GPCRs as Partners of LGR5 Cancer Stem Cells: Opportunities and Challenges

Hierarchical organization transpires within a tumor. It is appreciated that cancer stem cells (CSCs) are the cornerstone primary cells of such assemblies, fueled by molecular mechanisms that allow resistance to chemotherapy, vigorous self-renewal capacity, and resistance to immune therapy. Due to their powerful self-renewal capability, CSCs constantly initiate tumor cell proliferation, maintaining the growth state of the tumor. Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a known stem cell niche protein, is a G protein-coupled receptor (GPCR) that is involved in Wnt signaling. It was previously shown that members of protease-activated receptors (PARs) and another affiliate of GPCRs, the G protein-coupled receptor 25 (GPR25), elicit β-catenin stabilization and transcriptional activity. PARs and GPR25 can associate with LGR5 and markedly enhance β-catenin stabilization. The prospect of identifying additional cancer driver GPCRs partners of LGR5, such as the prostaglandin receptors, EP2 and EP4, and the lysophosphatidic acid receptors (LPARs), which have been demonstrated as capable of inducing β-catenin stabilization yet pending experimental association with LGR5, is discussed. The existence of an LGR5-GPCRs-β-catenin hub may potentially overcome tumor plasticity and alleviate drug resistance. It certainly elucidates new opportunities in the fight to eradicate cancer.