Wounding Therapy and Photocarcinogenesis

摘要 非黑色素瘤皮肤癌（NMSC）是一种主要困扰老年患者的疾病， 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，在本发明中， 老年人皮肤对致癌紫外线B（UVB）照射的反应方式是， 建立肿瘤细胞。虽然老化表皮与皮肤癌之间的相关性很明显， 负责这种关系的机制仍然不清楚。最近的体外证据以及 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的改变， 因子-1受体（IGF-1 R）信号网络。使用体外培养的正常人角质形成细胞， 1 Rs保护角质形成细胞免受UVB诱导的凋亡;然而， 当激活的IGF-1 R存活时，它们不能进一步细胞复制，事实上它们是衰老的。的 至关重要的观察结果是，在缺乏IGF-1 R活化的情况下，角质形成细胞更敏感， UVB诱导的细胞凋亡，但存活的角质形成细胞保留增殖的能力。在皮肤上， 角质形成细胞表达IGF-1 R，但它们不合成IGF-1。真皮成纤维细胞支持增殖 角质形成细胞分泌IGF-1。有趣的是，随着皮肤成纤维细胞的老化，它们的能力， 产生IGF-1严重减少;因此，在老年皮肤角质形成细胞提供了减少的供应 IGF-1和IGF-1 R活化的伴随减少。我们已经证明，老年皮肤反应， UVB照射的方式，可能会导致启动致癌角质形成细胞。这种不适当的UVB 可以通过用外源性IGF-1治疗来纠正这种反应。此外，我们还表明， 老年皮肤的非消融性皮肤再生疗法可以重新建立年轻的IGF-1水平， 随后在老年皮肤上恢复适当的UVB反应。此外，我们已经证明了这一点， 对急性UVB暴露的保护可持续长达两年。在这一建议中，我们将继续并扩大 我们正在进行的关于非烧蚀性创伤治疗的预防作用的临床试验， 防止UVB引起的皮肤癌。特别是，我们将为这些研究招募绝经后女性， 这是一个皮肤癌研究的不足人群。一种新型无创介观成像平台 将用于监测光化性肿瘤进展。此外，我们将审查负责的机制 非烧蚀性创伤治疗增加成纤维细胞相关IGF-1表达的能力。这些 研究将通过建立一种新的抗癌作用对NMSC的治疗产生重大影响， 皮肤创伤此外，这些研究的数据将证实一种新的范式， 年龄相关性皮肤癌的发病机制。这些研究的结果包括新的治疗策略， 以及非侵入性成像平台，用于监测高危人群中的现场致癌作用。

ABSTRACT Non-melanoma skin cancer (NMSC) 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 ultraviolet B (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 non-ablative dermal rejuvenation therapies can re-establish youthful IGF-1 levels and subsequently reinstate the appropriate UVB response on geriatric skin. Moreover, we have demonstrated this protection to acute UVB exposure is durable for up to two years. In this proposal, we will continue and expand our ongoing clinical trials on the prophylactic effect of non-ablative wounding therapies to both treat and prevent UVB-induced skin cancer. In particular, we will recruit post-menopausal females for these studies as this is an underserved population for skin cancer studies. A novel non-invasive mesoscopic imaging platform will be used to monitor actinic neoplasia progression. In addition, we will examine the mechanisms responsible for the ability of non-ablative wounding therapies to increase fibroblast-associated IGF-1 expression. 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. Outcomes for these studies include novel therapeutic strategies as well as non-invasive imaging platforms to monitor field carcinogenesis in at risk-populations.