如何阻止癌细胞转移?PNAS出妙招:抑制溶酶体
2018/08/28
很多癌症之所以凶险,都与肿瘤细胞转移有关。近日,《PNAS》期刊描述了科罗拉多大学癌症中心的科学家们发现的对抗癌转移的新策略:通过关闭细胞“自己吃自己”的重要一步,促使癌细胞无法转移。


细胞自噬

来自于科罗拉多大学癌症中心的科学家们关注的是“细胞自噬”(Autophagy)过程。

自噬源于希腊语中的“自己吃自己”(autophagy),是细胞维持物质周转的重要机制,负责将细胞垃圾运输至溶酶体。对于肿瘤细胞而言,通过自噬捕获、降解受损或者不必要的结构物质更有利于其生存。

自噬具体过程包括两步:首先,细胞垃圾会被自噬体(autophagosome)包裹;随后,自噬体会与溶酶体融合形成自噬溶酶体,进一步降解其所包裹的内容物,以实现细胞本身的代谢需要和某些细胞器的更新。


细胞自噬过程(图片来源:华威大学)

如何阻止癌细胞转移?

在这项研究中,科学家们比较了分别抑制自噬、溶酶体对于转移性细胞的影响差异——当人为抑制自噬时,转移性和非转移性癌细胞的生长都有所受限;当使用氯喹(Chloroquine)抑制自噬和溶酶体功能时,非转移性细胞生长同样受到阻碍,而转移性癌细胞却被杀死了。

文章作者Michael J. Morgan表示:“令人惊讶的是,对于转移性细胞而言,自噬本身并不是最重要的。如果在早期阶段抑制自噬,可以同时抑制转移性和非转移性细胞的生长。但是如果在晚期阻止,即自噬溶酶体阶段,我们则可以更有效地靶向转移性细胞,将其杀死。”

“高度转移性细胞离开‘原住址’需要承担很多压力。细胞应对压力的方式之一是处理细胞垃圾或者受损的细胞组件并回收。当我们抑制细胞内掌管回收的溶酶体的活性,癌细胞会因为压力过大而无法生存。”Michael J. Morgan解释道。


关键蛋白

研究人员推测,溶酶体中一定有特殊的“东西”是针对转移性细胞的。为了找到答案,他们构建了氯喹耐药性细胞。结果发现,随着对氯喹耐药性的增加,癌细胞会失去转移的潜力。

“当癌细胞能够抵抗氯喹,它们会失去转移的能力。当癌细胞可以转移时,它们会对氯喹敏感。因此,当它们依赖的处理氯喹的溶酶体活性受阻时,转移性癌细胞会停止生长且死亡。” Michael J. Morgan表示道。

研究团队提出一个假设:当癌细胞耐药时,即便它们仍然会继续生长,但是不会转移。这一结果有助于医生确定哪类癌症患者能够最大受益于氯喹治疗。

他们进一步发现,对药物抵抗和敏感的细胞之间的主要区别是一种叫做ID4的蛋白质水平——当ID4蛋白水平低时,癌细胞对氯喹敏感,具有转移特性;当ID4蛋白水平高,癌细胞对氯喹表现出耐药性,且转移能力减弱。

事实上,ID4已经被应用于膀胱癌、前列腺癌、乳腺癌中,即ID4水平越高,患者治疗效果往往越好。Michael J. Morgan说:“ID4是一个公认的生物标志物。转移性癌细胞表达的ID4水平较低。如果癌细胞对氯喹耐药,ID4水平会上升。”

总而言之,ID4水平有望被应用于预测癌细胞的转移性,而且这种转移性很大程度上依赖于溶酶体的作用。患者原发性肿瘤的ID4水平有望用于预测患者对氯喹药物治疗的反应。

责编:悠然

参考资料:

Study shows how to make (and destroy) a metastatic cancer cell

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  • Metastatic cells are preferentially vulnerable to lysosomal inhibition

    Molecular alterations that confer phenotypic advantages to tumors can also expose specific therapeutic vulnerabilities. To search for potential treatments that would selectively affect metastatic cells, we examined the sensitivity of lineage-related human bladder cancer cell lines with different lung colonization abilities to chloroquine (CQ) or bafilomycin A1, which are inhibitors of lysosome function and autophagy. Both CQ and bafilomycin A1 were more cytotoxic in vitro to highly metastatic cells compared with their less metastatic counterparts. Genetic inactivation of macroautophagy regulators and lysosomal proteins indicated that this was due to greater reliance on the lysosome but not upon macroautophagy. To identify the mechanism underlying these effects, we generated cells resistant to CQ in vitro. Surprisingly, selection for in vitro CQ resistance was sufficient to alter gene expression patterns such that unsupervised cluster analysis of whole-transcriptome data indicated that selection for CQ resistance alone created tumor cells that were more similar to the poorly metastatic parental cells from which the metastatic cells were derived; importantly, these tumor cells also had diminished metastatic ability in vivo. These effects were mediated in part by differential expression of the transcriptional regulator ID4 (inhibitor of DNA binding 4); depletion of ID4 both promoted in vitro CQ sensitivity and restored lung colonization and metastasis of CQ-resistant cells. These data demonstrate that selection for metastasis ability confers selective vulnerability to lysosomal inhibitors and identify ID4 as a potential biomarker for the use of lysosomal inhibitors to reduce metastasis in patients.

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