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Page 8 of 23 ALHulais et al. J Cancer Metastasis Treat 2019;5:3 I http://dx.doi.org/10.20517/2394-4722.2018.71

LGR5 is found expressed in many organs including the brain, reproductive organs, mammary glands,
[88]
the intestinal tract, stomach, hair follicles and the eyes . The Lgr5 gene is itself a WNT signalling target
and prostaglandin E2 (PGE2) treating colorectal cancer cell lines enhances LGR5 expression whereas
[84]
Lgr5 knockdown using siRNA inhibited the PGE2 survival response and induced cell death . These
results suggest that the PGE2 promotion of colorectal cancer cell survival at least in part proceeds via
increasing LGR5 expression. Given the relationship of LGR5 with WNT signalling and PGE2 production
by cyclooxygenase-2 (COX-2), it is likely that NSAIDs cause regression in familial adenomatous polyposis
patients by interfering with the LGR5/WNT mechanism for promoting cancer stemness and cell survival.
X-gal staining using the transgenic Lgr5 promoter driving b-galactosidase revealed that, following villus
morphogenesis, Lgr5 expression became restricted to dividing cells assembling in the intervillus region
[89]
and within the distal small intestine . Lgr5 deficiency is also known to cause premature Paneth cell
differentiation within the small intestine, without affecting the differentiation of other cell lineages, nor the
[89]
proliferation or migration of epithelial cells .
LGR5 was shown to be a biological marker for intestinal stem cells in the murine small bowel of Lgr5-
+
EGFP-IREScreERT2 mice, as well as being useful for cell lineage tracing studies where the LGR5 stem
[88]
cells developed into the different cell types comprising the intestinal crypt . LGR5 expression has been
closely linked with tumorigenesis including that of liver, colorectal, as well as ovarian cancers (for review,
[90]
see ). In the normal intestine, LGR5 is solely expressed by the cycling crypt columnar cells and genetic
lineage tracing studies identified these columnar cells in the base of the crypts as self-renewing, multipotent
cells and are therefore considered to be genuine intestinal stem cells [91,92] . LGR5 has also been shown to be
expressed in the stem cell niche by actively cycling cells of the murine hair follicle where lineage tracing
+
and transplantation studies revealed that the LGR5 cells were retained for long periods and generated new
[93]
hair follicles . LGR5 expression in multiple other organs has led to the proposal that it represents a global
[94]
marker of adult stem cells (reviewed in ).
Since LGR5 is involved in WNT signalling, it is not surprising that LGR5 and its ligands, the R-spondins
[95]
are important for normal brain development and hypoxia stimulates neural stem cell proliferation
by increasing hypoxia-inducible factor-1alpha (HIF-1α) expression and activating WNT/b-catenin
[96]
signaling . Hence, it is likely that WNT acts by increasing LGR5 expression to promote stemness and brain
[97]
CSCs . LGR5 functions in the maintenance of brain CSCs and the transcribed levels of Lgr5 is greater
[97]
in these cells and in the case of glioblastoma has been associated with poorer prognosis . In addition,
+
immunofluorescence staining revealed the localization of LGR5 cells in sections of glioblastoma and Lgr5
[97]
siRNA knockdown led to lower expression of the neuronal L1 cell-cell adhesion molecule .
[98]
Most colorectal cancer cell lines and sporadic colonic adenomas exhibit significant LGR5 expression ,
although this is linked with stemness and renewal but not tumor progression because overexpressing
LGR5 caused greater cell-cell adhesion, reduced tumor growth, invasiveness, migration and metastasis [98,99] .
Recently, LGR5 was established as a definitive surface marker for colorectal CSCs (reviewed in [90,100] ),
particularly when co-expressed with CD44 and EPCAM [101] . In these studies, the triple positive cells
exhibited more pronounced CSC-like traits with LGR5-positive subpopulations showing higher capacities
for colony formation, self-renewal, differentiation, and tumorigenicity as well as higher expression of
stemness genes than did any other subpopulation. Thus, LGR5 is a marker for early CSCs and relates to their
WNT promoted self-renewing capacity. Enhanced LGR5 expression remains persistent during adenoma
to carcinoma transition in human CRC samples, but markedly declines in the budding cancer cells at the
[98]
invasive tumor fronts, and was not associated with either WNT- or EMT-signalling pathways . In the
latter study, LGR5 overexpression attenuated proliferation, migration, and colony-forming capacities in
colon cancer cells. Unfortunately, the levels of TGFb expressed by these cells were not analysed in these
studies [96,98,99] given the observations above that TGFb switches the role of LGR5 to inhibit growth. These