The role of telomere-related tetraploidization in cancer

描述（由申请人提供）：本项目研究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肿瘤的标志之一，现在被认为是恶性转化的因素之一，但其起源尚不完全清楚。虽然零星的染色体获得和丢失可以充分解释相当一部分异常染色体数目，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是不足的。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。众所周知，四倍体细胞染色体的错误分离率很高，产生亚四倍体或近三倍体染色体数目的亚克隆，在癌症中观察到。这些考虑导致了对四倍体在肿瘤发生过程中产生的机制的探索。在我们开展工作之前，提出了三个主要机制。首先，四倍体细胞可以从（病毒介导的）细胞-细胞融合中产生，产生双核细胞，在下一次细胞分裂时转化为四倍体状态。其次，当细胞在有丝分裂中经历长时间的停滞时，可以产生四倍体。根据遗传环境的不同，有丝分裂可以发生滑移，在G1期产生一个具有单个四倍体核和两个中心体的细胞。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，细胞质分裂失败并产生四倍体。虽然这些途径中的每一个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，也不能解释高染色体数肿瘤的高百分比所暗示的高频率四倍体化。基于我们的初步数据，我们提出了一个新的四倍体化机制，涉及DNA损伤信号起源于缩短功能失调的端粒。人们早就知道，在端粒酶上调之前，大多数人类实体肿瘤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产生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，例如由双中心染色体引起的断裂-融合桥循环。这个假设很有吸引力，因为它可以解释实体肿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-是一种短暂状态。目前的项目旨在验证这一新的假设。鉴于大量肿瘤显示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。

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.