肠隐窝细胞如何参与化疗耐药性
  • 在肠上皮中靶向表达肠干细胞/祖细胞标志物MSI1,能增强其对化疗药物5-氟尿嘧啶(5-FU)诱导的细胞毒性的恢复能力;
  • MSI1表达增加时,Lgr5high干细胞对5-FU仍然敏感,而Lgr5low祖细胞则重编程为耐药表型;
  • 这导致表达MSI1的细胞亚群的扩增,提高了对DNA损伤的抵抗力和解毒能力,这是休眠癌症干细胞(CSC)的典型特征,而休眠CSC在化疗后可以重新激活;
  • 分析结直肠癌患者显示,MSI1表达水平与肿瘤分级、肿瘤干细胞表型和化疗耐药性相关。
主编推荐语
爱的抉择
肠道隐窝中Lgr5high干细胞负责体内稳态更新,但其他细胞也可转变为干细胞样表型维持上皮的完整性,两者都可认为是结直肠癌(CRC)细胞的来源。肠道干细胞/祖细胞标志物MSI1在肠道稳态中有重要作用,常常在CRC患者中过表达。Cancer Research近期发表的文章,揭示了MSI1在促进损伤后肠道再生的重要性,同时也发现MSI1在化疗耐药性的肠癌干细胞中的新功能。
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Cancer Research [IF:9.727]

Deciphering the role of intestinal crypt cell populations in resistance to chemotherapy

解读肠道隐窝细胞群在化疗耐药中的作用

10.1158/0008-5472.CAN-20-2450

03-19, Article

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Abstract:收起
Intestinal crypts are composed of heterogeneous and highly plastic cell populations. Lgr5high-stem cells (SC) are responsible for homeostatic renewal, but other cells can revert to an SC-like phenotype to maintain epithelial integrity. Despite their distinct roles in orchestrating homeostasis, both populations have been designated as the putative "cell-of-origin" of colorectal cancer (CRC). However, their respective involvement in the emergence of drug-resistant cancer-SCs (CSC), responsible for tumor relapse and associated with poor outcome of CRC, remains elusive. In this context, the intestinal SC/progenitor-marker Musashi1 (MSI1) is interesting as it plays important functions in intestinal homeostasis and is frequently overexpressed in human CRC. Therefore, our aims were: 1) to study the impact of chemotherapy on Lgr5-expressing and MSI1-expressing cell populations, 2) to explore the effect of increased MSI1 levels in response to treatment, and 3) to evaluate the relevance in human CRC. Engineered mouse models treated with the therapeutic agent 5-fluorouracil showed that upon increased MSI1 levels, Lgr5high-SCs remain sensitive while Lgr5low-progenitors reprogram to a drug-resistant phenotype. This resulted in the expansion of an MSI1-expressing cell subpopulation with improved resistance to DNA damage and increased detoxification, typical properties of dormant-CSCs that can reactivate after chemotherapy. Analysis in CRC patients revealed a correlation between MSI1 levels and tumor grading, CSC phenotype, and chemoresistance. Altogether, these results shed new light on the biology and plasticity of normal crypt and cancer cell populations and also open new perspectives to target MSI1 to improve chemotherapy outcome.

First Authors:
Carla Frau

Correspondence Authors:
Michelina Plateroti

All Authors:
Carla Frau,Catherine Jamard,Gaspard Delpouve,Gabriela D A Guardia,Christelle Machon,Camilla Pilati,Clementine Le Neve,Pierre Laurent-Puig,Jérôme Guitton,Pedro A F Galante,Luiz O Penalva,Jean-Noel Freund,Christelle de la Fouchardière,Michelina Plateroti

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