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Review
. 2017 Aug 11;9(1):1346-1355.
doi: 10.18632/oncotarget.20178. eCollection 2018 Jan 2.

LGR5 and LGR6 in stem cell biology and ovarian cancer

Adam J Schindler  1 , Arisa Watanabe  1 , Stephen B Howell  1
Affiliations
Review

LGR5 and LGR6 in stem cell biology and ovarian cancer

Adam J Schindler et al. Oncotarget. .

Abstract

Wnt signaling plays a fundamental role in patterning of the embryo and maintenance of stem cells in numerous epithelia. Epithelial stem cells are closeted in niches created by surrounding differentiated cells that express secreted Wnt and R-spondin proteins that influence proliferation rate and fate determination of stem cell daughters. R-spondins act through the LGR receptors to enhance Wnt signaling. This close association of stem cells with more differentiated regulatory cells expressing Wnt-pathway ligands is a feature replicated in all of the epithelial stem cell systems thus far examined. How the stem cell niche operates through these short-range interactions is best understood for the crypts of the gastrointestinal epithelium and skin. Less well understood are the stem cells that function in the ovarian surface epithelium (OSE) and fallopian tube epithelium (FTE). While the cuboidal OSE appears to be made up of a single cell type, the cells of the FTE progress through a life cycle that involves differentiation into ciliated and secretory subtypes that are eventually shed into the lumen in a manner similar to the gastrointestinal epithelium. Available evidence suggests that high grade serous ovarian carcinoma (HGSOC) originates most often from stem cells in the FTE and that Wnt signaling augmented by LGR6 supports tumor development and progression. This review summarizes current information on LGR5 and LGR6 in the OSE and FTE and how their niches are organized relative to that of the gastrointestinal epithelium and skin.

Keywords: LGR5; LGR6; RSPO; Wnt; ovarian cancer.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1. RSPO augmentation of Wnt signaling
Left panel: In the absence of RSPO1/2, ubiquitin ligases ZNRF3 and RNF43 ubiquitinate LRP5/6 and FZD receptors, which marks them for lysosomal degradation and limits their residence time on the cell surface. Right panel: Binding of RSPO1 or RSPO2 to LGR5 or LGR6 causes the receptor to clear ZNRF3/RNF43 from the membrane, which prolongs the plasma membrane residence time of LRP5/6 and FZD and augments Wnt signaling.
Figure 2
Figure 2. Schematic diagram of cellular organization of the fallopian tube epithelium
The PEG cells (green) have been identified as precursors of both the secretory (blue) and ciliated (brown) cells, but which cell type serves as the primary source of RSPO1/2 is unknown.
Figure 3
Figure 3. Expression of LGR5 and LGR6 at the mRNA level in the tumors in the TCGA database for which expression data is reported
Figure 4
Figure 4. Expression of RSPO1 and RSPO2 at the mRNA level in the tumors in the TCGA database for which expression data is reported
See this image and copyright information in PMC

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