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; 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年被诊断出100万名新患者被诊断出患有皮肤癌，占当年在美国发生的所有侵入性和原位癌症的40％。 这些统计数据的规模表明，美国对患者以及我们的医疗保健系统的治疗是一个重要的问题。 结论性的证据表明，患皮肤癌的主要环境风险因素是暴露于阳光下发现的紫外线波长（UVB）。 尽管皮肤癌可以在任何年龄发生，但皮肤癌的发展与增长年龄之间存在很强的相关性。 实际上，大多数皮肤癌是在60岁以上的人中发现的。因此，年龄是皮肤癌发展的第二个危险因素。 尽管老年表皮和皮肤癌之间的相关性显而易见，但导致这种关系的机制仍然晦涩难懂。 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因子1受体（IGF-1R）信号网络的改变。 使用正常的人角质形成细胞在体外生长，活化的IGF-1R可保护角质形成细胞免受UVB诱导的细胞凋亡的影响。但是，尽管UVB辐照的角质形成细胞具有活化的IGF-1R，但它们无法进一步的细胞复制，实际上它们是衰老的。 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，但是确实可以存活的角质形成细胞保留了增殖的能力。 在皮肤中，角质形成细胞表达IGF-1R，但没有合成IGF-1。 皮肤成纤维细胞通过分泌IGF-1来支持表皮中角质形成细胞的增殖。 有趣的是，随着皮肤成纤维细胞的年龄（或SENESCE），它们产生IGF-1的能力大大降低了；因此，在老化的皮肤角质形成细胞中，IGF-1的供应减少了。 在该提案中要检验的假设是，由于缺乏成纤维细胞功能，IGF-1R的激活减少可能是在老年人个体中观察到的非黑色素瘤皮肤癌的重要因素。 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辐照的敏感性的重要性。 这些研究将提供有关UVB（和其他遗传毒性损伤）的机制的重要见解 致癌作用，因此为新颖的药理学策略提供了动力，不仅是角质形成细胞的，而且为其他上皮衍生的癌症提供了动力。 公共卫生相关性：本提案中描述的实验旨在进一步扩展我们对IGF-1和IGF-1R在完整皮肤模型系统中的作用的理解。 从这些研究中得出的信息将使我们能够设计实验，以定义体内紫外线照射和皮肤致癌作用，并有可能创建治疗疗法以防止启动非黑色素瘤皮肤癌。