The Aging Cutaneous Microenvironment and Cancer Initiation

摘要 癌症显然是一种老年病。老龄化和癌症发病率之间的这种联系尤其是 皮肤癌是人类最常见的癌症形式，在人类癌症中所占比例更高 比美国所有其他癌症的总和还要多。这个应用程序的主要目标是了解 将与年龄相关的皮肤变化与皮肤癌的发生联系起来的细胞和分子机制的研究。 这一应用是基于我们的发现，即老年人皮肤中的成纤维细胞表达高水平的a 一种名为CCN1的基质细胞蛋白，这种升高的CCN1会有害地改变皮肤 皮肤隔膜，以创造一个微环境，促进癌症的发生。基于这些 据观察，我们已经创造了选择性表达高水平CCN1的转基因小鼠 真皮成纤维细胞(老年人皮肤中CCN1升高的来源)。这些老鼠展示了惊人的 加速皮肤衰老，并显示出人类皮肤中的多种衰老特征。重要的是 在真皮中表达CCN1水平升高的小鼠也有很高的皮肤肿瘤倾向 入会仪式。这些结果直接支持了这一应用的总体假设；即年龄- 在成纤维细胞表达CCN1的推动下，真皮微环境的相关变化创造了真皮 促进角质形成细胞癌发生的微环境。我们建议用以下方法来检验这一假设 以下是具体目标。目的1：明确CCN1诱导的皮肤加速衰老对皮肤的影响 角质形成细胞癌的发生。目的2：验证肝细胞生长因子激活的假设 CCN1诱导的皮肤衰老微环境途径驱动角质形成细胞癌的发生。目标 3：利用靶向基因缺失，检测真皮成纤维细胞对CCN1表达的需求 与衰老相关的皮肤微环境的发展和角质形成细胞癌的发生。目标 该提案直接涉及国家癌症研究所/国家老龄研究所的目标 宣布资助机会以了解与年龄相关的改变在 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.