In recent years, the research on stem cells has broadened people's knowledge of the occurrence and development of tumors. Nearly all tumors are related to stem cells，and stem cell markers have become the focus of current research. LGR5 is a type of leucine-rich repeat receptor (LGR), and studies confirm that LGR5 is expressed at various levels in the crypts of the floor of the small intestine, the crypts of the large intestine, the basal column cells of the gastric glands, and hair follicles. Therefore, LGR5 is one of the potential markers for cancer stem cells. LGR5 is a Wnt signaling ligand that plays an active role in ontogeny. LGR5's binding partner, R-spondin (RSPO), can control Wnt signaling along with LGR5. This article analyzes the signaling pathways of LGR5 in tumor stem cells, summarizes the role of LGR5 there, and points out future research directions.

Xinjie Tang, Yinghua Su, Chao Zhou. The Review of Contribution of LGR5 towards Cancer Stem Cells and Its Signal Pathway. Frontiers in Medical Science Research (2022) Vol. 4, Issue 14: 14-19. https://doi.org/10.25236/FMSR.2022.041403.

[1] Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008 Oct;8(10):755-68. doi: 10.1038/nrc2499. Epub 2008 Sep 11. PMID: 18784658. 

[2] Gires O. Lessons from common markers of tumor-initiating cells in solid cancers. Cell Mol Life Sci. 2011 Dec;68(24):4009-22. doi: 10.1007/s00018-011-0772-9. Epub 2011 Jul 24. PMID: 21786143.

[3] Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8. doi: 10.1073/pnas.0530291100. Epub 2003 Mar 10. Erratum in: Proc Natl Acad Sci U S A. 2003 May 27;100(11):6890. PMID: 12629218; PMCID: PMC153034..

[4] O'Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007 Jan 4;445(7123):106-10. doi: 10.1038/nature05372. Epub 2006 Nov 19. PMID: 17122772.

[5] Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111-5.

[6] Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396-401. doi: 10.1038/nature03128. PMID: 15549107.

[7] Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007 Oct 25;449(7165):1003-7. doi: 10.1038/nature06196. Epub 2007 Oct 14. PMID: 17934449.

[8] NIH [Internet].America:LGR5 leucine rich repeat containing G protein-coupled receptor 5 [ Homo sapiens (human) ];c2022[cited 2022 May 22]. Available from: https: // www. ncbi. nlm. nih. gov/ gene/ 8549.

[9] Yang L, Tang H, Kong Y, Xie X, Chen J, Song C, Liu X, Ye F, Li N, Wang N, Xie X. LGR5 Promotes Breast Cancer Progression and Maintains Stem-Like Cells Through Activation of Wnt/β-Catenin Signaling. Stem Cells. 2015 Oct;33(10):2913-24. doi: 10.1002/stem.2083. Epub 2015 Jul 14. PMID: 26086949.

[10] Cao W, Li M, Liu J, Zhang S, Noordam L, Verstegen MMA, Wang L, Ma B, Li S, Wang W, Bolkestein M, Doukas M, Chen K, Ma Z, Bruno M, Sprengers D, Kwekkeboom J, van der Laan LJW, Smits R, Peppelenbosch MP, Pan Q. LGR5 marks targetable tumor-initiating cells in mouse liver cancer. Nat Commun. 2020 Apr 23;11(1):1961. doi: 10.1038/s41467-020-15846-0. PMID: 32327656; PMCID: PMC7181628.

[11] Carmon KS, Gong X, Lin Q, Thomas A, Liu Q. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11452-7. doi: 10.1073/pnas.1106083108. Epub 2011 Jun 21. PMID: 21693646; PMCID: PMC3136304.

[12] Schuijers J, Clevers H. Adult mammalian stem cells: the role of Wnt, Lgr5 and R-spondins. EMBO J. 2012 Jun 13;31(12):2685-96. doi: 10.1038/emboj.2012.149. Epub 2012 May 22. PMID: 22617424; PMCID: PMC3380219.

[13] Kim YM, Kahn M. The role of the Wnt signaling pathway in cancer stem cells: prospects for drug development. Res Rep Biochem. 2014;4:1-12. doi: 10.2147/RRBC.S53823. Epub 2014 Jul 31. PMID: 26566491; PMCID: PMC4640466.

[14] Morgan RG, Mortensson E, Williams AC. Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic? Br J Cancer. 2018 May;118(11):1410-1418. doi: 10.1038/s41416-018-0118-6. Epub 2018 May 30. PMID: 29844449; PMCID: PMC5988707.

[15] Xu L, Lin W, Wen L, Li G. Lgr5 in cancer biology: functional identification of Lgr5 in cancer progression and potential opportunities for novel therapy. Stem Cell Res Ther. 2019 Jul 29;10(1):219. doi: 10.1186/s13287-019-1288-8. PMID: 31358061; PMCID: PMC6664754.

[16] Fredriksson R, Lagerström MC, Lundin LG, Schiöth HB. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol. 2003 Jun;63(6):1256-72. doi: 10.1124/mol.63.6.1256. PMID: 12761335.

[17] Ji TH, Grossmann M, Ji I. G protein-coupled receptors. I. Diversity of receptor-ligand interactions. J Biol Chem. 1998 Jul 10;273(28):17299-302. doi: 10.1074/jbc.273.28.17299. PMID: 9651309.

[18] Stevens RC, Cherezov V, Katritch V, Abagyan R, Kuhn P, Rosen H, Wüthrich K. The GPCR Network: a large-scale collaboration to determine human GPCR structure and function. Nat Rev Drug Discov. 2013 Jan;12(1):25-34. doi: 10.1038/nrd3859. Epub 2012 Dec 14. PMID: 23237917; PMCID: PMC3723354.

[19] Kumar KK, Burgess AW, Gulbis JM. Structure and function of LGR5: an enigmatic G-protein coupled receptor marking stem cells. Protein Sci. 2014 May;23(5):551-65. doi: 10.1002/pro.2446. Epub 2014 Mar 19. PMID: 24677446; PMCID: PMC4005707.

[20] Peng WC, de Lau W, Forneris F, Granneman JC, Huch M, Clevers H, Gros P. Structure of stem cell growth factor R-spondin 1 in complex with the ectodomain of its receptor LGR5. Cell Rep. 2013 Jun 27;3(6):1885-92. doi: 10.1016/j.celrep.2013.06.009. PMID: 23809763.

[21] Kemper K, Prasetyanti PR, De Lau W, Rodermond H, Clevers H, Medema JP. Monoclonal antibodies against Lgr5 identify human colorectal cancer stem cells. Stem Cells. 2012 Nov;30(11):2378-86. doi: 10.1002/stem.1233. PMID: 22969042.

[22] Walker F, Zhang HH, Odorizzi A, Burgess AW. LGR5 is a negative regulator of tumourigenicity, antagonizes Wnt signalling and regulates cell adhesion in colorectal cancer cell lines. PLoS One. 2011;6(7):e22733. doi: 10.1371/journal.pone.0022733. Epub 2011 Jul 28. PMID: 21829496; PMCID: PMC3145754.

[23] Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006 Jun 15;66(12):6063-71. doi: 10.1158/0008-5472.CAN-06-0054. PMID: 16778178; PMCID: PMC 4386278.

[24] von Rahden BH, Kircher S, Lazariotou M, Reiber C, Stuermer L, Otto C, Germer CT, Grimm M. LgR5 expression and cancer stem cell hypothesis: clue to define the true origin of esophageal adenocarcinomas with and without Barrett's esophagus? J Exp Clin Cancer Res. 2011 Feb 23;30(1):23. doi: 10.1186/1756-9966-30-23. PMID: 21345220; PMCID: PMC3058063.

[25] Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, Sato T, Stange DE, Begthel H, van den Born M, Danenberg E, van den Brink S, Korving J, Abo A, Peters PJ, Wright N, Poulsom R, Clevers H. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell. 2010 Jan 8;6(1):25-36. doi: 10.1016/j.stem.2009.11.013. PMID: 20085740.

[26] Lee HJ, Myung JK, Kim HS, Lee DH, Go HS, Choi JH, Koh HM, Lee SJ, Jang B. Expression of LGR5 in mammary myoepithelial cells and in triple-negative breast cancers. Sci Rep. 2021 Sep 7;11(1):17750. doi: 10.1038/s41598-021-97351-y. PMID: 34493772; PMCID: PMC8423726.

[27] J Jaks V, Barker N, Kasper M, van Es JH, Snippert HJ, Clevers H, Toftgård R. Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat Genet. 2008 Nov;40(11):1291-9. doi: 10.1038/ng.239. Epub 2008 Oct 12. PMID: 18849992.

[28] Fei G, Yan-Cai W, Chen Y. Stem cell marker LGR5: a new target for cancer therapy. Chinese Journal of Tissue Engineering Research. Chinese Journal of Tissue Engineering Research, 2015;19(6):962-8.

[29] Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007 Oct 25;449(7165):1003-7. doi: 10.1038/nature06196. Epub 2007 Oct 14. PMID: 17934449.

[30] Fukuma M, Tanese K, Effendi K, Yamazaki K, Masugi Y, Suda M, Sakamoto M. Leucine-rich repeat-containing G protein-coupled receptor 5 regulates epithelial cell phenotype and survival of hepatocellular carcinoma cells. Exp Cell Res. 2013 Feb 1;319(3):113-21. doi: 10.1016/j. yexcr.2012.10.011. Epub 2012 Nov 2. PMID: 23127514.

[31] Hsu HC, Liu YS, Tseng KC, Hsu CL, Liang Y, Yang TS, Chen JS, Tang RP, Chen SJ, Chen HC. Overexpression of Lgr5 correlates with resistance to 5-FU-based chemotherapy in colorectal cancer. Int J Colorectal Dis. 2013 Nov;28(11):1535-46. doi: 10.1007/s00384-013-1721-x. Epub 2013 Jun 20. PMID: 23784051.

[32] Zhu K, Dai Z, Pan Q, Wang Z, Yang GH, Yu L, Ding ZB, Shi GM, Ke AW, Yang XR, Tao ZH, Zhao YM, Qin Y, Zeng HY, Tang ZY, Fan J, Zhou J. Metadherin promotes hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res. 2011 Dec 1;17(23):7294-302. doi: 10.1158/1078-0432.CCR-11-1327. Epub 2011 Oct 5. PMID: 21976539.

[33] Raslan AA, Yoon JK. R-spondins: Multi-mode WNT signaling regulators in adult stem cells. Int J Biochem Cell Biol. 2019 Jan;106:26-34. doi: 10.1016/j.biocel.2018.11.005. Epub 2018 Nov 12. PMID: 30439551.

[34] Ootani A, Li X, Sangiorgi E, Ho QT, Ueno H, Toda S, Sugihara H, Fujimoto K, Weissman IL, Capecchi MR, Kuo CJ. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med. 2009 Jun;15(6):701-6. doi: 10.1038/nm.1951. Epub 2009 Apr 27. PMID: 19398967; PMCID: PMC2919216.

[35] Sato T, van Es JH, Snippert HJ, Stange DE, Vries RG, van den Born M, Barker N, Shroyer NF, van de Wetering M, Clevers H. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature. 2011 Jan 20;469(7330):415-8. doi: 10.1038/nature09637. Epub 2010 Nov 28. PMID: 21113151; PMCID: PMC3547360.

[36] Leung C, Tan SH, Barker N. Recent Advances in Lgr5+ Stem Cell Research. Trends Cell Biol. 2018 May;28(5):380-391. doi: 10.1016/j.tcb.2018.01.010. Epub 2018 Feb 21. PMID: 29477614.