LGR5: An Emerging Therapeutic Target for Cancer Metastasis and Chemotherapy Resistance

Overview

Journal Cancer Metastasis Rev

Date 2025 Jan 17

PMID 39821694

Authors

Wanqi Wang

Noor A Lokman

Simon C Barry

Martin K Oehler

Carmela Ricciardelli

Affiliations

Soon will be listed here.

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.

References

Zhou X, Geng L, Wang D, Yi H, Talmon G, Wang J . R-Spondin1/LGR5 Activates TGFβ Signaling and Suppresses Colon Cancer Metastasis. Cancer Res. 2017; 77(23):6589-6602. PMC: 5898809. DOI: 10.1158/0008-5472.CAN-17-0219. View

Yu L, Mao X, Wu S, Zhou L, Song W, Gong X . The correlation of the expressions of WWOX, LGR5 and vasohibin-1 in epithelial ovarian cancer and their clinical significance. Int J Clin Exp Pathol. 2020; 12(1):327-336. PMC: 6944017. View

Wong C, Mulero M, Barth E, Wang K, Shang X, Tikle S . Exploiting the Receptor-Binding Domains of R-Spondin 1 to Target Leucine-Rich Repeat-Containin G-Coupled Protein Receptor 5-Expressing Stem Cells in Ovarian Cancer. J Pharmacol Exp Ther. 2023; 385(2):95-105. PMC: 10108443. DOI: 10.1124/jpet.122.001495. View

Hou M, Chen P, Chu P . LGR5 overexpression confers poor relapse-free survival in breast cancer patients. BMC Cancer. 2018; 18(1):219. PMC: 5824537. DOI: 10.1186/s12885-018-4018-1. View

Wang B, Chen Q, Cao Y, Ma X, Yin C, Jia Y . LGR5 Is a Gastric Cancer Stem Cell Marker Associated with Stemness and the EMT Signature Genes NANOG, NANOGP8, PRRX1, TWIST1, and BMI1. PLoS One. 2016; 11(12):e0168904. PMC: 5199039. DOI: 10.1371/journal.pone.0168904. View

Forgham H, Johnson D, Carter N, Veuger S, Carr-Wilkinson J . Stem Cell Markers in Neuroblastoma-An Emerging Role for LGR5. Front Cell Dev Biol. 2015; 3:77. PMC: 4667032. DOI: 10.3389/fcell.2015.00077. View

Lv Z, Yu J, Zhang W, Xiong L, Wang F, Li L . Expression and functional regulation of stemness gene Lgr5 in esophageal squamous cell carcinoma. Oncotarget. 2017; 8(16):26492-26504. PMC: 5432274. DOI: 10.18632/oncotarget.15624. View

Morsy H, Gaballah A, Samir M, Nakundi V, Shamseya M, Mahrous H . LGR5, HES1 and ATOH1 in Young Rectal Cancer Patients in Egyptian. Asian Pac J Cancer Prev. 2021; 22(9):2819-2830. PMC: 8850894. DOI: 10.31557/APJCP.2021.22.9.2819. View

Yang L, Tang H, Kong Y, Xie X, Chen J, Song C . LGR5 Promotes Breast Cancer Progression and Maintains Stem-Like Cells Through Activation of Wnt/β-Catenin Signaling. Stem Cells. 2015; 33(10):2913-24. DOI: 10.1002/stem.2083. View

10.

Wang Q, Shi Y, Zhou K, Wang L, Yan Z, Liu Y . PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer. Cell Death Dis. 2018; 9(7):739. PMC: 6030128. DOI: 10.1038/s41419-018-0776-6. View

11.

Fevr T, Robine S, Louvard D, Huelsken J . Wnt/beta-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells. Mol Cell Biol. 2007; 27(21):7551-9. PMC: 2169070. DOI: 10.1128/MCB.01034-07. View

12.

Li C, Yang X, Cheng Y, Wang J . LGR5, a prognostic stem cell target, promotes endometrial cancer proliferation through autophagy activation. Transl Oncol. 2023; 40:101853. PMC: 10776661. DOI: 10.1016/j.tranon.2023.101853. View

13.

Hou H, Kang Y, Li Y, Zeng Y, Ding G, Shang J . miR-33a expression sensitizes Lgr5+ HCC-CSCs to doxorubicin via ABCA1. Neoplasma. 2016; 64(1):81-91. DOI: 10.4149/neo_2017_110. View

14.

Wu X, Xi H, Chen L . Lgr5 is a potential marker of colorectal carcinoma stem cells that correlates with patient survival. World J Surg Oncol. 2012; 10:244. PMC: 3506563. DOI: 10.1186/1477-7819-10-244. View

15.

Liu W, Zhang J, Gan X, Shen F, Yang X, Du N . LGR5 promotes epithelial ovarian cancer proliferation, metastasis, and epithelial-mesenchymal transition through the Notch1 signaling pathway. Cancer Med. 2018; 7(7):3132-3142. PMC: 6051213. DOI: 10.1002/cam4.1485. View

16.

Schindler A, Watanabe A, Howell S . LGR5 and LGR6 in stem cell biology and ovarian cancer. Oncotarget. 2018; 9(1):1346-1355. PMC: 5787443. DOI: 10.18632/oncotarget.20178. View

17.

Bindhya S, Sidhanth C, Krishnapriya S, Garg M, Ganesan T . Development and in vitro characterisation of an induced pluripotent stem cell model of ovarian cancer. Int J Biochem Cell Biol. 2021; 138:106051. DOI: 10.1016/j.biocel.2021.106051. View

18.

Ihemelandu C, Naeem A, Parasido E, Berry D, Chaldekas K, Harris B . Clinicopathologic and prognostic significance of LGR5, a cancer stem cell marker in patients with colorectal cancer. Colorectal Cancer. 2020; 8(4):CRC11. PMC: 7000925. DOI: 10.2217/crc-2019-0009. View

19.

Jang B, Lee B, Kim W . Distribution of LGR5+ cells and associated implications during the early stage of gastric tumorigenesis. PLoS One. 2013; 8(12):e82390. PMC: 3858308. DOI: 10.1371/journal.pone.0082390. View

20.

Barker N, Van Es J, Jaks V, Kasper M, Snippert H, Toftgard R . Very long-term self-renewal of small intestine, colon, and hair follicles from cycling Lgr5+ve stem cells. Cold Spring Harb Symp Quant Biol. 2009; 73:351-6. DOI: 10.1101/sqb.2008.72.003. View