Lgr5-Expressing Cells Are Sufficient and Necessary for Postnatal Mammary Gland Organogenesis

Plaks, Vicki; Brenot, Audrey; Lawson, Devon A.; Linnemann, Jelena R.; Kappel, E.C. van; Wong, Karren; Sauvage, Frédéric J. de; Klein, Ophir D.; Werb, Zena

doi:10.1016/j.celrep.2012.12.017

Cited by 184 publications

(188 citation statements)

References 47 publications

Supporting

Mentioning

174

Contrasting

Unclassified

Order By: Relevance

“…Based on present research, Lgr5 seemed the most likely candidate of these genes to putatively mark the nail stem cells. Functional experiments and genetic lineage analyses have established that Lgr5 is a stem cell marker of both the intestinal epithelium and the hair follicle (17,18), and recent experiments have shown it to mark epithelial stem cells in additional tissues, including the stomach, mammary gland, tongue, and ovary (27)(28)(29)(30). In most of these cases, Lgr5 expression is driven by canonical Wnt signaling, placing Lgr5 in a feed-forward loop to maintain high Wnt signaling within Lgr5-expressing stem cells.…”

Section: Discussionmentioning

confidence: 99%

Lgr6 marks nail stem cells and is required for digit tip regeneration

Lehoczky

Tabin

2015

Proc. Natl. Acad. Sci. U.S.A.

109

128

View full text Add to dashboard Cite

The tips of the digits of some mammals, including human infants and mice, are capable of complete regeneration after injury. This process is reliant on the presence of the overlaying nail organ and is mediated by a proliferative blastema. Epithelial Wnt/β-catenin signaling has been shown to be necessary for mouse digit tip regeneration. Here, we report on Lgr5 and Lgr6 (leucine-rich repeat-containing G protein-coupled receptor 5 and 6), two important agonists of the Wnt pathway that are known to be markers of several epithelial stem cell populations. We find that Lgr5 is expressed in a dermal population of cells adjacent to the specialized epithelia surrounding the keratinized nail plate. Moreover, Lgr5-expressing cells contribute to this dermis, but not the blastema, during digit tip regeneration. In contrast, we find that Lgr6 is expressed within cells of the nail matrix portion of the nail epithelium, as well as in a subset of cells in the bone and eccrine sweat glands. Genetic lineage analysis reveals that Lgr6-expressing cells give rise to the nail during homeostatic growth, demonstrating that Lgr6 is a marker of nail stem cells. Moreover, Lgr6-expressing cells contribute to the blastema, suggesting a potential direct role for Lgr6-expressing cells during digit tip regeneration. This role is confirmed by analysis of Lgr6-deficient mice, which have both a nail and bone regeneration defect.

show abstract

Section: Discussionmentioning

confidence: 99%

Lgr6 marks nail stem cells and is required for digit tip regeneration

Lehoczky

Tabin

2015

Proc. Natl. Acad. Sci. U.S.A.

109

128

View full text Add to dashboard Cite

show abstract

“…Using the same lineage tracing strategy, Lgr5 was subsequently found to mark stem cells in many other organs and tissues, including the stomach , pancreas , liver (Huch et al 2013b), kidney , and mammary gland (de Visser et al 2012;Plaks et al 2013). Lgr4, a close homolog of Lgr5, is coexpressed with Lgr5 in CBC cells but is expressed by all other crypt cells (de Lau et al 2011).…”

Section: Lgr5 Marks Intestinal Stem Cellsmentioning

confidence: 99%

The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength

et al. 2014

View full text Add to dashboard Cite

Lgr5 was originally discovered as a common Wnt target gene in adult intestinal crypts and colon cancer. It was subsequently identified as an exquisite marker of multiple Wnt-driven adult stem cell types. Lgr5 and its homologs, Lgr4 and Lgr6, constitute the receptors for R-spondins, potent Wnt signal enhancers and stem cell growth factors. The Lgr5/R-spondin complex acts by neutralizing Rnf43 and Znrf3, two transmembrane E3 ligases that remove Wnt receptors from the stem cell surface. Rnf43/Znrf3 are themselves encoded by Wnt target genes and constitute a negative Wnt feedback loop. Thus, adult stem cells are controlled by an intricate interplay of potent Wnt agonists, antagonists, and anti-antagonists.

show abstract

“…LGR5 (leucine-rich repeat-containing, G protein-coupled receptor 5) expression is highly elevated in gastrointestinal cancers of the colon, liver, pancreas, and stomach (2)(3)(4)(5). The LGR5 receptor was initially identified as a marker of intestinal crypt stem cells and has since been established as a bona fide marker of adult stem cells in several major epithelial tissues (6)(7)(8)(9)(10). In normal tissues, LGR5 is exclusively expressed at low levels on the cell surface of the adult stem cells (11,12).…”

Section: Introductionmentioning

confidence: 99%

LGR5-Targeted Antibody–Drug Conjugate Eradicates Gastrointestinal Tumors and Prevents Recurrence

Gong

Azhdarinia

Ghosh

et al. 2016

Molecular Cancer Therapeutics

101

119

View full text Add to dashboard Cite

Gastrointestinal cancer is one of the leading causes of cancerrelated mortality in men and women worldwide. The adult stem cell marker LGR5 (leucine-rich repeat-containing, G proteincoupled receptor 5) is highly expressed in a significant fraction of gastrointestinal tumors of the colon, liver, pancreas, and stomach, relative to normal tissues. LGR5 is located on the cell surface and undergoes rapid, constitutive internalization independent of ligand. Furthermore, LGR5-high cancer cells have been shown to exhibit the properties of tumor-initiating cells or cancer stem cells (CSC). On the basis of these attributes, we generated two LGR5-targeting antibody-drug conjugates (ADC) by tethering the tubulin-inhibiting cytotoxic drug monomethyl auristatin E to a highly specific anti-LGR5 mAb via a protease cleavable or noncleavable chemical linker and compared them in receptor binding, cell internalization, and cytotoxic efficacy in cancer cells. Here, we show that both ADCs bind LGR5 with high specificity and equivalent nanomolar affinity and rapidly internalize to the lysosomes of LGR5-expressing gastrointestinal cancer cells. The anti-LGR5 ADCs effectively induced cytotoxicity in LGR5-high gastrointestinal cancer cells, but not in LGR5-negative or -knockdown cancer cell lines. Overall, we demonstrate that the cleavable ADC exhibited higher potency in vitro and was able to eradicate tumors and prevent recurrence in a xenograft model of colon cancer. These findings provide preclinical evidence for the potential of LGR5-targeting ADCs as effective new therapeutics for the treatment and eradication of gastrointestinal tumors and CSCs with high LGR5 expression. Mol Cancer Ther; 15(7); 1580-90. Ó2016 AACR.

show abstract

Lgr5-Expressing Cells Are Sufficient and Necessary for Postnatal Mammary Gland Organogenesis

Cited by 184 publications

References 47 publications

Lgr6 marks nail stem cells and is required for digit tip regeneration

Lgr6 marks nail stem cells and is required for digit tip regeneration

The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength

LGR5-Targeted Antibody–Drug Conjugate Eradicates Gastrointestinal Tumors and Prevents Recurrence

Contact Info

Product

Resources

About