The role of telomere-related tetraploidization in cancer

端粒相关四倍体化在癌症中的作用

• 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
• 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

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，现在被公认为是恶性转化的因素之一，但其起源尚未完全理解。虽然偶然的染色体散发性收益和损失可以充分解释异常染色体数量的很大一部分，但在具有三倍体或几乎四倍体染色体数量的癌症的背景下，这种解释却缺乏。 已经提出，携带高染色体数的癌症来自不稳定的四倍体中间体。已知四倍体细胞会以高速率进行隔离染色体，从而产生与癌症中观察到的亚四倍体或近三倍体染色体数的亚克隆。 这些考虑因素导致了一种了解四倍体在肿瘤发生过程中产生的机制。在我们工作之前，提出了三种主要机制。首先，四倍体细胞可以由（病毒介导的）细胞 - 细胞融合产生，产生一个双核细胞，该细胞在下一个细胞分裂期间转化为四倍体状态。其次，当细胞长期停滞有丝分裂时，四倍体可能会出现。根据遗传环境，可能会发生有丝分裂滑移，从而产生一个单个四倍体核和G1中两个中心体的细胞。第三，当裂解沟被阻碍时，无论是在实验中（肌动蛋白抑制）还是通过滞后染色体，细胞因子会失败并产生四倍体。尽管这些途径中的每一种都可能在某些癌症中运作，但它们不太可能是肿瘤发生的一般方面，并且不能解释大染色体数量较大的肿瘤的高频率。 根据我们的初步数据，我们提出了一种新型四倍体化机制，涉及源自功能障碍端粒的DNA损伤信号。长期以来，众所周知，大多数人类实体瘤在端粒酶上调之前都经历了一段端粒缩短。我们建议所得的端粒功能障碍会产生DNA损伤响应，该反应可诱导四倍体化以及其他形式的基因组不稳定性，例如由二齿染色体引起的断裂融合桥周期。该假设很有吸引力，因为它可以解释实体瘤中四倍体化的一般性和高频。另外，驱动四倍体化的侮辱 - 端粒功能障碍 - 是瞬态状态。 当前的项目旨在检验这一新假设。鉴于大量肿瘤显示了过去四磷酸化的证据，我们的工作有可能对癌症中非整倍性起源的知识产生广泛的影响。