Wounding therapy and photocarcinogenesis

创伤治疗和光致癌

• 批准号: 8783059
• 负责人: DAN F SPANDAU
• 金额: $ 31.98万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783059
• 关键词: Actinic keratosis; Acute; Age; Aging; Animals; Apoptosis; Area; Buttocks; Cell Survival; Clinical Research; Cosmetics; DNA Damage; Data; Dermabrasion; Dermal; Development; Disease; Dorsal; Effectiveness; Elderly; Ensure; Environmental Risk Factor; Epidemiology; Epidermis; Exposure to; Fibroblasts; Forearm; Goals; HSPB1 gene; Healthcare Systems; Hip region structure; Human; Immunodeficient Mouse; In Vitro; Incidence; Individual; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Lasers; Lead; Malignant Neoplasms; Mediating; Mutation; Neoplasms; Patients; Photochemotherapy; Play; Population; Predisposition; Premalignant; Procedures; Production; Proliferating; Receptor Activation; Receptor Signaling; Rejuvenation; Risk; Risk Factors; Role; Signal Transduction; Skin; Skin Aging; Skin Cancer; Skin Carcinoma; Staining method; Stains; Stress; Sunlight; Survival Rate; Testing; The Sun; Therapeutic; Time; UVB induced; Ultraviolet B Radiation; United States; aged; cancer diagnosis; comparative effectiveness; design; in vivo; irradiation; keratinocyte; neoplastic cell; novel; prevent; prophylactic; public health relevance; repaired; response; senescence; skin xenograft; tumor; ultraviolet; young adult

DESCRIPTION (provided by applicant): Non-melanoma skin cancer is a disease primarily afflicting geriatric patients as evidenced by the fact that 80% of all non-melanoma skin cancers are diagnosed in patients over the age of 60 years. As such, geriatric skin responds to cancer-inducing UVB irradiation in a manner that allows the establishment of tumor cells. While the correlation between aged epidermis and skin cancer is obvious, the mechanism responsible for this relationship remains obscure. Recent in vitro evidence as well as epidemiological data suggests one possible mechanism may involve alterations in the insulin-like growth factor-1 receptor (IGF-1R) signaling network. Using normal human keratinocytes grown in vitro, activated IGF-1Rs protect keratinocytes from UVB-induced apoptosis; however, while UVB-irradiated keratinocytes with activated IGF-1Rs survive, they are incapable of further cellular replication, in fact they are senescent. The critically important observation was that in the absence of IGF-1R activation, keratinocytes are more sensitive to UVB-induced apoptosis, but the keratinocytes that do survive retain the capacity to proliferate. In the skin, keratinocytes express the IGF-1R but they do not synthesize IGF-1. Dermal fibroblasts support the proliferation of keratinocytes in the epidermis by secreting IGF-1. Interestingly, as dermal fibroblasts age, their capacity to produce IGF-1 is severely diminished; therefore, in aged skin keratinocytes are provided with a reduced supply of IGF-1 and a concomitant reduction in IGF-1R activation. We have demonstrated that geriatric skin responds to UVB irradiation in a manner that could lead to initiated carcinogenic keratinocytes. This inappropriate UVB response can be corrected by treatment with exogenous IGF-1. Furthermore, 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 use non- ablative dermal rejuvenation therapies to restore IGF-1 expression on sun-exposed geriatric skin to the levels seen in young adult skin and determine if these therapies can restore the appropriate UVB response. In addition, we will test the ability of non-ablative dermal rejuvenation therapies to protect against the formation of actinic keratoses and non-melanoma skin cancer. Finally, we will use human skin xenografts grown on immunodeficient mice to establish that the inhibition of the IGF-1R on epidermal keratinocytes sensitizes the keratinocytes to the development of UVB-induced actinic neoplasia. These studies will have a major impact on the treatment of NMSC by establishing a novel anti-carcinogenic role for dermal wounding. Furthermore, the data from these studies will confirm a new paradigm defining the mechanism of age-associated skin cancer.

描述（由申请人提供）：非黑色素瘤皮肤癌是一种主要影响老年患者的疾病，事实证明，80% 的非黑色素瘤皮肤癌是在 60 岁以上的患者中诊断出来的。 因此，老年皮肤对诱发癌症的 UVB 照射做出反应，从而促进肿瘤细胞的形成。 虽然老化表皮与皮肤癌之间的相关性是显而易见的，但造成这种关系的机制仍然不清楚。 最近的体外证据和流行病学数据表明，一种可能的机制可能涉及胰岛素样生长因子 1 受体 (IGF-1R) 信号网络的改变。 使用体外培养的正常人角质形成细胞，激活的 IGF-1R 可保护角质形成细胞免受 UVB 诱导的细胞凋亡；然而，虽然受到 UVB 照射且具有激活的 IGF-1R 的角质形成细胞能够存活，但它们无法进一步进行细胞复制，事实上它们正在衰老。 至关重要的观察结果是，在没有 IGF-1R 激活的情况下，角质形成细胞对 UVB 诱导的细胞凋亡更加敏感，但存活下来的角质形成细胞保留了增殖能力。 在皮肤中，角质细胞表达 IGF-1R，但不合成 IGF-1。 真皮成纤维细胞通过分泌 IGF-1 支持表皮角质形成细胞的增殖。 有趣的是，随着真皮成纤维细胞的衰老，它们产生 IGF-1 的能力严重减弱；因此，在老化的皮肤角质形成细胞中，IGF-1 的供应量减少，IGF-1R 活化也随之减少。 我们已经证明，老年皮肤对 UVB 照射的反应可能会导致致癌角质形成细胞的产生。 这种不适当的 UVB 反应可以通过外源 IGF-1 治疗来纠正。 此外，我们已经证明，采用剥脱性真皮再生疗法治疗老年皮肤可以重新建立年轻的 IGF-1 水平，并随后恢复防晒皮肤上适当的 UVB 反应。 在本提案中，我们将使用非剥脱性真皮再生疗法将暴露在阳光下的老年皮肤上的 IGF-1 表达恢复到年轻成人皮肤的水平，并确定这些疗法是否可以恢复适当的 UVB 反应。 此外，我们将测试非剥脱性真皮再生疗法预防光化性角化病和非黑色素瘤皮肤癌形成的能力。 最后，我们将使用在免疫缺陷小鼠上生长的人类皮肤异种移植物来确定 IGF-1R 对表皮角质形成细胞的抑制使角质形成细胞对 UVB 诱导的光化性肿瘤的发展敏感。 这些研究将通过建立针对皮肤伤口的新型抗癌作用，对 NMSC 的治疗产生重大影响。 此外，这些研究的数据将证实定义与年龄相关的皮肤癌机制的新范式。