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肿瘤特异性染色体错误分离通过保持肿瘤异质性来控制癌症的可塑性
来源:    作者:    发布时间:2016/12/28 9:06:17
肿瘤异质性是恶性肿瘤的特征之一,指的是肿瘤在生长过程中,经多次分裂增殖,子细胞呈现出分子生物学或基因方面的改变,从而使肿瘤的生长速度、侵袭能力、对药物的敏感性、预后等各方面产生差异。简言之同一肿瘤中可以存在很多不同的基因型或者亚型的细胞。因此同一种肿瘤在不同的个体身上可表现出不一样的治疗效果及预后,甚至同一个体身上的肿瘤细胞也存在不同的特性和差异。
 
近期,来自加州大学欧文分校、生物芯片上海国家工程中心、退役军人体检中心(美国)、弗吉尼亚理工大学、中山大学肿瘤防治中心、阿肯色大学医学院、贵州师范学院省计算纳米材料科学重点实验室、阿克伦大学、东北俄亥俄医科大学等多家研究机构的科学家就肿瘤异质性这一重大问题展开了深入的研究,他们珍贵的研究成果于2013年11月发表在PLOS ONE杂志上,文章题目为“Tumor-Specific Chromosome Mis-Segregation Controls Cancer Plasticity by Maintaining Tumor Heterogeneity”。生物芯片上海国家工程中心作为共同参与研究的单位,为本研究提供了优质的Agilent Human Genome CGH 244 k Microarray服务。
 
非整倍体染色体的不稳定性是癌症的一大特点。研究者观察了由原代细胞培养出的神经胶质瘤细胞的7号染色体(Chr7)拷贝数变异(CNV)情况,发现普遍出现在胶质瘤中的Chr7-CNV的肿瘤异质性细胞,在高级别的胶质瘤(携带超过2个拷贝数的Chr7)中出现的百分比较低级别的胶质瘤更高。更有趣的是,由亲本培养出的所有的Chr7-非整倍体细胞形成的胶质瘤细胞系再现了由单细胞衍生的次生培养物。
 
研究人员随即探究了三个同系胶质瘤培养物(具有不同的Chr7非整倍体类型的细胞)的生物学特性。他们发现细胞的表型差异伴随着Chr7的错误分离,这帮助了肿瘤在体内及体外的生长。进一步研究者采用数学模型来阐明染色体的不稳定性及不同细胞亚种的相互作用在重建肿瘤细胞类型最佳平衡态方面的作用。实验数据及数学模型均证明了肿瘤异质性的复杂性能够提高染色体结构异常(染色体错误分离除外)的出现率。
 
总体而言,本研究首次发现染色体的不稳定性与保持肿瘤异质性相关,这也为癌症的生长、维持、耐药性奠定了基础。
 
Figure 3. Distinct karyotypes of three subpopulation cells in U251. A, representative metaphase FISH pictures of PTEN/CEP10 and EGFR/ CEP7 dual probes showing all cells carrying one copy of Chr10, an unknown chromosome with a PTEN translocation, and three cell types differing in their composition of normal and derivative Chr7 (dChr7). Arrow points to dChr7; arrowhead to normal Chr7. B, percentage of majority cells in the parental culture, derived or converted SA or NS subcultures, and the parental culture after lentiviral transductions by pTRIPZ-Vec (P-Vec), pTRIPZEFEMP1 with (P-E1) or after withdrawal (P-E1wd) of doxycyclin. C–D, comparison of DNA copy number variation in chromosomes 7, 8, 17, and 22 for U251 parental derived or converted NS subcultures of NS1 or SA1-NS, respectively. The Y axis is the log ratio of intensity (the ratio of test sample and normal blood) from comparative genome hybridization. Amplifications or deletions are shown by blue lines above or below the red or green areas,respectively, based on Z-score, and those with marked changes are highlighted in purple.

原文出处:Tumor-Specific Chromosome Mis-Segregation Controls Cancer Plasticity by Maintaining Tumor Heterogeneity
 
Abstract: Aneuploidy with chromosome instability is a cancer hallmark. We studied chromosome 7 (Chr7) copy number variation (CNV) in gliomas and in primary cultures derived from them. We found tumor heterogeneity with cells having Chr7-CNV commonly occurs in gliomas, with a higher percentage of cells in high-grade gliomas carrying more than 2 copies of Chr7, as compared to low-grade gliomas. Interestingly, all Chr7-aneuploid cell types in the parental culture of established glioma cell lines reappeared in single-cell-derived subcultures. We then characterized the biology of three syngeneic glioma cultures dominated by different Chr7-aneuploid cell types. We found phenotypic divergence for cells following Chr7 missegregation, which benefited overall tumor growth in vitro and in vivo. Mathematical modeling suggested the involvement of chromosome instability and interactions among cell subpopulations in restoring the optimal equilibrium of tumor cell types. Both our experimental data and mathematical modeling demonstrated that the complexity of tumor heterogeneity could be enhanced by the existence of chromosomes with structural abnormality, in addition to their mis-segregations.
 
Overall, our findings show, for the first time, the involvement of chromosome instability in maintaining tumor heterogeneity, which underlies the enhanced growth, persistence and treatment resistance of cancers.

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