水平的理解。 然而，老化本身及其对UVR诱导的NMSC易感性的影响在很大程度上 被研究界忽视，可能是因为无法获得年长的动物以及高昂的成本 以及与收容2岁或以上的动物有关的时间。我们相信体内的皮肤癌 在幼鼠身上进行的研究不太可能解决环境诱导的人类疾病的发病机制 皮肤癌。因此，我们严重缺乏对与年龄相关的皮肤结构和功能变化的了解 它们对肿瘤易感性的影响是皮肤癌领域的一个关键缺口。此UH2应用程序(UH2/UH3) 旨在通过测试老化的小鼠皮肤更容易受到紫外线照射的假设来解决这一关键差距。 与青壮年皮肤相比，NMSC可引起皮肤损伤。为了检验我们的假设，我们将使用SKH- 1和ptch1+/-/SKH-1小鼠，这是UVR诱导的SCC和BCC的成熟的临床前模型， 分别进行了分析。在UH2阶段，我们将建立青年和老年SKH-1和ptch1+/-/SKH-1的队列 用于紫外线照射研究的小鼠以及紫外线照射引起的青年和老年人皮肤缺陷的实验基准 老鼠的皮肤。在UH3阶段，我们将进行慢性和急性UVR研究，以确定年龄 影响对UVR引起的皮肤缺陷和NMSC的敏感性。我们相信我们的SKH-1和PTCH1+/-/SKH- 1模型将为UVR诱导的老年小鼠NMSC研究奠定坚实的临床相关性，并影响 癌症领域，意味着需要将基于机制和治疗的研究转移到老年小鼠模型上 为了更接近太阳暴晒的历史及其在人类人口中的后果 并更好地为年龄相关的NMSCs寻找新的靶向治疗方法。

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.