LGR5: An emerging therapeutic target for cancer metastasis and chemotherapy resistance

Abstract

Cancer stem cells play an important role in tumor progression and chemotherapy resistance. Leucine-rich G repeat-containing protein-coupled receptor 5 (LGR5) has been identified as a cancer stem cell marker in several cancer types. LGR5 is involved in cancer development and progression via several pathways including WNT/β-catenin signaling pathway. LGR5 plays a role in tumor progression by promoting cancer cell migration, invasion, metastasis, and angiogenesis in many cancers including colorectal, brain, gastric, and ovarian cancer. This review summarises the current knowledge on the expression and functional role of LGR5 in cancers, the molecular mechanisms regulated by LGR5, and the relationship between LGR5 and chemotherapy resistance. The review also includes highlights potential strategies to inhibit LGR5 expression and function. The majority of functional studies have shown that LGR5 plays an important role in promoting cancer progression, metastasis and chemotherapy resistance however, in some contexts LGR5 can also activate tumor-suppressive pathways and LGR5 negative cells can also promote cancer progression. The review highlights that targeting LGR5 is a promising anti-cancer treatment but the functional effect of LGR5 on tumor cells is complex may be dependent on cancer type, tumor microenvironment and cross-talk with other molecules in the LGR5 signaling pathway.

Keywords: Chemoresistant; LGR5; Metastasis; WNT/β-catenin.

Fig. 1

LGR5 Structure. (a) General architecture of G-protein coupled receptors (GPCRs) consists of an N-terminal domain attached to the 3 intracellular loops (ICL1-ICL3, blue) and three extracellular loops (ECL1-ECL3, green) followed by the C-terminal domain. (b) LGR5 consists of a signal peptide (dark grey), a large N-terminal domain with 17 leucine-rich repeats (grey) and 7 transmembrane helices (yellow). Modified from Kumar K.K. 2014 [16]. Created in BioRender. Wang, J. (2024) https://BioRender.com/e54f457

Fig. 2

The role of LGR5 in the WNT/β-catenin pathway. (a) In absence of WNT, the canonical WNT/β-catenin signaling pathway is off. Central destruction complex including Axin, Glycogen Synthase Kinase 3 Beta (GSK3 β), Adenomatous Polyposis Coli (APC) and Casein kinase 1 (CK1) induce the degradation of β-catenin. (b) In the presence of WNT, WNT binds to receptors Frizzled (FZD) and Low-Density Lipoprotein Receptor Related Protein 5 and 6 (LRP5/6), inducing dissociation of β-catenin from central destruction complex, which leads to accumulation of β-catenin. β-catenin binds to transcription factors TFC/LEF and activation of proto-oncogenic WNT target genes (c-MYC, CyclinD1 and Axin2). RING finger protein 43 (RNF43) and its homolog Zinc/Ring finger protein 3 (ZNRF3) negatively regulate WNT pathway by internalizing and degrading FZD and LRP5/6. (c) In the presence of R-spondin (RSPO), LGR5 binds to RSPO, RNF43/ZNRF3 is neutralized, and intracellular β-catenin is accumulated and increased, leading to enhanced activation of the WNT signaling pathway. Created in BioRender. Wang, J. (2024) https://BioRender.com/a56w665