The Aging Cutaneous Microenvironment and Cancer Initiation

摘要 癌症显然是一种衰老疾病。衰老和癌症发病率之间的这种联系尤其重要。 皮肤癌是人类癌症中最常见的一种， 比美国所有其他癌症加起来还要多本申请的主要目的是了解 细胞和分子机制，将年龄相关的皮肤变化与皮肤癌的发生联系起来。 该应用基于我们的发现，即老年人皮肤中的成纤维细胞表达升高水平的 一种名为CCN 1的基质细胞蛋白，CCN 1的升高会导致皮肤 皮肤的一个区室，以创造一个微环境，增强癌症的启动。基于这些 通过观察，我们创造了转基因小鼠，选择性地表达高水平的CCN 1 在真皮成纤维细胞中（老年人皮肤中CCN 1升高的来源）。这些老鼠表现出惊人的 加速皮肤老化，并显示出在人类皮肤中看到的多种老化标志。重要的是， 在真皮中表达升高水平的CCN 1的小鼠也具有皮肤肿瘤的高倾向性 入会仪式这些结果为本申请的总体假设提供了直接支持;年龄- 由成纤维细胞表达CCN 1驱动的真皮微环境的相关变化， 微环境，增强角质形成细胞癌的启动。我们建议用以下方法来检验这一假设： 以下具体目标。目的1：确定CCN 1诱导的加速皮肤老化对 角化细胞癌的发生。目的2：验证肝细胞生长因子的激活 通过CCN 1诱导的皮肤老化微环境的信号通路驱动角质形成细胞癌的发生。目的 3：使用靶向基因缺失，测试CCN 1在真皮成纤维细胞中表达的需要， 老化相关的皮肤微环境的发展和角质形成细胞癌的发生。目标 该提案的目的是直接解决国家癌症研究所/国家老龄化研究所的目标 资助机会公告，以了解与年龄相关的改变的机制， 细胞生态位/微环境有助于癌症的发生。

ABSTRACT Cancer is clearly a disease of aging. This connection between aging and cancer incidence is especially true in the case of skin cancer, which is the most common form of human cancer, accounting for more than all other cancers combined in USA. The major objective of this application is to gain understanding of cellular and molecular mechanisms that link age-related skin changes to the initiation of skin cancer. This application is based on our findings that fibroblasts in aged human skin express elevated levels of a matricellular protein named CCN1, and that elevated CCN1 acts to deleteriously alter the dermal compartment of skin to create a microenvironment that enhances cancer initiation. Based on these observations, we have created genetically modified mice that express elevated levels of CCN1 selectively in dermal fibroblasts (source of elevated CCN1 in aged human skin). These mice exhibit strikingly accelerated dermal aging and display multiple hallmarks of aging that are seen in human skin. Importantly, mice that express elevated levels of CCN1 in the dermis also have a high propensity for skin tumor initiation. These results provide direct support for the overarching hypothesis of this application; that age- related changes in the dermal microenvironment, driven by fibroblast expression of CCN1, create a dermal microenvironment that enhances initiation of keratinocyte cancer. We propose to test this hypothesis with the following specific aims. Aim 1: define the impact of CCN1-induced accelerated dermal aging on keratinocyte cancer initiation. Aim 2: test the hypothesis that activation of the hepatocyte growth factor pathway by the CCN1-induced dermal aging microenvironment drives keratinocyte cancer initiation. Aim 3: using targeted gene deletion, test the requirement for CCN1 expression in dermal fibroblasts for the development of an aging-related dermal microenvironment and initiation of keratinocyte cancer. The aims of this proposal directly address the objectives of the National Cancer Institute/National Aging Institute Funding Opportunity Announcement to understand mechanisms by which age-related alterations in the cellular niche/microenvironment contribute to cancer initiation.