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

IGF-1 与非黑色素瘤皮肤癌的发生

• 批准号: 8967172
• 负责人: Jeffrey B. Travers
• 金额: --
• 依托单位: DAYTON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967172
• 关键词: Actinic keratosis; Acute; Affect; Age; Aging; Apoptosis; Area; Award; Cancerous; Cell Survival; Chronic; Clinical; Clinical Research; DNA; DNA Damage; DNA Sequence Alteration; Data; Dermabrasion; Dermal; Dermis; Development; Disease; Effectiveness; Elderly; Ensure; Environmental Risk Factor; Epidermis; Experimental Models; Exposure to; Fibroblasts; Forearm; Goals; Health; Healthcare; Healthcare Systems; Heating; Human; Immunodeficient Mouse; In Vitro; Incidence; Individual; Injection of therapeutic agent; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Intervention; Lasers; Link; Malignant Neoplasms; Mediating; Modality; Molecular; Morbidity - disease rate; Mutation; Neoplasms; Organ Transplantation; Patients; Play; Population; Predisposition; Premalignant; Process; Production; Proliferating; Proteins; Publishing; Radiation; Receptor Signaling; Recombinant IGF-I; Resources; Risk; Risk Factors; Role; Skin; Skin Aging; Skin Cancer; Skin Carcinoma; Solid; Source; Stress; Sun Exposure; Sunlight; Sunscreening Agents; Survival Rate; TP53 gene; Testing; The Sun; Time; Transplantation; UVB induced; Ultraviolet B Radiation; United States; Veterans; Xenograft procedure; age effect; aged; design; human subject; in vivo; inhibitor/antagonist; intradermal injection; irradiation; keratinocyte; mortality; neoplastic; novel; prevent; repaired; research study; response; senescence; skin disorder; skin xenograft; sun protection; tumor; ultraviolet

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.

描述（由申请人提供）： 这些临床研究的主要目的是确定胰岛素样生长因子1（IGF-1）在非黑色素瘤皮肤癌（NMSC）启动中的作用。结论性证据表明，发展活化性肿瘤（NMSC和癌性光化性角膜结构）的主要环境风险因素是暴露于紫外线波长。 随着年龄的增长，NMSC的发生率急剧增加，在60岁以上的个体中最为普遍。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与衰老相关的活化性肿瘤。 IGF-1蛋白的成纤维细胞产生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UVB损坏的角质形成细胞到无法完全修复其DNA的程度。如果IGF-1水平不足（如“老化”皮肤），则这些具有损坏DNA的角质形成细胞无法变得衰老，因此可以复制。这种对UVB的异常反应导致形成随着DNA损伤增殖的角裂叶子。 （主要是UVB）在阳光下发现。我们的假设是，这代表了角质形成细胞种群的机制，这种新的范式是，该应用程序中提出的数据支持UVB如何诱导阳光症，并有助于解释为什么皮肤癌主要在老年人中发现。此外，这种新的范式还解释了先前研究的结果，表明防晒霜/防晒量减少了阳光肿瘤的数量。我们正在进行的研究表明，用分级激光重塑或非燃烧性激光器的皮肤损伤可以通过增加成纤维细胞IGF-1的量来扭转衰老的影响，从而产生“正常”的UVB反应。提出的三个特定目标旨在提供IGF-1R信号传导与UVB介导的启动致癌角质形成细胞的产生之间的直接联系。第一个目的是研究测试IGF-1R抑制剂增强慢性UVB处理能力的能力，诱导启动角质形成细胞和使用人类皮肤移植到免疫缺陷小鼠上的人皮肤肿瘤。第二个目的将测试多种UVB处理对年轻局部区域的相对有效性，而年轻患者的皮肤癌中发生的局部区域。 老年沃尔前臂皮肤会产生最早的阳光肿瘤分子的变化，包括p53突变。 IGF-1的局部注射将用于抑制老年受试者中的这一过程。第三个目的将测试分离激光重霉素或非燃烧性激光处理的能力，以保护老年沃尔前臂皮肤，以防止这些慢性UVB介导的阳性性肿瘤变化。这些研究不仅会证实IGF-1R信号在活化性肿瘤发展中发挥作用的关键作用，而且还为涉及激光介导的皮肤损伤的新型干预措施提供了动力，以防止UVB介导的角质形成细胞启动。由于活化性肿瘤是退伍军人最常见的皮肤疾病，因此这些研究对退伍军人的医疗保健具有巨大的意义。