腫瘤特異性染色體的錯誤分離通過保持腫瘤異質性來控制癌癥的可塑性
腫瘤異質性是惡性腫瘤的特征之一，指的是腫瘤在生長過程中，經多次分裂增殖，子細胞呈現出分子生物學或基因方面的改變，從而使腫瘤的生長速度、侵襲能力、對藥物的敏感性、預后等各方面產生差異。簡言之同一腫瘤中可以存在很多不同的基因型或者亞型的細胞。因此同一種腫瘤在不同的個體身上可表現出不一樣的治療效果及預后，甚至同一個體身上的腫瘤細胞也存在不同的特性和差異。
近期，來自加州大學歐文分校、生物芯片上海國家工程中心、退役軍人體檢中心（美國）、弗吉尼亞理工大學、中山大學腫瘤防治中心、阿肯色大學醫學院、貴州師范學院省計算納米材料科學重點實驗室、阿克倫大學、東北俄亥俄醫科大學等多家研究機構的科學家就腫瘤異質性這一重大問題展開了深入的研究，他們珍貴的研究成果于2013年11月發表在PLOS ONE雜志上，文章題目為“Tumor-
Specific Chromosome Mis-Segregation Controls Cancer Plasticity by Maintaining Tumor Heterogeneity”。生物芯片上海國家工程中心作為共同參與研究的單位，為本研究提供了優質的 Agilent Human Genome CGH 244 k Microarray服務。
非整倍體染色體的不穩定性是癌癥的一大特點。研究者觀察了由原代細胞培養出的神經膠質瘤細胞的7號染色體（Chr7）拷貝數變異（CNV）情況，發現普遍出現在膠質瘤中的Chr7-CNV的腫瘤異質性細胞，在高級別的膠質瘤（攜帶超過2個拷貝數的Chr7）中出現的百分比較低級別的膠質瘤更高。更有趣的是，由親本培養出的所有的Chr7-非整倍體細胞形成的膠質瘤細胞系再現了由單細胞衍生的次生培養物。
研究人員隨即探究了三個同系膠質瘤培養物（具有不同的Chr7非整倍體類型的細胞）的生物學特性。他們發現細胞的表型差異伴隨著Chr7的錯誤分離，這幫助了腫瘤在體內及體外的生長。進一步研究者采用數學模型來闡明染色體的不穩定性及不同細胞亞種的相互作用在重建腫瘤細胞類型最佳平衡態方面的作用。實驗數據及數學模型均證明了腫瘤異質性的復雜性能夠提高染色體結構異常（染色體錯誤分離除外）的出現率。
總體而言，本研究首次發現染色體的不穩定性與保持腫瘤異質性相關，這也為癌癥的生長、維持、耐藥性奠定了基礎。
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 intheir composition of normal and derivative Chr7 (dChr7). Arrow points to dChr7; arrowhead to normal Chr7. B, percentage of majority cells in theparental culture, derived or converted SA or NS subcultures, and the parental culture after lentiviral transductions by pTRIPZ-Vec (P-Vec), pTRIPZEFEMP1with (P-E1) or after withdrawal (P-E1wd) of doxycyclin. C–D, comparison of DNA copy number variation in chromosomes 7, 8, 17, and 22 forU251 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 andnormal 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.
原文出處：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-CNVcommonly 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 gliomacell lines reappeared in single-cell-derived subcultures. We then characterized the biology of three syngeneic gliomacultures 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 involvementof chromosome instability and interactions among cell subpopulations in restoring the optimal equilibrium of tumor celltypes. Both our experimental data and mathematical modeling demonstrated that the complexity of tumor heterogeneitycould 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 tumorheterogeneity, which underlies the enhanced growth, persistence and treatment resistance of cancers.
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