LGR5 promotes tumorigenicity and invasion of glioblastoma stem‐like cells and is a potential therapeutic target for a subset of glioblastoma patients

• Published in: JOURNAL OF PATHOLOGY Vol. 247; no. 2; pp. 228 - 240
• Main Authors: Xie, Yuan, Sundström, Anders, Maturi, Naga P, Tan, E‐Jean, Marinescu, Voichita D, Jarvius, Malin, Tirfing, Malin, Jin, Chuan, Chen, Lei, Essand, Magnus, Swartling, Fredrik J, Nelander, Sven, Jiang, Yiwen, Uhrbom, Lene
• Format: Journal Article Publication
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.02.2019; Wiley Subscription Services, Inc
• Subjects: Animals; Biomarkers; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Brain tumors; Cell Movement - drug effects; Cell Movement - radiation effects; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Cell Self Renewal; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma - therapy; glioblastoma stem-like cells; Humans; invasion; Leucine; LGR5; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - radiation effects; Olig2 protein; Oligodendrocyte Transcription Factor 2 - genetics; Oligodendrocyte Transcription Factor 2 - metabolism; Patients; Phenotype; Phenotypes; radiation response; Radiation Tolerance; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; self-renewal; Signal Transduction; Stem cells; Therapeutic applications; Tumor Cells, Cultured; Tumorigenicity; glioblastoma stem-like cells; invasion; LGR5; self-renewal; radiation response
• ISSN: 0022-3417; 1096-9896; 1096-9896
• DOI: 10.1002/path.5186

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor which lacks efficient treatment and predictive biomarkers. Expression of the epithelial stem cell marker Leucine‐rich repeat‐containing G‐protein coupled receptor 5 (LGR5) has been described in GBM, but its functional role has not been conclusively elucidated. Here, we have investigated the role of LGR5 in a large repository of patient‐derived GBM stem cell (GSC) cultures. The consequences of LGR5 overexpression or depletion have been analyzed using in vitro and in vivo methods, which showed that, among those with highest LGR5 expression (LGR5high), there were two phenotypically distinct groups: one that was dependent on LGR5 for its malignant properties and another that was unaffected by changes in LGR5 expression. The LGR5‐responding cultures could be identified by their significantly higher self‐renewal capacity as measured by extreme limiting dilution assay (ELDA), and these LGR5high‐ELDAhigh cultures were also significantly more malignant and invasive compared to the LGR5high‐ELDAlow cultures. This showed that LGR5 expression alone would not be a strict marker of LGR5 responsiveness. In a search for additional biomarkers, we identified LPAR4, CCND2, and OLIG2 that were significantly upregulated in LGR5‐responsive GSC cultures, and we found that OLIG2 together with LGR5 were predictive of GSC radiation and drug response. Overall, we show that LGR5 regulates the malignant phenotype in a subset of patient‐derived GSC cultures, which supports its potential as a predictive GBM biomarker. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.