Role of Cellular Senescence in Carcinogenesis

细胞衰老在癌变中的作用

• 批准号: 8526962
• 负责人: Fatouma Alimirah
• 金额: $ 5.39万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526962
• 关键词: Address; Adult; Affect; Age; Aging; Animals; Antineoplastic Agents; Apoptosis; Attenuated; CDKN2A gene; Cancer Etiology; Cell Aging; Cell Culture Techniques; Cell Cycle; Cells; Characteristics; Coupled; DNA; Development; Diet; Disease; Elderly; Embryo; Epigallocatechin Gallate; Evolution; Excision; Fibroblasts; Ganciclovir; Goals; Green tea; Growth Inhibitors; Herpesviridae; Inflammatory; Laboratories; Malignant Neoplasms; Modeling; Molecular; Mus; Normal Cell; Oncogenic; Organism; Pathology; Pathway interactions; Peptide Hydrolases; Phenotype; Proliferating; Property; Role; Signal Transduction; Skin Cancer; Skin Carcinogenesis; Staging; TK Gene; Testing; Therapeutic Agents; Tissues; Transgenic Mice; Tumor Suppressor Proteins; Wild Type Mouse; Xenograft procedure; age related; aged; carcinogenesis; cell growth; cell injury; cell killing; chemokine; chemotherapeutic agent; cytokine; design; in vivo; insight; killings; malignant phenotype; mouse model; normal aging; novel; nucleoside analog; polyphenol; prevent; promoter; public health relevance; research study; response; senescence; tumor; tumor progression

DESCRIPTION (provided by applicant): Most adult cancers increase with age. Cellular senescence, a potent tumor suppressive mechanism, is now believed to contribute to age-related pathologies. In aging tissues, the protective properties of cellular senescence are derailed: as senescent cells accumulate, they secrete pro-inflammatory cytokines, chemokines and proteases creating a pro-carcinogenic microenvironment. The senescence associated secretory phenotype (SASP) drives this deleterious characteristic of cellular senescence. A direct role for senescent cells in cancer development and progression in vivo during normal aging remains unexplored. Thus, the first goal of this proposal is to determine the effect of senescent cells on age related carcinogenesis. The second goal is to determine the effect of the polyphenol epigallocatechingallate (EGCG), a potent anti-cancer agent found in green tea on the SASP. To accomplish these goals, a novel transgenic mouse model, p16-3MR, designed to selectively eliminate senescent cells expressing the established cellular senescence marker, p16INK4a (p16) coupled with the two-stage skin carcinogenesis model will be employed. To test this project's hypothesis that the accumulation of senescent cells in aged animals facilitates skin carcinogenesis and EGCG abrogates the negative aspects of cellular senescence, I plan to: (1) Determine whether senescent cells initiate skin cancer in aged mice. (2) Evaluate whether senescent cells promote skin cancer in old mice. (3) Examine the effect of EGCG on the SASP using both the skin carcinogenesis mouse model and embryonic fibroblasts (MEFs) derived from wild type mice. (4) Delineate the molecular mechanisms by which EGCG affects SASPs. The proposed experiments will delineate a novel role for aging in carcinogenesis and pave the way for the development of natural dietary compounds as therapeutic agents against cancer.

描述（由申请人提供）：大多数成年癌症随着年龄的增长而增加。细胞衰老是一种有效的肿瘤抑制机制，现在被认为有助于与年龄有关的病理。在衰老的组织中，细胞衰老的保护特性被脱落：随着衰老细胞的积累，它们会分泌促炎性细胞因子，趋化因子和蛋白酶，从而产生促癌性微环境。衰老相关的分泌表型（SASP）驱动了细胞衰老的有害特征。在正常衰老期间，衰老细胞在癌症发展和体内进展中的直接作用尚未探索。因此，该提案的第一个目标是确定衰老细胞对年龄相关的癌变的影响。第二个目标是确定多酚表肠含量（EGCG）的作用，这是一种在SASP上的绿茶中发现的有效的抗癌剂。为了实现这些目标，一种新型的转基因小鼠模型P16-3MR，旨在选择性地消除表达已建立的细胞衰老标记物P16INK4A（p16）以及两阶段皮肤癌变模型的衰老细胞。为了检验该项目的假设，即衰老动物中衰老细胞的积累促进了皮肤 致癌作用和EGCG消除了细胞衰老的负面方面，我计划：（1）确定衰老细胞是否启动老年小鼠的皮肤癌。 （2）评估衰老细胞是否促进老鼠的皮肤癌。 （3）使用源自野生型小鼠的皮肤致癌小鼠模型和胚胎成纤维细胞（MEF）检查EGCG对SASP的影响。 （4）描述EGCG影响SASP的分子机制。提出的实验将描述衰老在癌变中的新作用，并为开发自然饮食化合物作为抗癌的治疗剂铺平道路。