Nat Med:重磅!科学家采用了一种新的方法成功遏制了癌症转移!

2018-02-13 佚名 medicalxpress

来自凯斯西储大学医学院和其他六家机构的研究人员首次成功地阻止了癌细胞从身体的一部分扩散到另一部分。在这样做的过程中,他们依赖于一种新的癌症转移模式,该模型强调了表观遗传学,它研究了基因是如何开启和关闭的。

来自凯斯西储大学医学院和其他六家机构的研究人员首次成功地阻止了癌细胞从身体的一部分扩散到另一部分。在这样做的过程中,他们依赖于一种新的癌症转移模式,该模型强调了表观遗传学,它研究了基因是如何开启和关闭的。

在《自然医学》(Nature Medicine)杂志上发表的一项研究中,包括美国国家癌症研究所(National Cancer Institute)和克利夫兰诊所(Cleveland Clinic)的科学家在内的研究人员使用了创新的表观遗传学技术,以阻止骨癌(骨肉瘤)细胞在小鼠肺部的扩散。大多数与骨肉瘤相关的死亡是由于癌症扩散到肺部,这一过程被称为转移。大多数人的骨肉瘤病例发生在10岁至30岁之间的儿童和年轻人中,青少年是受影响最严重的年龄组。骨原性肉瘤患者的临床疗效已经超过30年没有得到改善,目前在广泛的临床应用中还没有针对该疾病的批准的靶向抗转移治疗。

“超过90%的癌症死亡是肿瘤转移的结果,而不是原发部位的肿瘤,”该研究的资深作者Peter Scacheri博士说,他是凯斯西储大学医学院遗传学和基因组科学的教授,也是病例综合癌症中心的成员。“虽然已经确定了许多负责转移的基因,但控制这些基因的机制并没有很好的定义。我们的研究结果表明,改变基因增强活性对癌细胞转移的能力是至关重要的。

基因增强子是DNA的短片段,当被称为转录因子的特殊蛋白质结合时,它就像开关一样激活基因。这一过程对于正常的发育至关重要,就像一个受精卵发育到组成身体的许多不同的细胞类型一样。每个细胞中有成千上万的基因增强子,远远超过基因的数量;它们将在不同的“on”和“off”位置,例如,眼睛和心脏细胞,(或其梯度,就像调光开关对光线亮度的影响)。这些独特的“开关”特征使细胞具有其独特的特性,尽管它们都具有相同的DNA。但是,有缺陷的强化调节似乎有助于肿瘤的形成和癌细胞的扩散。此外,不同的癌症可以通过不同的增强模式来区分。在这项新的研究中,作者指出癌细胞转移的开关在不同的位置,而不是在源肿瘤细胞中。

James J. Morrow说:“转移是由肿瘤细胞获得的一系列复杂的特征所导致的,这些特征与肿瘤最初形成时所必需的不同。不幸的是,寻找驱动转移的基因突变并没有显著改善转移性疾病患者的预后。”癌症患者的5年生存率在许多类型的癌症中都有显著的改善。但除了少数例外,转移性癌症患者的预后仍然停滞不前。主要的肿瘤形成是由遗传和表观遗传事件共同驱动的。因此,基于增强子促进正常细胞发育和肿瘤形成的知识,我们推测它们在癌细胞转移过程中可能扮演着类似的角色,从一个发育不同的组织转移到另一个细胞转移过程中。

通过表观基因组分析实验,凯斯西储大学的研究人员一直发现某些聚束的增强子——也就是所谓的“转移变异增强子”——在骨肉瘤患者肺转移的癌基因附近,表明它们是转移过程的中心。通过实验小鼠模型,研究人员发现,使用BET抑制剂(目前在临床试验中使用的抗癌药物)可以减轻肺部的骨肉瘤细胞的生长,这在很大程度上阻断了驱动基因表达的功能。

其次,他们证明,通过阻断由Met-VELs或驱动该调控的转录因子调控的单个基因的表达,可以减少骨肉瘤细胞的转移能力。他们证实特定的Met-VEL连接的基因组织因子(F3)对于转移性定植是必需的。具体来说,阻断F3的信号和促凝血(凝血)功能,抑制这些功能就足以防止转移。此外,他们还发现,通过TALEN基因编辑过程,删除单个的Met-VEL调控F3表达也会产生类似的效果。“我们的实验表明,移除肿瘤细胞中F3基因的单一增强剂,实际上消除了它们在小鼠体内转移的能力,”Scacheri说。“总的来说,我们的发现证实,增强因子赋予肿瘤细胞具有转移能力,并且有针对性地抑制与增强子改变相关的基因,或删除改变增强剂本身就足以阻止转移性的定植和增殖。虽然我们的研究关注的是骨肉瘤的肺转移,但这一发现对其他类型的转移性癌症也有影响。                                                    
凯斯西储大学医学院关注于表观遗传学的新研究代表了与主流转移模式的一次突破,该模式主要探索基因突变 - 而不是如果或如何打开或关闭某些基因。当前癌症研究的优势在疾病的早期阶段发生,例如肿瘤如何形成以及癌细胞与正常细胞的区别,而不是转移。此外,目前大多数癌症药物和治疗方法都是为了杀死原发性肿瘤,而不是在其他地方扩散的癌细胞。

原始出处:

James J Morrow, Ian Bayles, Alister P W Funnell, et.al. Positively selected enhancer elements endow osteosarcoma cells with metastatic competence. Nature Medicine 07 February 2018

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    2018-12-17 liye789132251
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    2018-02-23 杨利洪

    学习了提高了

    0

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    2018-02-15 xxxx1054
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    2018-02-14 1e1b8538m79(暂无匿称)

    不错的文章值得拥有

    0

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    2018-02-13 有备才能无患

    来自凯斯西储大学医学院和其他六家机构的研究人员首次成功地阻止了癌细胞从身体的一部分扩散到另一部分.在这样做的过程中.他们依赖于一种新的癌症转移模式.该模型强调了表观遗传学.它研究了基因是如何开启和关闭的.

    0

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