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。确凿的证据表明，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在紫外线波长下。NMSC的发病率随着年龄的增长而急剧增加，在60岁以上的人中最为常见。我们小组和其他人正在进行的研究发现，真皮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。如果有足够的IGF-1存在(就像在年轻的皮肤中一样)，角质形成细胞被紫外线破坏到DNA无法完全修复的程度就会衰老。如果IGF-1水平不够高(如“老化的”皮肤)，那么这些DNA受损的角质形成细胞不会衰老，因此允许复制。这种对UVB的异常反应导致角化细胞的形成，并伴随着DNA损伤而增殖。(主要是UVB)发现于阳光下。我们的假设是，这代表了角质形成细胞数量的机制这一关于UVB如何诱导光化性肿瘤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在老年人中发现。此外，这一新的范式还解释了先前研究的结果，即防晒霜/防晒霜减少了光化性肿瘤的数量。我们正在进行的研究表明，分次激光表面重铺或非消融性激光皮肤损伤可以通过增加成纤维细胞IGF-1的数量来逆转老化的影响，从而导致“正常”的UVB反应。提出的三个特定目的是为了在IGF-1R信号和UVB介导的启动致癌角质形成细胞的产生之间提供直接联系。第一个目标是通过将人皮肤移植到免疫缺陷小鼠身上，测试IGF-1R抑制剂的能力，以增强慢性UVB治疗诱导启动的角质形成细胞和光化性肿瘤的能力。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，以及老年患者皮肤癌的最终疗效。老年人前臂掌侧皮肤产生最早的光化性肿瘤分子变化，包括P53突变。在老年受试者中，局部注射IGF-1将用于抑制这一过程。第三个目标将测试分次激光表面重建或非消融性激光治疗的能力，以保护老年前臂掌侧皮肤免受这些由UVB介导的慢性光化性肿瘤变化的影响。这些研究不仅将证实IGF-1R信号在光化性肿瘤发生发展中的关键作用，还将为采用激光介导的真皮损伤以防止UVB介导的角质形成细胞启动的新型干预措施提供动力。由于光化性肿瘤是退伍军人最常见的皮肤病，这些研究对退伍军人的医疗保健具有巨大的意义。

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.