The role of senescent cells in late-life tumorigenesis

衰老细胞在晚年肿瘤发生中的作用

• 批准号: 8435619
• 负责人: Jan M. van Deursen
• 金额: $ 35.86万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435619
• 关键词: AP20187; Address; Age; Aging; Animals; Architecture; Attenuated; Biological Markers; Breast Cancer Model; Breeding; CDKN2A gene; Cell Aging; Cell Culture Techniques; Cells; Chronic; Complex; Data; Development; Elderly; Elements; Employee Strikes; Epigenetic Process; Epithelial; Evolution; Excision; Eye; Fatty acid glycerol esters; Functional disorder; Gene Silencing; Goals; Growth Factor; Immunologic Surveillance; In Vitro; Incidence; Individual; Inflammation; Knock-out; Knowledge; Lesion; Life; Malignant Neoplasms; Malignant neoplasm of lung; Mammary gland; Measures; Methods; Mouse Strains; Mus; Names; Nature; Neoplasm Metastasis; Neoplasms; Neoplastic Cell Transformation; Oncogene Activation; Organ; Oxidative Stress; Pathology; Peptide Hydrolases; Phenotype; Property; Proteins; Regulatory Pathway; Reporting; Research; Risk; Risk Factors; Role; Skeletal Muscle; Somatic Mutation; Surface; System; Testing; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Xenograft procedure; age related; anti-cancer therapeutic; cancer cell; cancer therapy; cell age; cell growth; cytokine; design; human disease; improved; in vivo; killings; lung tumorigenesis; malignant breast neoplasm; middle age; mouse model; neoplastic; neoplastic cell; novel; prevent; promoter; protective effect; public health relevance; research study; senescence; synthetic drug; telomere; theories; therapy development; tumor; tumor growth; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Advanced age is the major risk factor for cancer, particularly epithelial cancers. However the fundamental mechanisms underlying the dramatic increase in malignancies later in life remain largely unknown, impeding the development of interventions that prevent or attenuate late-life tumorigenesis. It has long been speculated that senescent cells, which accumulate with aging in many tissues and organs, stimulate the development and dissemination of cancer cells. At first glance, this seems paradoxical because cellular senescence is widely recognized as a crucial anticancer mechanism that prevents the growth of cells at risk for neoplastic transformation. However, recent evidence from in vitro studies supports the idea that cellular senescence may stimulate tumorigenesis by creating a pro-tumorigenic milieu. Senescent cells develop a complex phenotype, termed the senescence-associated secretory phenotype (SASP), in which they secrete high levels of numerous growth factors, cytokines, and proteases. It is thought that this secretome disrupts the architecture and functionality of neighboring cells in the tissue and creates a microenvironment that is permissive for the proliferation and dissemination of neoplastic lesions. The critical barrier to testing this idea in vivo has been the lack of a mouse model that allows for selective elimination of senescent cells. We made use of a biomarker for senescence, p16Ink4a, to generate a novel transgene, INK-ATTAC, which removes p16Ink4a-positive senescent cells upon administration of a synthetic drug. Using this and other mouse models, we will test the central hypothesis that cellular senescence is causally implicated in tumor development and that removal of senescent cells, or key malignancy-associated factors that they secrete, will have a profound tumor protective effect. We propose three specific aims. In the first aim we will determine the extent to which late-life clearance of senescent cells inhibits the development and metastasis of lung and breast cancer. In the second aim, we will establish the nature and consequences of the secretory phenotypes of senescent cells accumulating naturally in different mouse tissues with aging. In the third aim, we will dissect the mechanism by which senescent cells drive tumorigenesis by knocking out individual pro-tumorigenic SASP components specifically in senescent cells and then measuring the effect on mouse mammary gland tumorigenesis. The overall impact of this project is that it will critically test the longstanding untested hypothesisthat senescent cells promote tumorigenesis, address key fundamental questions about naturally occurring senescent cells, identify key components of the SASP that promote tumor development and/or metastasis, and test the entirely novel concept of targeting senescent cells or key elements of the SASP as an anti-cancer therapeutic strategy.

描述（由申请人提供）：高龄是癌症的主要风险因素，特别是上皮癌。然而，生命后期恶性肿瘤急剧增加的基本机制在很大程度上仍然未知，阻碍了预防或减轻晚期肿瘤发生的干预措施的发展。长期以来，人们一直推测，随着衰老在许多组织和器官中积累的衰老细胞刺激了癌细胞的发展和扩散。乍一看，这似乎是自相矛盾的，因为细胞衰老被广泛认为是一种重要的抗癌机制，可以防止有肿瘤转化风险的细胞生长。然而，最近来自体外研究的证据支持细胞衰老可能通过创造促肿瘤发生环境来刺激肿瘤发生的观点。衰老细胞形成复杂的表型，称为衰老相关分泌表型（SASP），其中它们分泌高水平的许多生长因子、细胞因子和蛋白酶。据认为，这种分泌蛋白质组破坏了组织中相邻细胞的结构和功能，并产生了允许肿瘤病变增殖和扩散的微环境。测试这个的关键障碍是 在体内的想法是缺乏一个小鼠模型，允许选择性消除衰老细胞。我们利用衰老的生物标志物p16 Ink 4a产生了一种新的转基因INK-ATTAC，它在施用合成药物后去除p16 Ink 4a阳性衰老细胞。使用这种和其他小鼠模型，我们将测试中心假设，即细胞衰老与肿瘤发展有因果关系，去除衰老细胞或它们分泌的关键恶性相关因子将具有深刻的肿瘤保护作用。我们提出三个具体目标。在第一个目标中，我们将确定 其衰老细胞的晚期清除抑制肺癌和乳腺癌的发展和转移。在第二个目标中，我们将建立衰老细胞的分泌表型的性质和后果自然积累在不同的小鼠组织中的老化。在第三个目标中，我们将剖析衰老细胞驱动肿瘤发生的机制，通过敲除衰老细胞中特定的促肿瘤发生SASP组分，然后测量对小鼠乳腺肿瘤发生的影响。该项目的总体影响是，它将严格测试长期未测试的假设，即衰老细胞促进肿瘤发生，解决有关自然发生的衰老细胞的关键基本问题，确定促进肿瘤发展和/或转移的SASP的关键成分，并测试靶向衰老细胞或SASP关键元素作为抗癌治疗策略的全新概念。