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Science颠覆性发现:抑癌基因突变后,通过逃避免疫系统监控而导致癌症

2021-09-22 “E药世界”公众号 “E药世界”公众号

,癌症——作为“众病之王”,却仿佛一道难以攻克的天堑,至今仍未被人类所战胜。

随着科技进步和医学发展,许多令古代医师束手无策的疾病在当下都逐一被缓解,甚至彻底治愈。然而,癌症——作为“众病之王”,却仿佛一道难以攻克的天堑,至今仍未被人类所战胜。

破解癌症发生发展的机制对癌症的治疗是至关重要的。肿瘤抑制基因的突变被认为是导致癌症的重要原因,长期以来,科学家们一直认为,基因突变促使癌细胞不受控制地生长。然而,一项最新研究却表明,实际情况比这要复杂得多。

2021年9月16日,哈佛医学院的研究人员在国际顶尖学术期刊 Science 发表了题为:The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation 的研究论文。

该研究发现,有超过100个突变的肿瘤抑制基因并不是直接作用于癌细胞,促使它们疯狂生长,而是采用“曲线救国”的方式——阻止免疫系统识别和摧毁肿瘤组织。这才是肿瘤组织不受控增殖的真实原因。

众所周知,许多癌细胞系都具有无限增殖的潜力,这被认为是肿瘤抑制基因突变的结果。但通常情况下,免疫系统会将癌细胞视为一种新兴的病原体,并试图将其消灭。因此,癌细胞仅仅拥有无限增殖的能力还远远不够,还必须通过基因突变进化出逃脱免疫系统监控的能力。

打个比方,这就像著名的科幻电影《黑客帝国》中,主角尼奥(癌细胞)脱离“矩阵”(人体)的掌控后,就会被无数黑衣人(免疫系统)的追捕,尼奥想要获得自由,就必须彻地击败或做好伪装瞒过黑衣人。而对于癌细胞来说,后者无疑更容易做到。

在这项研究中,研究团队利用CRISPR技术构建了7500个肿瘤抑制基因单突变的肿瘤细胞系,将这些细胞植入到小鼠体内。而这些小鼠也分为两组,对照组的野生型小鼠的免疫系统完好无损,实验组则为免疫缺陷小鼠。

基于CRISPR技术筛选肿瘤生长所需的基因突变

研究人员使用基因分析来确定哪些突变基因在肿瘤形成中起作用。他们发现,在每一种测试的肿瘤细胞系中,相对于免疫缺陷小鼠,野生型小鼠身上长出来的肿瘤存在肿瘤抑制基因缺失的显着富集。其中,三分之一的肿瘤抑制基因是通过免疫逃避作用的。

研究团队还将研究重点聚焦于一种特殊的基因——GNA13,并以此阐明了这一过程的发生机制。通过对该基因的深入研究,研究人员发现,该突变为癌细胞做了伪装,使得免疫系统的T细胞无法检测到它们。

GNA13缺失的抑瘤作用是由于CCL2的表达和分泌的增加,从而导致肿瘤巨噬细胞的增加

本研究的通讯作者 Stephen Elledge 博士表示:“令人震惊的是,这些基因突变都在教导癌细胞如何逃避免疫系统,而不是简单地说‘生长,生长,生长!’”

突变的肿瘤抑制基因及其产生的蛋白质是癌症药物开发中常见的靶点,但有些却令人沮丧地难以捉摸,比如p53。本月早些时候,范德堡大学的一个团队发表的一项研究表明,非整倍体的染色体异常现象在p53突变的细胞中很常见,他们认为这一发现可以为针对这种异常蛋白的药物开发提供信息。

此外,今年6月,瑞典卡罗林斯卡学院的 Galina Selivanova 等人在 Cancer Discovery 上发表文章显示,可以通过MDM2抑制剂来重新激活正常的p53。因此,MDM2抑制剂联合其他抑制免疫检查点的药物,可以更好地抑制癌细胞生长。

Stephen Elledge 博士认为,他们的研究提供了一份肿瘤抑制基因列表,这有助于科学家们更好地了解癌症是如何逃避免疫系统的。他说道:“肿瘤可能使用了数百种途径实现免疫逃避,而发现这些途径可能会激发治疗癌症的新方法。

原始出处:

TIMOTHY D. MARTIN, et al. The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation. Science,2021.

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    2021-09-24 jichang

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多年来,各类癌症捷报频传。但令人惋惜的是,在过去长达40年的时间里,喜讯似乎一直与白血病患者无缘。近日的一项研究或许可以打破这一僵局。耶路撒冷希伯来大学医学院的研究小组开发了一种新的生物药物,对于实验室小鼠的急性白血病治愈率高达50%。

Molecular Cell:揭示抑癌基因PTEN抑制糖酵解活性新机制

瓦博格效应(Warburg effect),即肿瘤细胞即使在氧气充足的情况下仍主要通过糖酵解途径代谢葡萄糖,是肿瘤细胞的一大特征。PTEN作为抑癌基因,通过抑制PI3K/AKT信号通路减少葡萄糖摄取等方式对糖酵解活性发挥间接抑制作用。但PTEN是否与糖酵解代谢酶相互作用直接抑制糖酵解活性尚不清楚。

Sci Trans Med:纳米技术助力恢复p53抑癌基因活性,成功延缓癌症发展!

众所周知,p53抑癌基因在癌症的发生发展中发挥着至关重要的作用。它在癌症患者体内突变率高达50%,是人体内突变频率最高的癌症相关基因。牵一发而动全身,从营养代谢、DNA的修复,到细胞的衰老、恶变和死亡都能看到它的身影。然而,对于那些没有出现p53基因突变的癌症患者,该基因的活性也处于抑制状态。多年来,科学家们一直在致力于寻找恢复p53基因活性的新方法……

PNAS:抑癌基因失活将导致胃肠道间质瘤恶性进展

中国科学院上海营养与健康研究所—长征医院联合转化医学中心王跃祥团队在国际上首次解析了胃肠道间质瘤恶性进展新机制,解析了抑癌基因的失活是间质瘤恶性进展的重要分子机制,提供了区分间质瘤恶性程度的分子标记物,为间质瘤的精准治疗提供依据。该研究成果 10 月 22 日发表于美国《国家科学院院刊》。

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