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J Cell Biol:靠吃同类幸存!科学家揭示化疗后癌细胞“卷土重来”的秘密

2019-09-25 杜姝 生物探索

自古以来,帝王将相的成功并不容易。或是一将成万骨枯,又或是本是同根生,相煎何太急。本以为人可以为了成功不折手段,万万没想到癌细胞的“不死之谜“也是如此。

自古以来,帝王将相的成功并不容易。或是一将成万骨枯,又或是本是同根生,相煎何太急。本以为人可以为了成功不折手段,万万没想到癌细胞的“不死之谜“也是如此。

这一“不死之谜”目前已被美国杜兰大学医学院的研究人员们所发现。他们表示:癌细胞在化疗中靠着“同类相食”的方式吞噬相邻细胞来求生。并且这类同类相残的行为可以为癌细胞提供生存所需的能量,并为化疗结束后的肿瘤复发奠定基础。该论文已于9月17日在期刊《Journal of Cell Biology》(JCB)上发表。

为什么乳腺癌化疗预后不良?

乳腺癌的化疗药物如阿霉素(doxorubicin)等,大致都是通过破坏 DNA 来杀死肿瘤细胞的,但是这样的化疗药物往往也会在最初治疗后诱导癌症复发。究其原因:相关化疗药物保留了癌细胞中 TP53 基因的拷贝。经过化疗后的癌细胞并不会因DNA 损伤而死亡,而只是停止了增殖,进入休眠的衰老模式。

保留了TP53基因又与化疗预后不良有何关系呢?说到这里,就必须解释一下关于TP53基因的“双面人生”。


突变型p53 

在人类肿瘤中,最常见的突变基因便是TP53——编码TP53蛋白。其存在两者类型:野生型(wtp53)和突变型(mtp53)。一个字母的区别却让这两个的基因有了不同的人生轨迹:野生型是一种抑癌基因,被称为“癌细胞警察”;而突变型则成了一种促癌基因,不仅丧失了抑癌的作用,而且抑制细胞的衰老和凋亡以剥夺细胞内的抑癌反应,帮助癌症的发展。

因此,一旦化疗药物保留了p53蛋白,则癌细胞就有“一线机会“通过仅保留的p53蛋白突变形式而重获新生。

该论文通讯作者、杜兰大学医学院生化与分子生物学系助理教授 James G. Jackson 在接受媒体采访时介绍也表示:乳腺癌的化疗药物并不会直接“杀死“具有 p53 活性的乳腺癌细胞,而是让其进入衰老状态。并且让人惊讶地是,这些衰老的癌细胞不仅能在化疗后维持生命,还能够分泌大量的炎症分子和促进肿瘤再生长的因子。这便是具有 p53 活性的乳腺癌患者在接受化疗后普遍生存率较低的原因。

衰老癌细胞如何“卷土重来“?

既然了解了乳腺癌化疗预后不良背后的秘密。如果想要改善其治疗效果,就必须了解这些处于衰老状态的癌细胞究竟是如何“复活”的。

该试验中,研究人员使用了荧光染色手段,在显微镜视野下发现:在接触阿霉素或其他化疗药物后,衰老的乳腺癌细胞常常“吃掉”邻近的癌细胞以侥幸生存。


小鼠体内乳腺癌衰老细胞(绿色)吞噬其他癌细胞(红色) 图片来源:杜兰大学医学院

让研究人员吃惊的是,这一“吃掉”过程显现不仅仅发生在培养皿中,在小鼠试验中也得以验证。并且,这不再是乳腺癌化疗后的特殊反应,在肺癌细胞和骨癌细胞中也发现了此类行为!

除此之外,研究人员还发现,尽管这并不是第一次发现癌细胞“同类相食”的现象,但在化疗药物的介导下,这样的吞噬同伴而求自保的发生率却比正常现象足足高出4倍之多!


化疗后衰老细胞吞噬同类癌细胞,白色箭头标识细胞被吞噬和降解 

进一步的研究再次发现震惊的现象:接受化疗后的衰老癌细胞消化能力极强,被“吃掉”的邻居癌细胞一般会在30-92个小时内被消化完毕,即使再难以下咽,也会在一周内被消化掉!并且,衰老癌细胞的食量也是十分惊人,不仅可以一次吞噬多个邻居癌细胞,还竟能够 “吃掉”正在高速增殖的邻居癌细胞。

杜兰大学医学院James G. Jackson实验室的博士后研究员Crystal A. Tonnessen-Murray及其同事对此现象进行了深入地研究,发现衰老的癌细胞会激活一组通常在白细胞中活跃的基因,这些基因可帮助白细胞吞噬入侵微生物和细胞碎片。在“吃掉”他们的邻居之后,这些衰老的癌细胞通过将“吃下”的邻居细胞输送到体内具有高度酸性结构的溶酶体中,来完全消化它们。

更为重要的是,研究人员确定了这一“同类相食“的现象能够帮助化疗后的衰老癌细胞保持活力,并且狠心吃掉邻居癌细胞的衰老细胞存活时间远大于不吃的衰老细胞。研究人员推测,这可能是因为“被迫牺牲”的邻居细胞为其提供了生存所需的能量和材料。

潜在治疗方式的启示


James G. Jackson博士 图片来源:杜兰大学医学院

James G. Jackson博士在采访中表示:抑制这类吞噬邻居癌细胞的行为可能会为乳腺癌的治疗提供新的方式。但仍有一些问题亟待解决,例如肿瘤是癌细胞和基质细胞(如血管免疫细胞)的复杂混合物,目前尚不清楚化疗治疗的癌细胞可以吞噬哪些细胞类型。吞噬的细胞所获得的优势,以及它究竟是如何导致复发的,需要进行更深入的检查。

同时,他还补充道:截至目前,癌细胞相互吞噬的现象并没有在乳腺癌患者体内得到证实。因为乳腺癌是一类高度异质性肿瘤,其组织学形态和基因组差异明显,需要大量患者样本才能保证研究质量。此外患者治疗的时间跨度差异也决定着衰老细胞吞噬的表型。这些问题在人类患者中都难以控制。

在接下来的研究中,James G. Jackson博士他们将继续试验以确定如何控制衰老癌细胞的状态以消除药物化疗的不良预后情况,从而给予患者更好的治疗。

原始出处:Crystal A. Tonnessen-Murray, Wesley D. Frey, Sonia G. Rao, et al. Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival. J Cell Biol. September 17, 2019

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    2020-04-27 sunylz
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    2019-10-31 维他命
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    2019-09-26 yxch36

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