Abstract
Cancer stem cells (CSCs) or tumor-initiating cells (TICs) are thought to be the main drivers for disease progression and treatment resistance across various cancer types. Identifying and targeting these rare cancer cells, however, remains challenging with respect to therapeutic benefit. Here, we report the enrichment of LGR5 expressing cells, a well-recognized stem cell marker, in mouse liver tumors, and the upregulation of LGR5 expression in human hepatocellular carcinoma. Isolated LGR5 expressing cells from mouse liver tumors are superior in initiating organoids and forming tumors upon engraftment, featuring candidate TICs. These cells are resistant to conventional treatment including sorafenib and 5-FU. Importantly, LGR5 lineage ablation significantly inhibits organoid initiation and tumor growth. The combination of LGR5 ablation with 5-FU, but not sorafenib, further augments the therapeutic efficacy in vivo. Thus, we have identified the LGR5+ compartment as an important TIC population, representing a viable therapeutic target for combating liver cancer.
Highlights
Cancer stem cells (CSCs) or tumor-initiating cells (TICs) are thought to be the main drivers for disease progression and treatment resistance across various cancer types
By adopting Lgr5–diphtheria toxin receptor (DTR)–green florescent protein (GFP) knock-in mice (Fig. 1a), we first investigated the presence of LGR5+ cells (GFP-co-expressing cells) in the healthy and injured liver, and during carcinogenesis
LGR5 cells are absent in the homeostatic liver (Fig. 1c), either a single course or repeated administration of DEN can rapidly trigger the emergence of LGR5–GFP+ cells
Summary
Cancer stem cells (CSCs) or tumor-initiating cells (TICs) are thought to be the main drivers for disease progression and treatment resistance across various cancer types. Identifying and targeting these rare cancer cells, remains challenging with respect to therapeutic benefit. Within the framework of this theory, CSCs/TICs would be characterized by a large capacity for self-renewal, a potential for differentiation into different cell types that constitute the tumor, and a resistance to conventional treatment[1]. Our results show that in liver cancer, an LGR5+ compartment exists that is superior in tumor initiation and mediates therapy resistance Targeting this compartment constitutes a rational avenue for combating this disease
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