Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer.
Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer.
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DOI：
10.1126/science.1227670
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发表时间：
2013-02-01
期刊：
影响因子：
56.9
通讯作者：
Dick, John E.
中科院分区：
文献类型：
--
作者：
Kreso, Antonija;O'Brien, Catherine A.;van Galen, Peter;Gan, Olga I.;Notta, Faiyaz;Brown, Andrew M. K.;Ng, Karen;Ma, Jing;Wienholds, Erno;Dunant, Cyrille;Pollett, Aaron;Gallinger, Steven;McPherson, John;Mullighan, Charles G.;Shibata, Darryl;Dick, John E.
肿瘤内异质性是通过肿瘤进展过程中遗传多样性亚克隆的进化而产生的。然而，它仍然是未知的细胞在单一的遗传克隆是否是功能等同的。通过结合DNA拷贝数改变（CNA）分析、测序和慢病毒谱系追踪，我们通过小鼠中的连续异种移植传代，跟踪了来自10种人类结直肠癌的150个单一慢病毒标记谱系的再增殖动力学。CNA和突变分析区分个别克隆，并表明克隆保持稳定后，连续移植。尽管这种稳定性，增殖，持久性和化疗耐受性的慢病毒标记的谱系是可变的每个克隆。化疗促进了以前次要或休眠谱系的优势。因此，除了遗传多样性，肿瘤细胞在肿瘤增殖潜力方面表现出固有的功能变异性，这有助于癌症生长和治疗耐受性。实体瘤由功能多样的肿瘤细胞组成。流行的观点是，这种“肿瘤内异质性”源于肿瘤生长过程中突变的积累，导致多个基因定义的细胞亚克隆以不同的方式对选择性压力（如化疗）作出反应。Kreso等人（第543页，12月13日在线发表;参见Marusyk和Polyak的Perspective）同时监测了在小鼠中连续传代的人类结直肠癌细胞的遗传特征和生长行为。单一遗传谱系内的单个肿瘤细胞在存活率、生长动力学和对化疗药物的反应方面表现出广泛的差异。因此，额外的多样性产生机制，如表观遗传调节或微环境变异性似乎在遗传克隆中起作用，赋予肿瘤细胞亚群强大的生存潜力，特别是在应激期间。
Intratumoral heterogeneity arises through the evolution of genetically diverse subclones during tumor progression. However, it remains unknown whether cells within single genetic clones are functionally equivalent. By combining DNA copy number alteration (CNA) profiling, sequencing, and lentiviral lineage tracking, we followed the repopulation dynamics of 150 single lentivirus-marked lineages from 10 human colorectal cancers through serial xenograft passages in mice. CNA and mutational analysis distinguished individual clones and showed that clones remained stable upon serial transplantation. Despite this stability, the proliferation, persistence, and chemotherapy tolerance of lentivirally marked lineages were variable within each clone. Chemotherapy promoted the dominance of previously minor or dormant lineages. Thus, apart from genetic diversity, tumor cells display inherent functional variability in tumor propagation potential, which contributes to both cancer growth and therapy tolerance. Solid tumors are composed of functionally diverse tumor cells. The prevailing view is that this “intratumoral heterogeneity” arises from the accumulation of mutations during tumor growth, resulting in multiple genetically defined subclones of cells that respond in different ways to selective pressures such as chemotherapy. Kreso et al. (p. 543, published online 13 December; see the Perspective by Marusyk and Polyak) simultaneously monitored the genetic profiles and growth behavior of human colorectal cancer cells that were serially passaged in mice. Individual tumor cells within a uniform genetic lineage displayed extensive variation in survival, growth dynamics, and response to a chemotherapeutic drug. Thus, additional diversity-generating mechanisms such as epigenetic regulation or microenvironmental variability appear to operate within a genetic clone, endowing a subset of tumor cells with robust survival potential, especially during stress.
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影响因子：
64.5
作者：
Roesch A;Fukunaga-Kalabis M;Schmidt EC;Zabierowski SE;Brafford PA;Vultur A;Basu D;Gimotty P;Vogt T;Herlyn M
通讯作者：
Herlyn M
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
影响因子：
4.8
作者：
Flynn, Dan F. B.;Mirotchnick, Nicholas;Naeem, Shahid
通讯作者：
Naeem, Shahid
DOI：
10.1073/pnas.0712345105
发表时间：
2008-03-18
影响因子：
11.1
作者：
Jones, Sian;Chen, Wei-dong;Markowitz, Sanford D.
通讯作者：
Markowitz, Sanford D.
影响因子：
64.5
作者：
Nik-Zainal S;Van Loo P;Wedge DC;Alexandrov LB;Greenman CD;Lau KW;Raine K;Jones D;Marshall J;Ramakrishna M;Shlien A;Cooke SL;Hinton J;Menzies A;Stebbings LA;Leroy C;Jia M;Rance R;Mudie LJ;Gamble SJ;Stephens PJ;McLaren S;Tarpey PS;Papaemmanuil E;Davies HR;Varela I;McBride DJ;Bignell GR;Leung K;Butler AP;Teague JW;Martin S;Jönsson G;Mariani O;Boyault S;Miron P;Fatima A;Langerød A;Aparicio SA;Tutt A;Sieuwerts AM;Borg Å;Thomas G;Salomon AV;Richardson AL;Børresen-Dale AL;Futreal PA;Stratton MR;Campbell PJ;Breast Cancer Working Group of the International Cancer Genome Consortium
通讯作者：
Breast Cancer Working Group of the International Cancer Genome Consortium