The role of telomere-related tetraploidization 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：非整倍体的起源。非整倍体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，但其起源并不完全清楚。虽然染色体的零星获得和丢失可以充分解释相当一部分的异常染色体数目，但这种解释在具有三倍体或近四倍体染色体数目的癌症的背景下福尔斯不足的。 已经提出携带高染色体数目的癌症起源于不稳定的四倍体中间体。已知四倍体细胞以高比率错误分离染色体，产生具有在癌症中观察到的亚四倍体或近三倍体染色体数目的亚克隆。 这些考虑导致了对理解肿瘤发生过程中四倍体产生的机制的探索。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，其在下一次细胞分裂期间转化为四倍体状态。第二，当细胞在有丝分裂中经历长时间的停滞时，四倍体可以出现。根据遗传背景，有丝分裂滑移可能发生，产生一个细胞与一个单一的四倍体细胞核和两个中心体在G1。第三，当卵裂沟受到阻碍时，无论是实验性的（肌动蛋白抑制）还是落后的染色体，胞质分裂失败，四倍体出现。虽然这些途径中的每一个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，也不能解释大比例的具有高染色体数目的肿瘤所暗示的高频率四倍体化。 基于我们的初步数据，我们提出了一种新的四倍化机制，涉及DNA损伤信号来源于缩短的功能失调的端粒。人们早就知道，大多数人实体瘤在端粒酶上调之前经历一段时间的端粒缩短。我们提出，由此产生的端粒功能障碍产生的DNA损伤反应，可以诱导四倍体化以及其他形式的基因组不稳定性，如断裂融合桥周期由双着丝粒染色体。这一假说很有吸引力，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，驱动四倍化的损伤-端粒功能障碍-是一种短暂的状态。 目前的项目旨在测试这一新的假设。鉴于大量的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体起源的知识产生广泛的影响。 公共卫生相关性：大多数人类实体瘤通常显示异常的染色体数目，这种现象被称为非整倍体。非整倍体是人类癌症形成的重要因素，但目前尚不清楚非整倍体是如何产生的。这个项目测试了一个关于非整倍体起源的新假设。

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. PUBLIC HEALTH RELEVANCE: Most human solid tumors often show aberrant chromosome numbers, a phenomenon referred to as aneuploidy. Aneuploidy is an important factor in the formation of human cancer but it is not understood how aneuploidy arises. This project tests a new hypothesis on the origin of aneuploidy.