Tumor Suppression by Telomere Dysfunction Induced Senescence

端粒功能障碍诱导衰老抑制肿瘤

基本信息

批准号：
8471003
负责人：
Utz Herbig
金额：
$ 4.17万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-09 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8471003
关键词：
Abbreviations Acetylcysteine Antineoplastic Agents Area Benign Benign Prostatic Hypertrophy Biochemical Biological Biological Assay Biological Markers Biological Models Bypass Cell Aging Cell Culture Techniques Cell Proliferation Cells Chromosomes Cultured Cells Cyclin D1 DNA Damage DNA Double Strand Break DNA damage checkpoint Data Development Diagnostic Neoplasm Staging Disseminated Malignant Neoplasm Enzymes Fluorescence Microscopy Functional disorder Growth HRAS gene Human Image Individual Intraductal Hyperplasia K-cyclin Knowledge Laboratory Animals Length Lesion Maintenance Malignant - descriptor Malignant Neoplasms Measures Methods Modeling Mus Mutation Neoplasm Metastasis Neoplasms Non-Small-Cell Lung Carcinoma Noninfiltrating Intraductal Carcinoma Oncogenes Oncogenic Pancreatic Intraepithelial Neoplasia Premalignant Process Prostatic Intraepithelial Neoplasias Reactive Oxygen Species Research Risk Assessment Role Sentinel Signal Transduction Somatic Cell Staging Stress Structure System Telomerase Telomere Maintenance Telomere Shortening Testing Tissues Tumor Suppression Tumor stage Xenograft Model Xenograft procedure base beta-Galactosidase biological adaptation to stress cancer initiation cancer therapy cell growth cell transformation cell type gene therapy in vivo infiltrating duct carcinoma insight mouse model neoplastic cell novel novel diagnostics positional cloning prevent public health relevance research study response senescence telomere tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Most cancers arise by an evolutionary process as mutations accumulate in chromosomes of somatic cells allowing them to escape the proliferative restrains that control cell growth. To counteract uncontrolled cellular proliferation, metazoans developed a number of innate tumor suppressing mechanisms, one of them being a terminal growth arrest called cellular senescence. In recent years, as we and others identified novel senescence markers, the biological role and importance of this stress response in arresting cells in pre- malignant lesions has been demonstrated. Why cells undergo senescence in vivo and thereby prevent tumor progression in humans however, remains poorly understood. Studies in human cell cultures revealed that cellular senescence is triggered by a number of stresses including dysfunction of telomeres, the physical ends of linear chromosomes. Our studies revealed that when telomeres become critically short, due to continuous cell proliferation and other stresses, they become recognized as double strand DNA breaks and initiate a signaling cascade that results in telomere dysfunction induced cellular senescence (TDIS). In this proposal we demonstrate that the majority of cells in three human cancer precursor lesions, but not in their malignant cancer counterparts, display dysfunctional telomeres and other markers of cellular senescence. Our data therefore indicate that TDIS is a critical and universal tumor suppressing mechanism that limits the growth of pre-malignant human neoplasias. In addition, we discovered that oncogenic signals, often associated with initiation of cancer growth, dramatically accelerate telomere erosion and dysfunction in pre-malignant human cells. It is therefore possible that telomeres act as sentinels of hyperproliferative stresses that rapidly induce cellular senescence once cellular growth control mechanisms become compromised. To test these predictions we will 1) analyze a number of common cancer precursor lesions as well as their malignant counterparts for markers of TDIS by fluorescence microscopy and 2) generate a mouse tumor model system that can analyze whether TDIS suppresses malignant progression of transformed human cells in tumor cell xenografts. In addition we will 3) determine the causes for telomere dysfunction under conditions that cause aberrant cell proliferation. We will use assays to measure telomere-shortening, -dysfunction and - structure, employ forward- and reverse- genetic interventions to manipulate telomere dysfunction, and identify telomere maintenance factors critical for triggering TDIS. The proposed experiments will reveal the impact of TDIS in preventing human tumor progression, identify novel diagnostic markers for tumor stage, and provide detailed insights into the causes of telomere dysfunction in pre-malignant human cells. This knowledge is critical for developing novel therapies that prevent the malignant progression of human cancer.

描述（由申请人提供）：大多数癌症是由进化过程产生的，因为突变在体细胞染色体中积累，使它们能够逃脱控制细胞生长的增殖抑制。为了对抗不受控制的细胞增殖，后生动物发展出许多先天的肿瘤抑制机制，其中之一是称为细胞衰老的终末生长停滞。近年来，随着我们和其他人发现了新的衰老标志物，这种应激反应在阻止癌前病变细胞中的生物学作用和重要性已经得到证明。然而，为什么细胞在体内经历衰老并从而阻止人类肿瘤的进展，人们仍然知之甚少。对人类细胞培养物的研究表明，细胞衰老是由许多压力引发的，包括端粒（线性染色体的物理末端）功能障碍。我们的研究表明，当端粒由于持续的细胞增殖和其他压力而变得非常短时，它们就会被认为是双链 DNA 断裂，并启动信号级联反应，导致端粒功能障碍诱导的细胞衰老 (TDIS)。在这项提议中，我们证明，三种人类癌症前体病变中的大多数细胞（但不是其恶性癌症对应物中的细胞）表现出功能失调的端粒和其他细胞衰老标志物。因此，我们的数据表明，TDIS 是一种关键且普遍的肿瘤抑制机制，可限制癌前人类肿瘤的生长。此外，我们发现致癌信号通常与癌症生长的起始相关，可显着加速癌前人类细胞的端粒侵蚀和功能障碍。因此，端粒可能充当过度增殖应激的哨兵，一旦细胞生长控制机制受到损害，就会迅速诱导细胞衰老。为了测试这些预测，我们将 1) 通过荧光显微镜分析一些常见的癌症前体病变及其恶性对应物的 TDIS 标记物，2) 生成一个小鼠肿瘤模型系统，该系统可以分析 TDIS 是否抑制转化的人类细胞的恶性进展在肿瘤细胞异种移植物中。此外，我们将3）确定在导致异常细胞增殖的条件下端粒功能障碍的原因。我们将使用检测方法来测量端粒缩短、功能障碍和结构，采用正向和反向遗传干预来操纵端粒功能障碍，并确定对触发 TDIS 至关重要的端粒维持因素。拟议的实验将揭示 TDIS 在预防人类肿瘤进展方面的影响，识别肿瘤阶段的新诊断标记物，并提供对癌前人类细胞端粒功能障碍原因的详细见解。这些知识对于开发预防人类癌症恶性进展的新疗法至关重要。