The Aging Cutaneous Microenvironment and Cancer Initiation

老化的皮肤微环境与癌症发生

• 批准号: 10490433
• 负责人: ANDRZEJ A. DLUGOSZ
• 金额: $ 43.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490433
• 关键词: Accounting; Address; Age; Aging; American; COL1A2 gene; Carcinoma; Cell Culture Techniques; Cutaneous; Dermal; Dermis; Development; Diagnosis; Disease; Elderly; Epithelial; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Funding Opportunities; Gene Deletion; Genetically Engineered Mouse; Goals; Growth Factor; HGF gene; Human; Incidence; Individual; Inflammatory; Intervention; Link; Malignant Neoplasms; Modeling; Molecular; Mus; Mutation; Names; National Cancer Institute; National Institute on Aging; Pathway interactions; Peptide Hydrolases; Persons; Phenotype; Physiological; Production; Proteins; Publishing; Skin; Skin Aging; Skin Cancer; Skin Carcinogenesis; Skin Neoplasms; Source; TP53 gene; Testing; Tissues; age related; aged; autocrine; base; cancer initiation; cancer prevention; cancer type; cytokine; driver mutation; keratinocyte; mouse model; notch protein; novel; novel therapeutic intervention; paracrine; secretory protein; senescence; tool; tumor initiation; tumorigenesis

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.

抽象的 癌症显然是一种衰老疾病。衰老与癌症发病率之间的联系尤其重要 对于皮肤癌来说确实如此，皮肤癌是人类癌症中最常见的形式，占更多 比美国所有其他癌症的总和还要多。该应用程序的主要目的是获得理解 将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。 该应用基于我们的发现，即老年人类皮肤中的成纤维细胞表达水平升高的 称为 CCN1 的基质细胞蛋白，升高的 CCN1 会有害地改变真皮 皮肤隔室创造一个促进癌症发生的微环境。基于这些 根据观察，我们创造了选择性表达升高水平的 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）。这些小鼠表现出惊人的 加速真皮老化并表现出人类皮肤中常见的多种老化特征。重要的是， 真皮中 CCN1 表达水平升高的小鼠也有很高的皮肤肿瘤倾向 引发。这些结果为本申请的总体假设提供了直接支持；那个年纪—— 由 CCN1 成纤维细胞表达驱动的真皮微环境的相关变化，产生了真皮 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个假设 具体目标如下。目标 1：确定 CCN1 诱导的加速真皮老化对皮肤的影响 角质形成细胞癌的发生。目标 2：检验肝细胞生长因子激活的假设 CCN1 诱导的真皮衰老微环境的通路驱动角质形成细胞癌的发生。目的 3：利用靶向基因删除，测试真皮成纤维细胞对CCN1表达的要求 与衰老相关的真皮微环境的发展和角质形成细胞癌的发生。目标 该提案的内容直接涉及国家癌症研究所/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变化的机制 细胞生态位/微环境有助于癌症的发生。