Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
Cancer Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
Nature. 2017 Mar 29;543(7647):676-680. doi: 10.1038/nature21713.
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.
癌症干细胞（CSCs）被假设为肿瘤进展和转移的驱动力，使它们成为有吸引力的癌症靶点。然而，对于大多数恶性肿瘤，仍然缺乏其功能相关性的明确实验证据。在这里，我们展示了富含亮氨酸重复序列的 G 蛋白偶联受体 5（Lgr5）可鉴定出在设计用于重现人类结直肠癌临床进展的小鼠肿瘤中肠道 CSCs。我们证明，选择性 Lgr5 细胞消融可限制原发性肿瘤生长，但不会导致肿瘤消退。相反，肿瘤由增殖性 Lgr5 细胞维持，这些细胞不断试图补充 Lgr5 CSC 池，导致在治疗停止后迅速重新开始肿瘤生长。值得注意的是，CSC 对于源自结直肠癌的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 可能是治疗转移性疾病的一个治疗机会。
