Impact of age-related changes of the dermal extracellular matrix on skin cancer

真皮细胞外基质与年龄相关的变化对皮肤癌的影响

• 批准号: 9233494
• 负责人: GARY J FISHER
• 金额: $ 7.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233494
• 关键词: Age; Aging; American; Applications Grants; Architecture; Attention; Binding; Biochemical; Carcinoma; Collagen; Collagen Fibril; Connective Tissue; Cutaneous Melanoma; Data; Dermal; Dermis; Development; Diagnosis; Disease; Elderly; Epithelial; Epithelium; Extracellular Matrix; Fibroblasts; Genes; Goals; Healthcare Systems; Histologic; Homeostasis; Human; Incidence; Individual; Inflammaging; Inflammatory; Malignant Neoplasms; Morbidity - disease rate; Mus; Mutation; Neoplasm Metastasis; Normal tissue morphology; Oncogenes; Phenotype; Protein Family; Proteins; Protocols documentation; Quality of life; Risk Factors; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Skin Neoplasms; Source; Structure; Testing; Therapeutic Intervention; Thinness; Transgenic Mice; age related; aged; base; cancer prevention; carcinogenesis; cell type; collagenase; cost; cytokine; in vivo; keratinocyte; member; mouse model; novel; promoter; ras Oncogene; resilience; senescence; targeted treatment; tumor; tumor progression

The major goal of this grant application is to test a novel hypothesis that age-related changes in the dermal extracellular matrix (ECM) microenvironment promote skin cancer development. Cancer is a disease of aging. For example, keratinocyte skin cancer, the most common form of human cancer, rarely occurs in individuals under the age of 40, but very common in the elderly. The importance of stromal connective tissue microenvironment in epithelial cancer is receiving increased recognition. However, the concept that natural aging brings about changes in the ECM microenvironment that promote cancer development has received little attention. In human skin, dermal fibroblasts are responsible for homeostasis of the collagenous ECM, which comprises the bulk of skin. Our recent studies reveal that aged dermal fibroblasts in vivo, express elevated levels of a protein called CCN1 (first member of CCN family proteins), which is secreted and binds to the dermal ECM. We find that elevated CCN1 up-regulates numerous proteins related to senescence-associate secretory phenotype (SASP), and thus promotes dermal connective tissue aging. These alterations include: 1) reduced levels of collagens, which causes dermal thinning; 2) elevated levels of multiple collagen-degrading enzymes, which cause increased fragmentation of ECM; and 3) increased levels of multiple pro-inflammatory cytokines, which contributes to dermal inflammaging. Importantly, all of these CCN1-indced alterations are readily observed in aged human skin in vivo. Based on these considerations, we have created a transgenic mouse model that expresses CCN1 under control of a fibroblast-specific promoter, the source of elevated CCN1 in aged human skin (col-CCN1TG). These mice display alterations of the dermal ECM microenvironment by secretion of SASP-related genes. In the transgenic mice, skin is thin, finely wrinkled, and collagen fibrils are fragmented and disorganized, as observed in aged human skin. Importantly, these mice display a high propensity for skin tumor formation elicited by two- stage carcinogenesis protocol. Based on these data, we hypothesize that age-associated dermal ECM microenvironment promotes epithelial tumor development. This application will test the above hypothesis using a novel cell-type-specific double-transgenic mouse model, in which the epidermal oncogene Ras is specifically expressed in the skin epithelium and aged-associated dermal ECM microenvironment is generated by fibroblast-specific expression of CCN1. The proposed studies will directly investigate the novel concept that age-associated dermal ECM microenvironment promotes skin cancer development in cooperation with epithelial oncogene, and thus may have profound impact on the field of cancer prevention/treatment in the aged by identifying age-associated dermal microenvironment as a key target for therapeutic intervention.

这项拨款申请的主要目标是测试一个新的假设，即真皮层中与年龄相关的变化 细胞外基质（ECM）微环境促进皮肤癌的发展。癌症是一种衰老疾病。 例如，角化细胞皮肤癌是人类癌症最常见的形式，但很少发生在个体中 40岁以下，但在老年人中很常见。 间质结缔组织微环境在上皮癌中的重要性日益增加 认出。然而，自然衰老带来ECM微环境变化的概念 促进癌症发展却很少受到关注。在人体皮肤中，真皮成纤维细胞负责 构成皮肤大部分的胶原 ECM 的稳态。我们最近的研究表明，老年人 体内真皮成纤维细胞表达 CCN1 蛋白（CCN 家族的第一个成员）水平升高 蛋白质），它被分泌并与真皮 ECM 结合。我们发现 CCN1 升高会上调许多 与衰老相关分泌表型 (SASP) 相关的蛋白质，从而促进真皮结缔组织 组织老化。这些改变包括：1）胶原蛋白水平降低，导致真皮变薄； 2） 多种胶原蛋白降解酶水平升高，导致 ECM 碎片增加；和 3) 多种促炎细胞因子水平升高，导致皮肤炎症。重要的是， 所有这些 CCN1 引起的改变都很容易在体内衰老的人类皮肤中观察到。 基于这些考虑，我们创建了表达CCN1的转基因小鼠模型 成纤维细胞特异性启动子的控制，是衰老人类皮肤中 CCN1 升高的来源 (col-CCN1TG)。这些 小鼠通过分泌 SASP 相关基因显示出真皮 ECM 微环境的改变。在 据观察，转基因小鼠的皮肤很薄，有细小的皱纹，胶原纤维破碎且杂乱 在老化的人类皮肤中。重要的是，这些小鼠表现出由两种因素引起的皮肤肿瘤形成的高倾向： 阶段致癌协议。根据这些数据，我们假设与年龄相关的真皮 ECM 微环境促进上皮性肿瘤的发展。 该应用程序将使用新型细胞类型特异性双转基因小鼠模型来测试上述假设， 其中表皮癌基因 Ras 在皮肤上皮中特异性表达，与衰老相关 真皮 ECM 微环境是由成纤维细胞特异性表达 CCN1 产生的。拟议的研究 将直接研究与年龄相关的真皮 ECM 微环境促进皮肤的新概念 癌症的发展与上皮癌基因合作，因此可能对该领域产生深远的影响 通过确定与年龄相关的真皮微环境作为关键来预防/治疗老年人的癌症 治疗干预的目标。