The LGR5 gene (Leucine-rich repeat-containing G protein-coupled receptor 5) encodes a crucial cell-surface receptor that acts as a universal marker for stem cells.
It drives rapid tissue renewal and drives the Wnt signaling pathway, playing major roles in organ maintenance and cancer progression.
Plasticity of some cancerous epithelial cells allows them to transform into mesenchymal cells.
The transformation causes cells to lose normal epithelial traits such as cell to cell adhesion, and acquire mesenchymal traits, such as motility that can help them evade targeted therapy.
As a result, tumors tend to grow become resistant to treatment and metastasize.
Cells in epithelial tissue that exhibit plasticity expressed leucine-rich repeat containing G protein coupled receptive 5 (LGR5).
LGR5 is an epithelial stem cell receptor involved in signaling and proliferation, acting as a pathway for cells to switch between epithelial and a mesenchymal state.
LGR5 primarily marks actively dividing, multipotent stem cells in adult tissues, such as the intestinal tract, hair follicles, and endometrium.
When bound to R-spondin ligands, LGR5 interacts with Wnt receptors to trigger the β-catenin signaling pathway.
This network is instrumental in regulating tissue regeneration and stemness.
Cancer Stem Cells: In many tumors (e.g., colorectal, gastric, ovarian, and brain cancers), LGR5 is upregulated and helps define a subpopulation of cancer stem cells capable of tumor initiation, metastasis, and therapy resistance.
LGR5 is a therapeutic target for novel antibody-drug conjugates (ADCs) and bispecific antibodies in colorectal cancer.
LGR5 is a cell-surface receptor and established marker of adult stem cells and cancer stem cells, with significant implications as both a biomarker and an emerging therapeutic target across multiple cancer types.
LGR5 (also known as GPR49) is a seven-transmembrane domain receptor of the rhodopsin family. Its primary signaling functions include:
Wnt/catenin potentiation.
Cell adhesion regulation: LGR5 promotes cell-cell adhesion.
LGR5 constitutively activates NF-signaling contributing to intestinal crypt growth and colon cancer cell survival.
LGR5 rapidly and constitutively internalizes to the trans-Golgi network.
LGR5 is a marker of actively cycling adult stem cells in the intestinal crypts, stomach, hair follicle, mammary gland, and eye.
Single isolated LGR5+ intestinal cells can generate self-organizing crypt/villus organoid structures in vitro, demonstrating their full stem cell potential.
LGR5 is overexpressed in numerous malignancies and marks cancer stem cell (CSC) populations that drive tumor initiation, progression, metastasis, and therapeutic resistance.
Colorectal cancer: LGR5+ cells serve as CSCs with self-renewal and differentiation capacity.
Selective ablation of LGR5+ CSCs leads to tumor regression, though tumors can regrow through plasticity-differentiated KRT20+ cells can revert to LGR5+ CSCs.
Loss of LGR5 through therapy or gene ablation activates MET-STAT3 signaling, conferring resistance.
Hepatocellular carcinoma: LGR5 marks tumor-initiating cells resistant to sorafenib and 5-FU; LGR5 lineage ablation combined with 5-FU augments therapeutic efficacy.
LGR5 also regulates metabolic plasticity via the mTORC2/RAC1/AKT axis.
Breast cancer: LGR5 overexpression is associated with recurrence and poor outcomes; LGR5-high cells exhibit CSC properties including self-renewing sphere formation and high tumorigenicity.
LGR5 promotes migration, invasion, metastasis, and angiogenesis in Gastric, ovarian, prostate, and brain cancers:
Importantly, LGR5’s role is context-dependent in some settings (e.g., certain colorectal cancer cell lines, B-cell malignancies), LGR5 can paradoxically act as a tumor suppressor, restricting invasion and antagonizing Wnt signaling.
Several LGR5-directed therapeutic modalities are in preclinical and early clinical development:
Antibody-drug conjugates (ADCs): Anti-LGR5 ADCs exploit LGR5’s constitutive internalization to deliver cytotoxic payloads (e.g., MMAE) selectively to LGR5+ cancer cells, with demonstrated tumor eradication and prevention of recurrence in colon cancer xenografts.
Bispecific T-cell engagers (BiTEs):LGR5-BiTE constructs promote T-cell-mediated killing of LGR5+ cancer cells.
CAR-T cells show specific and potent LGR5+ cancer cell killing in vitro and effective tumor targeting in vivo.
Peptibody-drug conjugates and bispecific antibodies show promising efficacy and tolerability in colorectal cancer and other tumor types.
A key challenge is cancer cell plasticity is that LGR5-negative cells can dedifferentiate back into LGR5+ CSCs after LGR5+ cell ablation, suggesting that combination strategies (e.g., LGR5 targeting plus chemotherapy or MET-STAT3 inhibition) may be necessary for durable responses.