Wounding therapy and photocarcinogenesis

创伤治疗和光致癌

• 批准号: 9185418
• 负责人: DAN F SPANDAU
• 金额: $ 31.02万
• 依托单位: WRIGHT STATE UNIVERSITY
• 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/9185418
• 关键词: Wounding; therapy; photocarcinogenesis

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(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，80%的非黑色素瘤皮肤癌患者被诊断为60岁以上的患者就是明证。因此，老年皮肤对诱发癌症的UVB辐射的反应方式是允许建立肿瘤细胞。虽然老年表皮与皮肤癌之间的相关性是显而易见的，但导致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。利用体外培养的正常人角质形成细胞，激活的IGF-1Rs保护角质形成细胞免受UVB诱导的细胞凋亡；然而，在UVB照射下，具有激活的IGF-1Rs的角质形成细胞存活下来，它们不能进一步的细胞复制，事实上它们已经衰老。关键的观察结果是，在没有IGF-1R激活的情况下，角质形成细胞对UVB诱导的凋亡更敏感，但存活的角质形成细胞保留了增殖的能力。在皮肤中，角质形成细胞表达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，在衰老的皮肤中，角质形成细胞的IGF-1供应减少，IGF-1R的激活也随之减少。我们已经证明，老年皮肤对UVB辐射的反应方式可能导致启动致癌角质形成细胞。这种不适当的UVB反应可以通过外源性IGF-1治疗来纠正。此外，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，我们将使用非消融性皮肤嫩肤疗法将IGF-1在暴露在阳光下的老年皮肤上的表达恢复到年轻人皮肤中的水平，并确定这些疗法是否能恢复适当的UVB反应。此外，我们将测试非消融性皮肤年轻化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，我们将使用生长在免疫缺陷小鼠身上的人皮肤异种移植来建立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一种新的皮肤损伤的抗癌作用，对NMSC的治疗产生重大影响。此外，这些研究的数据将证实一种定义年龄相关性皮肤癌机制的新范式。