Role of senescent fibroblasts in UVB-induced carcinogenesis

描述（由申请人提供）：美国癌症协会估计，2005年有超过一百万新患者被诊断患有皮肤癌，占当年美国发生的所有浸润性和原位癌症的40%。 这些统计数据的数量表明，在美国，皮肤癌的治疗对患者和我们的医疗保健系统来说都是一个重大问题。 结论性证据表明，发生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）。 虽然皮肤癌可以发生在任何年龄，但皮肤癌的发展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，年龄是皮肤癌发生的第二个风险因素。 虽然老化表皮和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-1 R）信号网络的改变。 使用体外生长的正常人角质形成细胞，活化的IGF-1 Rs保护角质形成细胞免受UVB诱导的细胞凋亡;然而，当UVB照射的角质形成细胞与活化的IGF-1 Rs存活时，它们不能进一步细胞复制，事实上它们是衰老的。 然而，至关重要的观察是，在IGF-1 R活化的情况下，角质形成细胞对UVB诱导的细胞凋亡更敏感，但存活的角质形成细胞保留增殖的能力。 在皮肤中，角质形成细胞表达IGF-1 R，但它们不合成IGF-1。 真皮成纤维细胞通过分泌IGF-1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老化（或衰老），它们产生IGF-1的能力严重降低;因此，在老化的皮肤中，角质形成细胞提供的IGF-1供应减少。 本提案中待检验的假设是，由于成纤维细胞功能缺陷导致的IGF-1 R活化减少可能是老年人中观察到的非黑色素瘤皮肤癌急剧增加的重要因素。 通过使用体外三维皮肤器官培养，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（和其他遗传毒性损伤）可能导致的机制提供重要见解。 因此，不仅为角质形成细胞而且为潜在的其他上皮来源的癌症提供了新的药理学策略的动力。 公共卫生相关性：本提案中描述的实验旨在进一步扩大我们对IGF-1和IGF-1 R在完整皮肤模型系统中UV照射后的作用的理解。 从这些研究中获得的信息将使我们能够更好地设计实验，定义体内紫外线照射和皮肤致癌作用，并可能创造治疗方法，以防止非黑色素瘤皮肤癌的发生。

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.