A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer
A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer
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DOI：
10.1038/nature21713
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发表时间：
2017-03-30
期刊：
影响因子：
64.8
通讯作者：
de Sauvage, Frederic J.
中科院分区：
文献类型：
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作者：
de Sousa e Melo, Felipe;Kurtova, Antonina V.;de Sauvage, Frederic J.
癌症干细胞（CSCs）被认为是肿瘤进展和转移背后的驱动力，使它们成为有吸引力的癌症靶点。然而，在大多数恶性肿瘤中，仍然缺乏结论性的实验证据来证明它们的功能相关性。在这里，我们展示了富含亮氨酸的含有重复序列的g蛋白偶联受体5 （Lgr5）在小鼠肿瘤中识别肠道CSCs，以重现人类结直肠癌的临床进展。我们证明选择性Lgr5（+）细胞消融限制原发肿瘤生长，但不导致肿瘤消退。相反，肿瘤是由增殖的Lgr5细胞维持的，这些细胞不断尝试补充Lgr5+ CSC库，导致肿瘤在治疗停止后快速重新开始生长。值得注意的是，CSCs对于结直肠癌肝转移的形成和维持至关重要。总之，我们的数据突出了原发性肿瘤与转移性肿瘤生长的不同CSC依赖性，并表明靶向CSC可能代表了转移性疾病管理的治疗机会。
Cancer stem cells (CSCs) have been hypothesized to represent the driving force behind tumour progression and metastasis, making them attractive cancer targets. However, conclusive experimental evidence for their functional relevance is still lacking for most malignancies. Here we show that the leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) identifies intestinal CSCs in mouse tumours engineered to recapitulate the clinical progression of human colorectal cancer. We demonstrate that selective Lgr5(+) cell ablation restricts primary tumour growth, but does not result in tumour regression. Instead, tumours are maintained by proliferative Lgr5-cells that continuously attempt to replenish the Lgr5+ CSC pool, leading to rapid re-initiation of tumour growth upon treatment cessation. Notably, CSCs are critical for the formation and maintenance of liver metastasis derived from colorectal cancers. Together, our data highlight distinct CSC dependencies for primary versus metastasic tumour growth, and suggest that targeting CSCs may represent a therapeutic opportunity for managing metastatic disease.