Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic?

Abstract

Leucine-rich repeat-containing G-protein coupled receptor (LGR5 or GPR49) potentiates canonical Wnt/β-catenin signalling and is a marker of normal stem cells in several tissues, including the intestine. Consistent with stem cell potential, single isolated LGR5+ cells from the gut generate self-organising crypt/villus structures in vitro termed organoids or ‘mini-guts’, which accurately model the parent tissue. The well characterised deregulation of Wnt/β-catenin signalling that occurs during the adenoma-carcinoma sequence in colorectal cancer (CRC) renders LGR5 an interesting therapeutic target. Furthermore, recent studies demonstrating that CRC tumours contain LGR5+ subsets and retain a degree of normal tissue architecture has heightened translational interest. Such reports fuel hope that specific subpopulations or molecules within a tumour may be therapeutically targeted to prevent relapse and induce long-term remissions. Despite these observations, many studies within this field have produced conflicting and confusing results with no clear consensus on the therapeutic value of LGR5. This review will recap the various oncogenic and tumour suppressive roles that have been described for the LGR5 molecule in CRC. It will further highlight recent studies indicating the plasticity or redundancy of LGR5+ cells in intestinal cancer progression and assess the overall merit of therapeutically targeting LGR5 in CRC.

Characterization of LGR5 expression in poorly differentiated colorectal carcinoma with mismatch repair protein deficiency

“…It has been pointed out that there is a difference in LGR5 expression between the adenoma-carcinoma sequence and the serrated neoplasia pathway in RNA in situ hybridization [23] [24]. Because LGR5 is a target of Wnt/ β-catenin signaling that occurs during the adenoma-carcinoma sequence in CRC, LGR5 expression in MMR-P cases, which may involve the adenoma-carcinoma sequence, may be higher than that in MMR-D cases, which may involve the serrated neoplasia pathway [25].…”

Cancer Stem Cell Marker DCLK1 Correlates with Tumorigenic Immune Infiltrates in the Colon and Gastric Adenocarcinoma Microenvironments

“…In conclusion, our results demonstrate that DCLK1 is linked with functional regulation of the tumor microenvironment and may have potential as a prognostic biomarker and adjuvant target to promote immunotherapy sensitivity in colon and gastric cancer patients.for exposure to pathogens and inflammatory injury in tumor initiation [8][9][10]. In addition, colorectal and stomach epithelium contains LGR5+ stem cells and DCLK1+ tuft cells, both of which have been linked to human GI cancer initiation and progression, and identified as GI cancer cells-of-origin using mouse models [11][12][13][14]. Based on these shared characteristics, it may be possible to identify similar targeting strategies to improve colon and stomach cancer outcomes.Several treatment strategies are employed in GI cancer including surgery, chemotherapy, radiotherapy, and molecularly targeted therapy.…”

“…for exposure to pathogens and inflammatory injury in tumor initiation [8][9][10]. In addition, colorectal and stomach epithelium contains LGR5+ stem cells and DCLK1+ tuft cells, both of which have been linked to human GI cancer initiation and progression, and identified as GI cancer cells-of-origin using mouse models [11][12][13][14]. Based on these shared characteristics, it may be possible to identify similar targeting strategies to improve colon and stomach cancer outcomes.…”

Unveiling role of Sphingosine-1-phosphate receptor 2 as a brake of epithelial stem cell proliferation and a tumor suppressor in colorectal cancer

“…The precise mechanisms that nely control survival, proliferation, and self-renewal of stem cells remain largely unknown. However, perturbations to this delicate balance leading to an excessive self-renewal would expand the stem cell pool at the base of the crypt, increasing the risk of intestinal tumorigenesis 28,29 . Speci cally, targeted ablation of Lgr5 stem cell population in cancerous tissues revealed that it is dispensable for primary tumor maintenance 30,31 .…”