Wounding therapy and photocarcinogenesis

描述（由申请人提供）：非黑色素瘤皮肤癌是一种主要折磨老年患者的疾病，80%的非黑色素瘤皮肤癌在60岁以上的患者中被诊断出来。因此，老年皮肤对诱导癌症的UVB照射的反应方式允许肿瘤细胞的建立。虽然衰老的表皮和皮肤癌之间的相关性是明显的，但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-1Rs保护角质形成细胞免受uvb诱导的凋亡；然而，虽然uvb照射下具有活化IGF-1Rs的角质形成细胞存活，但它们无法进一步进行细胞复制，实际上它们是衰老的。至关重要的观察结果是，在缺乏IGF-1R激活的情况下，角质形成细胞对uvb诱导的凋亡更敏感，但存活下来的角质形成细胞保留了增殖能力。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老化，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，同时IGF-1R激活减少。我们已经证明，老年皮肤对UVB照射的反应方式可能导致致癌角质形成细胞的启动。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，用烧蚀性皮肤年轻化疗法治疗老年皮肤可以重新建立年轻的IGF-1水平，并随后在防晒皮肤上恢复适当的UVB反应。在这项建议中，我们将使用非消融性皮肤年轻化疗法将暴露在阳光下的老年人皮肤上的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，我们将测试非烧蚀性皮肤年轻化疗法防止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类皮肤异种移植物来证实抑制表皮角质形成细胞的IGF-1R会使角质形成细胞对uvb诱导的光化性肿瘤的发展变得敏感。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，来自这些研究的数据将证实一个新的范式来定义与年龄相关的皮肤癌的机制。

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.