Role of senescent fibroblasts in UVB-induced carcinogenesis

衰老成纤维细胞在 UVB 诱导的癌发生中的作用

• 批准号: 7753681
• 负责人: DAN F SPANDAU
• 金额: $ 16.75万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753681
• 关键词: Acute; Adherent Culture; Age; Aging; American Cancer Society; Apoptosis; Biological Models; Carcinoma in Situ; Cell Survival; Chronic; Cutaneous; DNA Damage; Data; Dermal; Dermis; Development; Diagnosis; Elderly; Environmental Risk Factor; Epidemiology; Epidermis; Epithelial; Exposure to; Fibroblasts; Figs - dietary; Goals; Healthcare Systems; Human; In Vitro; Individual; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Ligands; Light; Malignant Neoplasms; Mutation; Oncogenic; Organ Culture Techniques; Patients; Production; Proliferating; Risk Factors; Role; Signal Pathway; Signal Transduction; Skin; Skin Aging; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Stress; Sunlight; Survival Rate; Testing; Therapeutic; Time; Tissues; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; United States; aged; carcinogenesis; design; in vitro Model; in vivo; insight; irradiation; keratinocyte; novel; prevent; public health relevance; repaired; research study; response; senescence; statistics; ultraviolet; ultraviolet irradiation; young adult

DESCRIPTION (provided by applicant): The American Cancer Society estimates over one million new patients were diagnosed with skin cancer in 2005, representing 40% of all invasive and in situ cancers that occurred in the United States that year. The magnitude of these statistics suggests that the treatment of skin cancer in the United States is a significant problem for patients as well as our healthcare system. Conclusive evidence has demonstrated that the main environmental risk factor for developing skin cancer is exposure to ultraviolet wavelengths of light (UVB) found in sunlight. Although skin cancer can occur at any age, there is a strong correlation between the development of skin cancer and advancing age. In fact, the majority of skin cancers are found in people over the age of 60; therefore, age is a second risk factor for the development of skin cancer. 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. However, 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 (or senesce), their capacity to produce IGF-1 is severely diminished; therefore, in aged skin keratinocytes are provided with a reduced supply of IGF-1. The hypothesis to be tested in this proposal is that the reduced activation of the IGF-1R due to deficient fibroblast function could be an important factor in the dramatic increase of non-melanoma skin cancer observed in geriatric individuals. Through the use of in vitro three-dimensional skin organ cultures, we will determine the importance of proper fibroblast function on the sensitivity of keratinocytes to UVB irradiation. These studies will provide important insights into the mechanism(s) by which UVB (and other genotoxic insults) can result in carcinogenesis, and thus provide impetus for novel pharmacological strategies not only for keratinocytes but potentially other epithelial-derived cancers. PUBLIC HEALTH RELEVANCE: The experiments described in this proposal are designed to further expand our understanding of the roles of IGF-1 and the IGF-1R following UV irradiation in an intact skin model system. The information derived from these studies will better enable us to design experiments defining UV irradiation and cutaneous carcinogenesis in vivo and potentially create therapeutic therapies to prevent the initiation of non-melanoma skin cancer.

描述（由申请人提供）：美国癌症协会估计，2005 年有超过 100 万新患者被诊断患有皮肤癌，占当年美国发生的所有侵袭性和原位癌症的 40%。 这些统计数据的规模表明，美国皮肤癌的治疗对于患者以及我们的医疗保健系统来说都是一个重大问题。 确凿的证据表明，患皮肤癌的主要环境风险因素是暴露于阳光中的紫外线波长 (UVB)。 尽管皮肤癌可以发生在任何年龄，但皮肤癌的发生与年龄增长之间存在很强的相关性。 事实上，大多数皮肤癌发生在 60 岁以上的人群中；因此，年龄是发生皮肤癌的第二个危险因素。 虽然老化表皮与皮肤癌之间的相关性是显而易见的，但造成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-1R 可保护角质形成细胞免受 UVB 诱导的细胞凋亡；然而，虽然受到 UVB 照射且具有激活的 IGF-1R 的角质形成细胞能够存活，但它们无法进一步进行细胞复制，事实上它们正在衰老。 然而，至关重要的观察结果是，在没有 IGF-1R 激活的情况下，角质形成细胞对 UVB 诱导的细胞凋亡更敏感，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老化（或衰老），它们产生 IGF-1 的能力严重减弱；因此，老化皮肤角质形成细胞中 IGF-1 的供应量减少。 该提案要检验的假设是，由于成纤维细胞功能缺陷而导致的 IGF-1R 激活减少可能是在老年人中观察到的非黑色素瘤皮肤癌急剧增加的一个重要因素。 通过使用体外三维皮肤器官培养物，我们将确定适当的成纤维细胞功能对角质形成细胞对 UVB 照射的敏感性的重要性。 这些研究将为 UVB（和其他基因毒性损伤）导致的机制提供重要见解。 致癌作用，从而为新的药理学策略提供动力，不仅针对角质形成细胞，而且可能针对其他上皮衍生癌症。 公共健康相关性：本提案中描述的实验旨在进一步扩大我们对完整皮肤模型系统中紫外线照射后 IGF-1 和 IGF-1R 作用的理解。 从这些研究中获得的信息将使我们能够更好地设计定义紫外线照射和体内皮肤癌发生的实验，并有可能创造出预防非黑色素瘤皮肤癌发生的治疗方法。