The role of senescent cells in late-life tumorigenesis

衰老细胞在晚年肿瘤发生中的作用

基本信息

批准号：
8780613
负责人：
Jan M. van Deursen
金额：
$ 34.38万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8780613
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 Health 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 research study senescence synthetic drug telomere theories therapy development tumor tumor growth tumorigenesis tumorigenic

项目摘要

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）：高龄是癌症的主要危险因素，尤其是上皮癌。但是，生命后期的恶性肿瘤急剧增加的基本机制在很大程度上是未知的，这阻碍了预防或减弱晚期肿瘤发生的干预措施的发展。长期以来，人们一直猜测，在许多组织和器官中随着衰老而累积的衰老细胞刺激了癌细胞的发展和传播。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至关重要的抗癌机制，可防止细胞在肿瘤转化风险中的生长。然而，来自体外研究的最新证据支持了这样的观念，即细胞衰老可能通过创建促肿瘤的环境来刺激肿瘤发生。衰老细胞形成复杂的表型，称为衰老相关的分泌表型（SASP），其中它们分泌了众多生长因子，细胞因子和蛋白酶的高水平。据认为，该分介体破坏了组织中相邻细胞的结构和功能，并创造了一种微环境，该微环境允许肿瘤病变的增殖和传播。测试这一点的关键障碍体内的想法缺乏小鼠模型，可以选择性消除衰老细胞。我们利用生物标志物用于衰老，P16INK4A来产生一种新型的转基因Ink-Attac，该墨水在施用合成药物后消除了P16INK4A阳性衰老细胞。使用这种和其他小鼠模型，我们将检验一个中心假设，即细胞衰老与肿瘤的发育有关，并且去除衰老细胞或它们分泌的关键恶性相关因素将具有深远的肿瘤保护作用。我们提出了三个具体目标。在第一个目标中，我们将确定衰老细胞的晚期清除抑制了肺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，这些表型自然地在随着衰老的不同小鼠组织中积累。在第三个目标中，我们将通过淘汰专门在衰老细胞中的单个亲瘤性SASP成分，然后测量对小鼠乳腺肿瘤发生的影响，从而剖析衰老细胞驱动肿瘤发生的机制。该项目的总体影响在于，它将批判性地测试长期未经测试的假说，即衰老细胞促进了肿瘤的发生，解决有关自然发生的衰老细胞的关键基本问题，确定SASP的关键组成部分，促进肿瘤发展和/或转移的肿瘤发展和/或转移，并测试靶向SENESCICT SERESECTENSECTENSECTENSCENT SERSECTENSSPART OER EXPER stragtion seant-cant and anti-canc的新颖概念。