“改造”癌细胞对抗癌症?Science子刊展示:巧用“魔剪”的新思路
2018/07/18
“利用癌细胞自己攻击自己”——这是《Science Translational Medicine》期刊最新一篇文章揭示的一种抗癌新尝试。科学家们借助“魔剪”CRISPR对癌细胞进行“改造”,使其能够对抗自己的同类。这一招“借力打力”有望适用于多种癌症类型。


图片来源:Pixabay

这一“利用癌细胞治疗癌症”的创新由布列根和妇女医院的科学家们完成。他们利用基因编辑的力量,在不同类型的癌症细胞上进行了临床前试验,均取得了良好结果,为治疗原发性、复发性和转移性癌症的临床转化迈出了关键一步。

“这只是冰山一角,”通讯作者、BWH神经外科的干细胞治疗和成像中心主任Khalid Shah表示,“我们的研究表明,‘改造’患者自身的癌细胞并利用它们对抗癌症是可行的。”


这一新策略利用了癌细胞的自我归巢能力(self-homing ability)——癌细胞能够追踪同类型的病变细胞(位于同一器官或者已经扩散至其他身体部位),回到主要的肿瘤区域。科学家们猜想,以癌细胞作为载体,可以克服药物运输的困难,有助于快速定位肿瘤的位置。

研究小组开发并检测了两种利用癌细胞能力的技术:1)“off the shelf”技术,使用的是预先改造过的肿瘤细胞(对治疗耐受,需要与患者的HLA表型相匹配),能够在原发性肿瘤区域分泌死亡受体靶向配体;2)“autologous”技术,利用CRISPR技术编辑患者癌细胞(对治疗敏感)的基因组,并插入治疗分子,适用于转移性、复发性癌症。这些经过修饰的细胞随后会回输至患者体内。


28天内,经CRISPR改造过的癌细胞(绿色)逐步向胶质母细胞瘤(红色)迁移的过程(图片来源:C. Reinshagen et al., Science Translational Medicine)

为了检测这两种方法,研究团队构建了原发性、复发性脑癌和乳腺癌(已经扩散至大脑)四种小鼠模型。结果发现,改造过的癌细胞会直接迁移至肿瘤位置,而且,这些细胞会针对性地消灭小鼠体内的复发性、转移性癌症。

这一疗法增加了小鼠的存活率。改造过的细胞配备有“自杀开关”,在治疗结束后,这一开关会被激活,细胞因此而消亡。

“我们的研究展现了利用癌细胞自我归巢特性在抗癌中的潜能。”Khalid Shah总结道。

责编:艾曼

参考资料:

Engineered cancer cells can fight primary and metastatic cancer

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  • CRISPR-enhanced engineering of therapy-sensitive cancer cells for self-targeting of primary and metastatic tumors

    Tumor cells engineered to express therapeutic agents have shown promise to treat cancer. However, their potential to target cell surface receptors specific to the tumor site and their posttreatment fate have not been explored. We created therapeutic tumor cells expressing ligands specific to primary and recurrent tumor sites (receptor self-targeted tumor cells) and extensively characterized two different approaches using (i) therapy-resistant cancer cells, engineered with secretable death receptor–targeting ligands for “off-the-shelf” therapy in primary tumor settings, and (ii) therapy-sensitive cancer cells, which were CRISPR-engineered to knock out therapy-specific cell surface receptors before engineering with receptor self-targeted ligands and reapplied in autologous models of recurrent or metastatic disease. We show that both approaches allow high expression of targeted ligands that induce tumor cell killing and translate into marked survival benefits in mouse models of multiple cancer types. Safe elimination of therapeutic cancer cells after treatment was achieved by co-engineering with a prodrug-converting suicide system, which also allowed for real-time in vivo positron emission tomography imaging of therapeutic tumor cell fate. This study demonstrates self-tumor tropism of engineered cancer cells and their therapeutic potential when engineered with receptor self-targeted molecules, and it establishes a roadmap toward a safe clinical translation for different cancer types in primary, recurrent, and metastatic settings.

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