Lgr5 and Lgr6 as markers to study adult stem cell roles in self-renewal and cancer

Leushacke, Marc; Barker, Nick

doi:10.1038/onc.2011.479

Cited by 116 publications

(100 citation statements)

References 103 publications

(128 reference statements)

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“…Moreover, nearly 20% of tumors harbor mutations in GPCRs, and~10% of cancer-related mutations have been mapped to G proteins (7). Related work has not only concentrated on the physiological or pathophysiological mechanisms and pharmaceutical aspects of GPCR action but has also been extended to include stem cell research (8,9). Notably, in this context, 365 nonolfactory human GPCRs are treated as potential drug targets (10) and~40% of approved drugs target GPCRs (11).…”

Section: Introductionmentioning

confidence: 99%

Construction of Structural Mimetics of the Thyrotropin Receptor Intracellular Domain

Press

Zvagelsky

Vyazmensky

et al. 2016

Biophysical Journal

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The signaling of a G protein-coupled receptor (GPCR) is dictated by the complementary responsiveness of interacting intracellular effectors such as G proteins. Many GPCRs are known to couple to more than one G protein subtype and induce a multitude of signaling pathways, although the in vivo relevance of particular pathways is mostly unrecognized. Dissecting GPCR signaling in terms of the pathways that are activated will boost our understanding of the molecular fundamentals of hormone action. The structural determinants governing the selectivity of GPCR/G protein coupling, however, remain obscure. Here, we describe the design of soluble GPCR mimetics to study the details of the interplay between G-proteins and activators. We constructed functional mimetics of the intracellular domain of a model GPCR, the thyrotropin receptor. We based the construction on a unique scaffold, 6-Helix, an artificial protein that was derived from the elements of the trimer-of-hairpins structure of HIV gp41 and represents a bundle of six a-helices. The 6-Helix scaffold, which endowed the substituted thyrotropin receptor intracellular domain elements with spatial constraints analogous to those found in native receptors, enabled the reconstitution of a microdomain that consists of intracellular loops 2 and 3, and is capable of binding and activating Ga-(s). The 6-Helix-based mimetics could be used as a platform to study the molecular basis of GPCR/G protein recognition. Such knowledge could help investigators develop novel therapeutic strategies for GPCR-related disorders by targeting the GPCR/G protein interfaces and counteracting cellular dysfunctions via focused tuning of GPCR signaling.

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Section: Introductionmentioning

confidence: 99%

Construction of Structural Mimetics of the Thyrotropin Receptor Intracellular Domain

Press

Zvagelsky

Vyazmensky

et al. 2016

Biophysical Journal

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“…In the zoned model, the active stem cells divide into progenitor cells that are subsequently able to differentiate into mature cells [36]. The progenitor cells constitute a compartment that serves to expand the cell pool available for supplying the host tissue with various functional lineages by rapid cell division.…”

Section: Active Stem Cellsmentioning

confidence: 99%

“…The progenitor cells constitute a compartment that serves to expand the cell pool available for supplying the host tissue with various functional lineages by rapid cell division. Optimal functionality in the host tissue is ensured by the restricted lifespan of the terminally differentiated mature cells, which are derived from the progeny compartments [36].…”

Section: Active Stem Cellsmentioning

confidence: 99%

Cancer stem cells and addicted cancer cells

Logtenberg¹,

Boonstra²

2013

Oncol Discov

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Advanced tumors represent a genetically heterogeneous population of cells, which compromise subpopulations with distinct properties. Research indicates that a specific population of cells within the heterogeneous population contain stem cell-like properties. These 'cancer stem cells' are much like normal stem cells and have the capacity to self-renew, sustain the entire cancerous tissues and provide a reservoir of cells for recurrence after therapy and drug resistance. Cancer stem cells can arise from normal, adult stem cells, from progenitor cells or from fully matured cell types. They are likely generated by the process of epithelial-mesenchymal transition, through which differentiated cells acquire stem-cell like properties. This process potentially underlies the mechanism by which metastases evolve. Furthermore, mutations may render cancer cells dependent on the activity of one or more specific signaling pathways in the cell. This phenomenon is termed 'oncogene addiction' and represents the Achilles' heel of the cancer cell. As the concept of oncogene addiction in tumor cells proves to be very complex, additional models have been proposed to account for the variations in pathway dependencies and their intricate interactions. The combined knowledge concerning cancer stem cells, oncogene addiction and drug therapy resistance may lead to the identification of new avenues to improved drug strategies that address tumor heterogeneity and mechanisms of escape.

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“…Lgr5 therefore is a facultative Wnt receptor that mediates Wnt signal enhancement by soluble R-spondin proteins [210,211]. Lgr5 is expressed on Wnt/β-catenin-dependent adult stem cell populations of the intestine, colon and hair-follicle [212]. Expression of Lgr5 has been demonstrated on intestinal crypt stem cells, which are the cells-of-origin of intestinal cancer [213], indicating that Lgr5 is a functional marker of intestinal CSCc involved in intestinal and colorectal carcinogenesis [214,215].…”

Section: Anti-lgr5mentioning

confidence: 99%

Targeting Human Cancer Stem Cells with Monoclonal Antibodies

Naujokat¹

2012

J Clin Cell Immunol

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Cancer stem cells (CSCs) constitute a distinct subpopulation of tumor cells that exhibit self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of cancer cells that comprise the tumor. CSCs possess various intrinsic mechanisms of resistance to conventional chemotherapeutics, novel tumor-targeted drugs and radiation therapy, permitting them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Different cell surface and transmembrane proteins expressed by CSCs, including CD44, CD47, EpCAM (CD326), CD123, CD133, GD2, Lgr5, insulin-like growth factor receptor I (IGF-IR), and members of the Notch and Wnt signaling pathways, have been identified and mainly used for the characterization of CSCs in experimental settings. Recently, monoclonal antibodies and antibody constructs such as Triomabs and BiTEs raised against these CSC proteins have shown efficacy against CSCs in human xenograft mice, and some of them have been demonstrated to induce tumor regression in clinical trials.Since current cancer therapies fail to eliminate CSCs, ultimately leading to cancer recurrence and progression, selective targeting of CSCs with mAbs and antibody constructs reviewed herein may represent a novel and promising therapeutic strategy to eradicate cancer.

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Lgr5 and Lgr6 as markers to study adult stem cell roles in self-renewal and cancer

Cited by 116 publications

References 103 publications

Construction of Structural Mimetics of the Thyrotropin Receptor Intracellular Domain

Construction of Structural Mimetics of the Thyrotropin Receptor Intracellular Domain

Cancer stem cells and addicted cancer cells

Targeting Human Cancer Stem Cells with Monoclonal Antibodies

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