腫瘤特異性染色體的錯誤分離通過保持腫瘤異質(zhì)性來控制癌癥的可塑性

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腫瘤異質(zhì)性是惡性腫瘤的特征之一，指的是腫瘤在生長過程中，經(jīng)多次分裂增殖，子細(xì)胞呈現(xiàn)出分子生物學(xué)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(yù)后等各方面產(chǎn)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(xì)胞。因此同一種腫瘤在不同的個體身上可表現(xiàn)出不一樣的治療效果及預(yù)后，甚至同一個體身上的腫瘤細(xì)胞也存在不同的特性和差異。

近期，來自加州大學(xué)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(xué)、中山大學(xué)腫瘤防治中心、阿肯色大學(xué)醫(yī)學(xué)院、貴州師范學(xué)院省計(jì)算納米材料科學(xué)重點(diǎn)實(shí)驗(yàn)室、阿克倫大學(xué)、東北俄亥俄醫(yī)科大學(xué)等多家研究機(jī)構(gòu)的科學(xué)家就腫瘤異質(zhì)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(fā)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(yōu)質(zhì)的 Agilent Human Genome CGH 244 k Microarray服務(wù)。

非整倍體染色體的不穩(wěn)定性是癌癥的一大特點(diǎn)。研究者觀察了由原代細(xì)胞培養(yǎng)出的神經(jīng)膠質(zhì)瘤細(xì)胞的7號染色體（Chr7）拷貝數(shù)變異（CNV）情況，發(fā)現(xiàn)普遍出現(xiàn)在膠質(zhì)瘤中的Chr7-CNV的腫瘤異質(zhì)性細(xì)胞，在高級別的膠質(zhì)瘤（攜帶超過2個拷貝數(shù)的Chr7）中出現(xiàn)的百分比較低級別的膠質(zhì)瘤更高。更有趣的是，由親本培養(yǎng)出的所有的Chr7-非整倍體細(xì)胞形成的膠質(zhì)瘤細(xì)胞系再現(xiàn)了由單細(xì)胞衍生的次生培養(yǎng)物。

研究人員隨即探究了三個同系膠質(zhì)瘤培養(yǎng)物（具有不同的Chr7非整倍體類型的細(xì)胞）的生物學(xué)特性。他們發(fā)現(xiàn)細(xì)胞的表型差異伴隨著Chr7的錯誤分離，這幫助了腫瘤在體內(nèi)及體外的生長。進(jìn)一步研究者采用數(shù)學(xué)模型來闡明染色體的不穩(wěn)定性及不同細(xì)胞亞種的相互作用在重建腫瘤細(xì)胞類型最佳平衡態(tài)方面的作用。實(shí)驗(yàn)數(shù)據(jù)及數(shù)學(xué)模型均證明了腫瘤異質(zhì)性的復(fù)雜性能夠提高染色體結(jié)構(gòu)異常（染色體錯誤分離除外）的出現(xiàn)率。

總體而言，本研究首次發(fā)現(xiàn)染色體的不穩(wěn)定性與保持腫瘤異質(zhì)性相關(guān)，這也為癌癥的生長、維持、耐藥性奠定了基礎(chǔ)。

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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腫瘤特異性染色體的錯誤分離通過保持腫瘤異質(zhì)性來控制癌癥的可塑性