IGF-1 and the initiation of non-melanoma skin cancer

描述（由申请人提供）： 这些临床研究的主要目标是确定胰岛素样生长因子-1（IGF-1）在非黑色素瘤皮肤癌（NMSC）发生中的作用。结论性证据表明，发生光化性肿瘤（NMSC和癌前光化性角化病）的主要环境风险因素是暴露于紫外线波长。 NMSC的发病率随着年龄的增长而急剧增加，在60岁以上的个体中变得最常见。我们小组和其他人正在进行的研究发现，皮肤成纤维细胞参与了与衰老相关的光化性肿瘤的增加。成纤维细胞产生的IGF-1蛋白似乎决定了角质形成细胞对UVB的反应。如果存在足够的IGF-1（如在年轻的皮肤中），则被UVB损伤到其DNA不能完全修复的角化细胞会衰老。如果IGF-1水平不足（如在“老化”皮肤中），则这些DNA受损的角质形成细胞无法衰老，从而允许复制。这种对UVB的异常反应导致角质形成细胞增殖，DNA损伤。（主要是UVB）在阳光下发现。我们的假设是，这代表了负责角质形成细胞群体的机制。UVB如何诱导光化性瘤形成的新范例得到了本申请中提供的数据的支持，并有助于解释为什么皮肤癌主要发生在老年人中。此外，这种新的范式也解释了以前的研究结果，表明防晒霜/防晒霜可以减少光化性肿瘤的数量。我们正在进行的研究表明，皮肤创伤与分次激光换肤或非烧蚀激光可以逆转老化的影响，通过增加成纤维细胞IGF-1的量，导致一个“正常”的UVB反应。提出的三个具体目标旨在提供IGF-1 R信号传导和UVB介导的致癌角质形成细胞的产生之间的直接联系。第一个目标是使用移植到免疫缺陷小鼠的人皮肤，测试IGF-1 R抑制剂增强慢性UVB治疗诱导起始角质形成细胞和光化性瘤形成的能力。第二个目标将测试多种UVB治疗对年轻人局部区域的相对有效性，以及对老年患者皮肤癌的相对有效性。 老年人前臂掌侧皮肤产生最早的光化性肿瘤分子改变，包括p53突变。IGF-1的局部注射将用于抑制老年受试者的这一过程。第三个目标将测试分次激光表面置换或非烧蚀性激光治疗保护老年人前臂掌侧皮肤免受这些慢性UVB介导的光化性肿瘤变化的能力。这些研究不仅证实了IGF-1 R信号在光化性瘤形成中的关键作用，还为涉及激光介导的皮肤损伤以防止UVB介导的角质形成细胞启动的新型干预措施提供了动力。由于光化性肿瘤是退伍军人最常见的皮肤疾病，这些研究对退伍军人的健康护理有巨大的意义。

DESCRIPTION (provided by applicant): The primary goal of these clinical research studies is to define the role of insulin-like growth factor-1 (IGF-1) in the initiation of non-melanoma skin cancer (NMSC). Conclusive evidence has demonstrated that the major environmental risk factor for developing actinic neoplasia (NMSC and pre-cancerous actinic keratoses) is exposure to the ultraviolet wavelengths. The incidence of NMSC increases dramatically with increasing age, becoming most common in individuals over 60 years old. Ongoing studies by our group and others have discovered the involvement of dermal fibroblasts in the increased actinic neoplasia associated with aging. Fibroblast production of the IGF-1 protein appears to dictate how keratinocytes respond to UVB. If sufficient IGF-1 is present (as in young skin), keratinocytes damaged by UVB to the point where their DNA cannot be fully repaired become senescent. If IGF-1 levels are not adequate (as in "aged" skin), then these keratinocytes with damaged DNA fail to become senescent and are thus allowed to replicate. This abnormal response to UVB results in the formation of keratino-cytes proliferating with DNA damage. (primarily UVB) found in sunlight. Our hypothesis is that this represents the mechanism responsible for the population of keratinocytes This new paradigm of how UVB induces actinic neoplasia is supported by data presented in this application, and help explains why skin cancers are predominantly found in older individuals. Moreover, this new paradigm also explains results of previous studies indicating that sunscreen/sun protection decreases the numbers of actinic neoplasia. Our ongoing studies demonstrate that dermal wounding with fractionated laser resurfacing or non-ablative laser can reverse the effects of aging by increasing the amounts of fibroblast IGF-1, resulting in a "normal" UVB response. The three specific aims proposed are designed to provide a direct link between IGF-1R signaling and UVB-mediated production of initiated carcinogenic keratinocytes. The first aim consists of studies testing the ability of an IGF-1R inhibitor to augment the abilityof chronic UVB treatments to induce initiated keratinocytes and actinic neoplasia using human skin transplanted onto immunodeficient mice. The second aim will test the relative effectiveness of multiple UVB treatments on localized areas of young versus that eventuate in skin cancers in geriatric patients. geriatric volar forearm skin to create the earliest actinic neoplastic moleculr changes including p53 mutations. Localized injections of IGF-1 will be used to inhibit this process in geriatric subjects. The third aim will test the ability of fractionated laser resurfacin or non-ablative laser treatments to protect geriatric volar forearm skin against these chronic UVB-mediated actinic neoplastic changes. These studies will not only confirm the critical role that IGF-1R signaling plays in the development of actinic neoplasia, they provide the impetus for novel interventions involving laser-mediated dermal wounding to protect against UVB-mediated keratinocyte initiation. Since actinic neoplasia is the most common skin disorder of veterans, these studies have tremendous significance for veteran's health care.