Mechanisms of photocarcinogenesis in geriatric skin

描述(申请人提供)：非黑色素瘤皮肤癌(NMSC)是美国所有癌症中发病率最高的。虽然NMSC很少致命，但据估计，NMSC的治疗每年花费我们的医疗系统超过10亿美元。因此，预防而不是切除NMSC有可能对医疗成本产生重大影响。虽然暴露在阳光下的紫外线成分(特别是UVB)可以启动和促进NMSC的发展，但一些人患皮肤癌和角质形成细胞存活的原因是以复制能力为代价的， 即角质形成细胞变得衰老。没有IGF-1受体的激活，角质形成细胞对UVB诱导的凋亡更敏感，但存活的角质形成细胞保留了增殖的能力，这是一种不适当的UVB反应。在活体中，我们已经证明年轻皮肤中的角质形成细胞对UVB照射有适当的反应；然而，令人惊讶的是，老年人皮肤中有高比例的角质形成细胞对UVB照射有不适当的反应。我们推测，老年人皮肤对UVB辐射的这种不适当反应可能导致启动致癌角质形成细胞。此外，老年角质形成细胞对UVB的不适当反应是由于老年皮肤中IGF-1表达的沉默(以及相应的IGF-1受体失活)所致。最后，我们已经证明，用消融性真皮嫩肤疗法治疗老年皮肤可以恢复年轻的IGF-1水平，随后在防晒皮肤上恢复适当的UVB反应。在这项提案中，我们将扩展我们的研究，将老年皮肤对UVB诱导的癌症的易感性与IGF-1/IGF-1R信号通路联系起来。尽管皮肤癌可能发生在任何年龄，但皮肤癌的发展与年龄的增长之间存在很强的相关性。事实上，皮肤癌大多数发现于60岁以上的人；因此，年龄也是皮肤癌发生的风险因素。利用最近的体外、体内和流行病学数据，我们已经证明了老年皮肤中胰岛素样生长因子-1(IGF-1)/IGF-1受体信号的异常导致了他们对NMSC的易感性增加。在体外，IGF-1受体的激活调节正常人角质形成细胞对UVB辐射的反应，其他尚不完全清楚。IGF-1受体依赖的UVB反应增强首先，我们将确定老年皮肤的真皮嫩肤疗法是否会在较长时间内提高IGF-1水平并纠正不适当的UVB反应。第二，使用人皮肤移植到免疫缺陷小鼠身上，我们将从机械上将依赖于IGF-1受体的不恰当反应与光化性肿瘤的增加发展联系起来。最后，机制研究将在体外和体内使用UVB辐射的人皮肤来检测角质形成细胞中IGF-1R信号通路的元件。这些特定目标的成功完成将在老年皮肤中不适当的UVB反应与老年患者NMSC的发展之间提供直接联系。此外，我们将继续评估预防性治疗的有效性，以防止与衰老相关的光癌的发生。 公共卫生相关性：在研究非黑色素瘤皮肤癌风险在50岁后突然上升的原因时，我们先前已经证明，老年个体在紫外线照射后更容易导致DNA损伤，这取决于IGF-1/IGF-1R信号转导途径的变化。此外，使用皮肤嫩肤技术的研究表明，这种对紫外线的不适当反应可以在老年患者中得到纠正。这项提议中的实验结果将使我们能够确定皮肤年轻化的益处持续多久，并确定老年人对紫外线的不适当反应如何导致非黑色素瘤皮肤癌的发生机制。

DESCRIPTION (provided by applicant): Non-melanoma skin cancer (NMSC) has the highest incidence of all cancers in the United States. While rarely fatal, the treatment of NMSC is estimated to cost our healthcare system over a billion dollars annually. Therefore, the prevention rather than the excision of NMSC has the potential to have a major impact on healthcare costs. While it is clear that exposure to the ultraviolet components in sunlight (specifically UVB) can initiate and promote the development of NMSC, the reasons why some individuals develop skin cancer and survival of keratinocytes at the cost of replicative potential, i.e. keratinocytes become senescent. Absence of IGF-1 receptor activation, keratinocytes are more sensitive to UVB-induced apoptosis, but the keratinocytes that do survive retain the capacity to proliferate, an inappropriate UVB response. In vivo, we have demonstrated that keratinocytes in young skin respond appropriately to UVB exposure; however, a surprisingly high percentage of keratinocytes in geriatric skin respond inappropriately to UVB irradiation. We hypothesize that this inappropriate response to UVB irradiation in geriatric skin could lead to initiated carcinogenic keratinocytes. Furthermore, the inappropriate UVB response in geriatric keratinocytes is due to the silencing of IGF-1 expression (and corresponding inactivation of the IGF-1 receptor) in geriatric skin. Finally, we have shown that treatment of geriatric skin with ablative dermal rejuvenation therapies can re- establish youthful IGF-1 levels and subsequently reinstate the appropriate UVB response on sun-protected skin. In this proposal, we will expand our studies linking the susceptibility of geriatric skin to UVB-induced cancer to the IGF-1/IGF-1R signaling pathway. Although skin cancer can occur at any age, there is a strong correlation between the development of skin cancer and advancing age. In fact, the majority of skin cancers are found in people over the age of 60; therefore, age is also a risk factor for the development of skin cancer. Using data derived from recent in vitro, in vivo, and epidemiological data, we have demonstrated that aberrations in insulin-like growth factor-1 (IGF-1)/IGF-1 receptor signaling in geriatric skin contributes to their enhanced susceptibility to develop NMSC. In vitro, activation of the IGF-1 receptor regulates the response of normal human keratinocytes to UVB irradiation others do not are not fully understood. The IGF-1 receptor-dependent UVB response results in enhanced In the First, we will determine whether dermal rejuvenation therapies on geriatric skin will increase IGF-1 levels and correct the inappropriate UVB response for extended periods of time. Second, using human skin grafted onto immunodeficient mice we will mechanistically link the IGF-1 receptor-dependent inappropriate response to increased development of actinic neoplasia. Finally, mechanistic studies will examine elements of the IGF-1R signaling pathway in keratinocytes using UVB- irradiated human skin in vitro and in vivo. The successful completion of these specific aims will provide a direct link between the inappropriate UVB response in geriatric skin and the development of NMSC in geriatric patients. Furthermore, we will continue to evaluate the utility of prophylactic therapies that can prevent the occurrence of aging-associated photocarcinogenesis. PUBLIC HEALTH RELEVANCE: While investigating why the risk of non-melanoma skin cancer rises abruptly after the age of 50, we have previously demonstrated that geriatric individuals have an enhanced susceptibility to incur DNA damage following ultraviolet light exposure which is dependent on alterations in the IGF-1/IGF-1R signal transduction pathway. Furthermore, studies using dermal rejuvenation techniques indicate that this inappropriate response to ultraviolet light can be corrected in geriatric patients. The results of experiments in this proposl will allow us to determine how long the benefits from dermal rejuvenation are sustained and define mechanisms how the inappropriate response to ultraviolet light by geriatric individuals leads to the development of non-melanoma skin cancer.