The role of telomere-related tetraploidization in cancer

端粒相关四倍体化在癌症中的作用

基本信息

批准号：
8320130
负责人：
Titia de Lange
金额：
$ 35.17万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8320130
关键词：
Actins Address Anchorage-Independent Growth Aneuploidy Automobile Driving Biological Models Cell Line Cell Nucleus Cell division Cell fusion Cells Centrosome Chromosome abnormality Chromosomes Complement Cytokinesis DNA Damage Data Development Diagnostic Neoplasm Staging Dicentric chromosome Diploidy Epithelial Cells Fibroblasts Frequencies Functional disorder Geminin Genetic Genomic Instability Human In Vitro Knowledge Lead Length Life Malignant - descriptor Malignant Neoplasms Mammary gland Mediating Mitosis Mitotic Modeling Monitor Mus Nude Mice Oncogenes Pancreas Pathway interactions Phosphotransferases Ploidies Proliferating Proteins Protocols documentation Recording of previous events Research Retinal Role S Phase Signal Transduction Solid Neoplasm Squamous Cell Staging System Telomerase Telomere Shortening Testing Tetraploidy Transgenes Tumorigenicity Work Zeocin base cell type cellular imaging chromosome loss design dimethylbenzanthracene drug sensitivity experience falls genome-wide improved in vivo indexing keratinocyte mouse model novel precursor cell research study response restoration telomere tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): This project addresses a key problem in human cancer: the origins of aneuploidy. Aneuploidy is among the hallmarks of human solid tumors and is now recognized as one of the contributing factors in malignant transformation but its origin is not fully understood. While sporadic gains and losses of chromosomes can adequately explain a substantial fraction of the aberrant chromosome numbers, this explanation falls short in the context of cancers with a triploid or near-tetraploid chromosome number. It has been proposed that cancers carrying a high chromosome number originate from an unstable tetraploid intermediate. Tetraploid cells are known to mis-segregate chromosomes at a high rate, generating subclones with the sub-tetraploid or near-triploid chromosome numbers observed in cancer. These considerations have led to a quest to understand the mechanism by which tetraploidy arises during tumorigenesis. Prior to our work, three main mechanisms had been proposed. First, tetraploid cells can arise from (virally-mediated) cell-cell fusion, yielding a bi-nucleated cell which is converted into a tetraploid state during the next cell division. Second, tetraploidy can arise when cells experience a prolonged arrest in mitosis. Depending on the genetic context, mitotic slippage can occur, yielding a cell with a single tetraploid nucleus and two centrosomes in G1. Third, when the cleavage furrow is impeded, either experimentally (actin inhibition) or by a lagging chromosome, cytokinesis fails and tetraploidy arises. While each of these pathways may be operational in some cancers, they are unlikely to be a general aspect of tumorigenesis and do not explain the high frequency of tetraploidization suggested by the large percentage of tumors with a high chromosome number. Based on our preliminary data, we propose a novel mechanism for tetraploidization that involves the DNA damage signal originating from shortened dysfunctional telomeres. It has long been known that most human solid tumors experience a period of telomere shortening before telomerase is upregulated. We propose that the resulting telomere dysfunction generates a DNA damage response that can induce tetraploidization as well as other forms of genome instability, such as the Breakage-Fusion Bridge cycles resulting from dicentric chromosomes. This hypothesis is attractive because it can explain the generality and high frequency of tetraploidization in solid tumors. In addition, the insult driving tetraploidization - telomere dysfunction - is a transient state. The current project is designed to test this new hypothesis. Given the large number of tumors showing evidence of past tetraploidization, our work has the potential to have broad impact on the knowledge of the origins of aneuploidy in cancer.

描述（由申请人提供）：该项目解决了人类癌症的一个关键问题：非整倍性的起源。非整倍性是人类实体瘤的标志之一，现在被认为是恶性转化的促成因素之一，但其起源尚不完全清楚。虽然染色体的零星获得和丢失可以充分解释大部分异常染色体数量，但这种解释在具有三倍体或接近四倍体染色体数量的癌症的背景下是不够的。有人提出，携带高染色体数的癌症起源于不稳定的四倍体中间体。已知四倍体细胞的染色体错误分离率很高，产生具有在癌症中观察到的亚四倍体或接近三倍体染色体数目的亚克隆。这些考虑导致人们寻求了解肿瘤发生过程中四倍体产生的机制。在我们开展工作之前，已经提出了三个主要机制。首先，四倍体细胞可以由（病毒介导的）细胞-细胞融合产生，产生双核细胞，在下一次细胞分裂期间转化为四倍体状态。其次，当细胞经历有丝分裂的长期停滞时，就会出现四倍体。根据遗传背景，可能会发生有丝分裂滑移，产生具有单个四倍体核和两个 G1 中心体的细胞。第三，当卵裂沟受阻时，无论是实验性的（肌动蛋白抑制）还是滞后染色体，胞质分裂就会失败，四倍体就会出现。虽然这些途径中的每一种都可能在某些癌症中起作用，但它们不太可能是肿瘤发生的一般方面，并且不能解释高染色体数肿瘤所暗示的高四倍体化频率。根据我们的初步数据，我们提出了一种新的四倍体化机制，其中涉及源自缩短的功能失调端粒的 DNA 损伤信号。人们早就知道，大多数人类实体瘤在端粒酶上调之前都会经历一段端粒缩短的时期。我们提出，由此产生的端粒功能障碍会产生 DNA 损伤反应，从而诱导四倍体化以及其他形式的基因组不稳定，例如双着丝粒染色体引起的断裂-融合桥循环。这个假说很有吸引力，因为它可以解释实体瘤中四倍体化的普遍性和高频率。此外，驱动四倍体化的损伤——端粒功能障碍——是一种暂时状态。当前的项目旨在检验这一新假设。鉴于大量肿瘤显示出过去四倍体化的证据，我们的工作有可能对癌症非整倍性起源的认识产生广泛影响。