Mitosis, Aneuploidy and Cancer

描述(申请人提供)：非整倍体是一种异常的染色体数目，是肿瘤细胞的共同特征，发生在所有人类癌症中的85%。非整倍体常常是由于有丝分裂过程中染色体分离的错误而出现的。非整倍体和有丝分裂错误在肿瘤细胞中的高度流行促使人们提出非整倍体是肿瘤发生的原因的假设。然而，这一点很难确定。我们最近发现，由有丝分裂特异的动蛋白样马达蛋白CENP-E(着丝粒相关蛋白-E)减少引起的非整倍体既促进肿瘤又抑制肿瘤，这取决于背景。这些发现可能具有治疗意义，特别是因为一种CENP-E运动活性的抑制剂目前正在进行临床试验。这项建议的总体目标是确定决定CENP-E减少引起的非整倍体是否会促进或抑制肿瘤的上下文相关因素。初步研究表明，具有遗传不稳定水平的肿瘤容易受到非整倍体介导的肿瘤抑制，这是由于一个或多个必要染色体的两个副本丢失导致的细胞死亡增加所致。目标1中的实验将确定非整倍体介导的细胞死亡的机制(S)，并为预测哪些肿瘤易感提供基础。目的2确定抑癌基因P53和APC(腺瘤性息肉病结肠)的缺失或突变诱导的肿瘤是否易受CENP-E降低引起的非整倍体介导的细胞死亡的影响。以前的研究表明，降低CENP-E可以抑制缺乏p19ARF肿瘤抑制因子的动物的肿瘤。AIM 3将扩展初步研究，发现p19ARF在有丝分裂过程中的染色体分离中扮演了以前未被怀疑的角色。总之，这些实验将定义决定特定肿瘤是否对非整倍体介导的肿瘤抑制敏感的特征，并将为目前处于临床试验中的CENP-E抑制剂的使用提供翻译相关信息。 与公共卫生相关：癌症是美国第二大常见死亡原因。细胞分裂过程中的错误在癌细胞中很常见，但这些错误对肿瘤的影响是复杂的。这项提案中的实验将定义细胞分裂过程中的错误如何影响肿瘤，最终目标是产生临床有用的治疗方法。

DESCRIPTION (provided by applicant): Aneuploidy, an abnormal chromosome number, is a common characteristic of tumor cells, occurring in ~85% of all human cancers. Aneuploidy frequently arises due to errors in chromosome segregation during mitosis. The high prevalence of aneuploidy and mitotic errors in tumor cells prompted the hypothesis that aneuploidy is a cause of tumor genesis. However, this has been difficult to establish. We recently discovered that aneuploidy caused by reduction of the mitosis-specific kinesin-like motor protein CENP- E (CENtromere associated Protein-E) both promotes and suppresses tumors, depending on the context. These findings may have therapeutic implications, particularly since an inhibitor of CENP-E motor activity is currently in clinical trials. The overall goal of this proposal is to define the context-dependent factors that determine whether aneuploidy caused by reduction of CENP-E will promote or suppress tumors. Preliminary studies suggest that tumors with a pre-existing level of genetic instability are susceptible to aneuploidy-mediated tumor suppression, which occurs due to an increase in cell death caused by loss of both copies of one or more essential chromosomes. Experiments in Aim 1 will determine the mechanism(s) of aneuploidy-mediated cell death, and provide a basis to predict which tumors are susceptible. Aim 2 will determine whether tumors induced by reduction or mutation of the tumor suppressors p53 and APC (Adenomatous Polyposis Coli) are susceptible to aneuploidy-mediated cell death caused by reduction of CENP-E. Previous studies have shown that reduction of CENP-E suppresses tumors in animals lacking the p19ARF tumor suppressor. Aim 3 will extend preliminary studies that identified a previously unsuspected role for p19ARF in chromosome segregation during mitosis. Together, these experiments will define the characteristics that determine whether a given tumor is susceptible to aneuploidy-mediated tumor suppression and will provide translationally relevant information for use of the CENP-E inhibitor currently in clinical trials. PUBLIC HEALTH RELEVANCE: Cancer is the second most common cause of death in the USA. Errors during cell division are common in cancer cells, but the effects of these errors on tumors are complex. The experiments in this proposal will define how errors during cell division affect tumors, with the ultimate goal of producing clinically useful therapies.