Differentiation therapy and the mechanisms that terminate cancer cell proliferation without harming normal cells.
Differentiation therapy and the mechanisms that terminate cancer cell proliferation without harming normal cells.
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分化疗法和终止癌细胞增殖的机制而不会损害正常细胞。
DOI：
10.1038/s41419-018-0919-9
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发表时间：
2018-09-06
影响因子：
9
通讯作者：
Korc M
中科院分区：
文献类型：
--
作者：
Enane FO;Saunthararajah Y;Korc M
化疗药物具有激活肿瘤细胞凋亡的共同意图。然而，细胞凋亡的主要调节因子（例如，p53，p16/CDKN 2A）在癌症中经常被遗传灭活，导致多药耐药性。另一种终止恶性增殖的非p53依赖性方法是参与终末分化。正常情况下，由主转录因子（TF）MYC协调的谱系定向祖细胞的指数增殖是通过向终末谱系命运的前向分化而自我限制的。然而，在癌症中，这种指数增殖与终末分化无关。这种脱钩背后的机制大多是未知的。我们对已发表的文献（2007年1月至2018年6月）进行了系统性综述，以确定与三种治疗失败的癌症（肝细胞癌（HCC），卵巢癌（OVC）和胰腺导管腺癌（PDAC））中分化失败相关的基因通路。我们分析了各种凋亡，增殖和分化途径中的关键基因改变，以确定是否有可能预测治疗结果并提出新的治疗方法。分化差的肿瘤与不同组织学类型的生存率较差有关。我们的分析表明，谱系命运的主TF驱动因子及其辅因子的功能丧失事件与分化失败有关：TCGA和ICGC数据库中的基因组数据表明谱系主TF的频繁单倍不足（例如，GATA 4/6）;这些TF用于激活基因（例如ARID 1A、PBRM 1）的共激活因子也经常因基因突变和/或缺失而失活。相比之下，辅阻遏物组分（例如，DNMT 1、EED、UHRF 1和BAZ 1A/B），它们与抑制或关闭基因的辅激活因子相反，经常被扩增，并且在低分化病变中扩增水平最高。肿瘤进化对转录辅阻遏物的不平衡活性的这种选择表明这些酶作为抑制的候选靶点，旨在重新参与正向分化。这一观点得到了临床前和临床试验文献的支持。
Chemotherapeutic drugs have a common intent to activate apoptosis in tumor cells. However, master regulators of apoptosis (e.g., p53, p16/CDKN2A) are frequently genetically inactivated in cancers, resulting in multidrug resistance. An alternative, p53-independent method for terminating malignant proliferation is to engage terminal-differentiation. Normally, the exponential proliferation of lineage-committed progenitors, coordinated by the master transcription factor (TF) MYC, is self-limited by forward-differentiation to terminal lineage-fates. In cancers, however, this exponential proliferation is disengaged from terminal-differentiation. The mechanisms underlying this decoupling are mostly unknown. We performed a systematic review of published literature (January 2007–June 2018) to identify gene pathways linked to differentiation-failure in three treatment-recalcitrant cancers: hepatocellular carcinoma (HCC), ovarian cancer (OVC), and pancreatic ductal adenocarcinoma (PDAC). We analyzed key gene alterations in various apoptosis, proliferation and differentiation pathways to determine whether it is possible to predict treatment outcomes and suggest novel therapies. Poorly differentiated tumors were linked to poorer survival across histologies. Our analyses suggested loss-of-function events to master TF drivers of lineage-fates and their cofactors as being linked to differentiation-failure: genomic data in TCGA and ICGC databases demonstrated frequent haploinsufficiency of lineage master TFs (e.g., GATA4/6) in poorly differentiated tumors; the coactivators that these TFs use to activate genes (e.g. ARID1A, PBRM1) were also frequently inactivated by genetic mutation and/or deletion. By contrast, corepressor components (e.g., DNMT1, EED, UHRF1, and BAZ1A/B), that oppose coactivators to repress or turn off genes, were frequently amplified instead, and the level of amplification was highest in poorly differentiated lesions. This selection by neoplastic evolution towards unbalanced activity of transcriptional corepressors suggests these enzymes as candidate targets for inhibition aiming to re-engage forward-differentiation. This notion is supported by both pre-clinical and clinical trial literature.
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影响因子：
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作者：
Ebrahem Q;Mahfouz RZ;Ng KP;Saunthararajah Y
通讯作者：
Saunthararajah Y
影响因子：
3.7
作者：
Clark-Knowles KV;Senterman MK;Collins O;Vanderhyden BC
通讯作者：
Vanderhyden BC
影响因子：
5.9
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Chan AL;La HM;Legrand JMD;Mäkelä JA;Eichenlaub M;De Seram M;Ramialison M;Hobbs RM
通讯作者：
Hobbs RM
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Garcia-Ortiz JE;Pelosi E;Omari S;Nedorezov T;Piao Y;Karmazin J;Uda M;Cao A;Cole SW;Forabosco A;Schlessinger D;Ottolenghi C
通讯作者：
Ottolenghi C
影响因子：
5.7
作者：
Balch, C;Yan, P;Nephew, KP
通讯作者：
Nephew, KP