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Cancers:狡猾!肺癌细胞如何利用“抑癌因子”对化疗产生抗性?

2019-09-28 药明康德 药明康德

对非小细胞肺癌(NSCLC)而言,化疗的抗药性是一个大问题。特别是复发时,癌症往往会变得更具有侵袭性。近日,乔治亚大学医学院和奥古斯塔大学乔治亚癌症中心Amyn Rojiani博士领导的科学家团队揭示了NSCLC癌细胞在化疗中规避凋亡的一条途径。在近日发表在Cancers期刊上的文章中,在该团队重新定义了金属蛋白酶1的组织抑制剂(Tissue inhibitor of metalloprotein

对非小细胞肺癌NSCLC)而言,化疗的抗药性是一个大问题。特别是复发时,癌症往往会变得更具有侵袭性。近日,乔治亚大学医学院和奥古斯塔大学乔治亚癌症中心Amyn Rojiani博士领导的科学家团队揭示了NSCLC癌细胞在化疗中规避凋亡的一条途径。在近日发表在Cancers期刊上的文章中,在该团队重新定义了金属蛋白酶1的组织抑制剂(Tissue inhibitor of metalloproteinase-1,TIMP-1)水平的升高,对癌细胞产生化疗抗药性的作用。

癌细胞大量使用基质金属蛋白酶(matrix metalloproteinase,MMP)来介导原发肿瘤位的生长和转移。MMPs通常会在组织损伤后分泌,从而降解邻近组织(如胶原蛋白),以便细胞和蛋白因子的涌入,进而进入修复状态。而在修复过程即将结束时,TIMP-1的水平会显著增加。TIMP-1是MMP的天然抑制剂,它既防止修复过程失控,也防止健康组织被破坏。此前多项研究报道,相对于健康的肺细胞,TIMP-1在肺癌细胞中水平显著升高。因为其抑制MMP的功能,TIMP-1通常被认为是一种抑癌因子,然而在NSCLC患者中,其高水平表达与癌症患者的预后不良相关。
 


▲MMPs和TIMP-1可以促进癌细胞的生长和扩散

该团队揭示的途径显示,当面对化疗这一最常见的NSCLC疗法时,肺癌细胞首先会表达高水平TIMP-1分子,TIMP-1随后提高了可以调节炎症反应的免疫系统调节剂IL-6的表达。化疗时,两者的水平都进一步得到提高。IL-6已被认为与化疗抗药性有关,而在某些癌症中,IL-6已被证明可调节TIMP-1。但至少在NSCLC中,科学家发现是TIMP-1率先引导了对细胞凋亡的规避。

实验中,研究人员对比了两种一线化疗药品吉西他滨和顺铂对人类NSCLC癌细胞,以及敲除了TIMP-1的相同细胞的活性。他们发现在缺少TIMP-1的细胞中,IL-6的产量下降了,引发了细胞的死亡。当添加回TIMP-1时,IL-6水平升高,并伴随着细胞存活率的升高。而使用抗体中和TIMP-1也会降低IL-6的水平。此外,存活下来的癌细胞的抗药性甚至高于原来的细胞,并且具有更高的TIMP-1和IL-6水平。研究人员接着研究了IL-6信号通路的下游靶点STAT3。基因调控分子STAT3参与控制细胞生长和分裂,运动和凋亡,这些活动皆与癌细胞周期有关。在IL-6高水平的情况下,他们观察到STAT3进入细胞核,这意味着它也被激活了。

“这是首篇在NSCLC中,描述TIMP-1影响IL-6,IL-6激活STAT3的报道,展示了至少在肺癌中,TIMP-1在控制IL-6,”乔治亚大学医学院病理学系主任,文章的共同作者Amyn Rojiani博士表示:“我们以多种不同的方式证明两者之间的协同效应,如果TIMP-1上升,IL-6则上升;如果TIMP-1下降,IL-6则下降。”

该团队的工作表明,TIMP-1和IL-6的水平可能是判断患者预后更有价值的新指标,也是改善预后的重要新靶点。

原始出处:.
 Wei Xiao, Lan Wang, John Howard, et al. TIMP-1-Mediated Chemoresistance via Induction of IL-6 in NSCLC. Cancers. Aug 2019.

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    2020-04-02 anminleiryan
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    2020-03-02 yige2012
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    2019-09-30 yxch36

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疾病控制率100% 安全性良好 非小细胞肺癌有望迎来靶向药

近日举行的IASLC 2019世界肺癌大会(WCLC 2019)上,一项测试KRAS抑制剂AMG 510毒性的临床试验表明,在晚期非小细胞肺癌患者中,AMG 510对KRAS G12C突变患者显示出早期有潜力的抗肿瘤活性,且副作用很少。这项1期临床试验吸引了业界众多的关注,是本次大会最瞩目的研发项目之一。图示:胸片上可见肺癌。(来源:James Heilman医学博士/维基百科)KRAS是一种鸟嘌

Lancet oncol:Pegilodecakin联合抗PD-1单克隆抗体是否可为晚期实体肿瘤提供新的治疗机会?

IL-10具有抗炎和CD8+T细胞刺激作用。Pegilodecakin (聚乙二醇化的 IL-10)是一类长效IL-10受体激动剂,可诱导单克隆T细胞扩增,在晚期实体肿瘤中具有单药活性。现研究人员对pegilodecakin联合抗PD-1单克隆抗体抑制剂治疗晚期实体肿瘤的安全性和活性进行评估。这是一个在USA的12个癌症研究中心开展的多中心、多队列的开放性1b期试验(IVY),招募年满18岁的病理

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