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Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

G Protein-coupled Receptors in Cancer Stem Cells

Author(s): Yuhong Jiang*, Xin Zhuo and Canquan Mao

Volume 26, Issue 17, 2020

Page: [1952 - 1963] Pages: 12

DOI: 10.2174/1381612826666200305130009

Price: $65

Abstract

G protein-coupled receptors (GPCRs) are highly expressed on a variety of tumour tissues while several GPCR exogenous ligands become marketed pharmaceuticals. In recent decades, cancer stem cells (CSCs) become widely investigated drug targets for cancer therapy but the underlying mechanism is still not fully elucidated. There are vigorous participations of GPCRs in CSCs-related signalling and functions, such as biomarkers for CSCs, activation of Wnt, Hedgehog (HH) and other signalling to facilitate CSCs progressions. This relationship can not only uncover a novel molecular mechanism for GPCR-mediated cancer cell functions but also assist our understanding of maintaining and modulating CSCs. Moreover, GPCR antagonists and monoclonal antibodies could be applied to impair CSCs functions and consequently attenuate tumour growth, some of which have been undergoing clinical studies and are anticipated to turn into marketed anticancer drugs. Therefore, this review summarizes and provides sufficient evidences on the regulation of GPCR signalling in the maintenance, differentiation and pluripotency of CSCs, suggesting that targeting GPCRs on the surface of CSCs could be potential therapeutic strategies for cancer therapy.

Keywords: Cancer stem cells (CSCs), G protein-coupled receptors (GPCRs), cell signalling, cancer therapy, Hedgehog (HH), Wnt.

[1]
Batlle E, Clevers H. Cancer stem cells revisited. Nat Med 2017; 23(10): 1124-34.
[http://dx.doi.org/10.1038/nm.4409] [PMID: 28985214]
[2]
Beck B, Blanpain C. Unravelling cancer stem cell potential. Nat Rev Cancer 2013; 13(10): 727-38.
[http://dx.doi.org/10.1038/nrc3597] [PMID: 24060864]
[3]
Han L, Shi S, Gong T, et al. Cancer stem cells: therapeutic implications and perspectives in cancer therapy. Acta Pharm Sin B 2013; 3: 65-75.
[http://dx.doi.org/10.1016/j.apsb.2013.02.006]
[4]
Espinoza I, Miele L. Deadly crosstalk: Notch signaling at the intersection of EMT and cancer stem cells. Cancer Lett 2013; 341(1): 41-5.
[http://dx.doi.org/10.1016/j.canlet.2013.08.027] [PMID: 23973264]
[5]
Rich JN. Cancer stem cells in radiation resistance. Cancer Res 2007; 67(19): 8980-4.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-0895] [PMID: 17908997]
[6]
Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med 2011; 17(3): 313-9.
[http://dx.doi.org/10.1038/nm.2304] [PMID: 21386835]
[7]
Ming Y, Li Y, Xing H, et al. Circulating tumor cells: from theory to nanotechnology-based detection. Front Pharmacol 2017; 8: 35.
[http://dx.doi.org/10.3389/fphar.2017.00035] [PMID: 28203204]
[8]
Leushacke M, Barker N. Lgr5 and Lgr6 as markers to study adult stem cell roles in self-renewal and cancer. Oncogene 2012; 31(25): 3009-22.
[http://dx.doi.org/10.1038/onc.2011.479] [PMID: 22002312]
[9]
Trautmann F, Cojoc M, Kurth I, et al. CXCR4 as biomarker for radioresistant cancer stem cells. Int J Radiat Biol 2014; 90(8): 687-99.
[http://dx.doi.org/10.3109/09553002.2014.906766] [PMID: 24650104]
[10]
Liu C, Kelnar K, Liu B, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 2011; 17(2): 211-5.
[http://dx.doi.org/10.1038/nm.2284] [PMID: 21240262]
[11]
Takebe N, Miele L, Harris PJ, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 2015; 12(8): 445-64.
[http://dx.doi.org/10.1038/nrclinonc.2015.61] [PMID: 25850553]
[12]
Callihan P, Mumaw J, Machacek DW, Stice SL, Hooks SB. Regulation of stem cell pluripotency and differentiation by G protein coupled receptors. Pharmacol Ther 2011; 129(3): 290-306.
[http://dx.doi.org/10.1016/j.pharmthera.2010.10.007] [PMID: 21073897]
[13]
Rosenbaum DM, Rasmussen SG, Kobilka BK. The structure and function of G-protein-coupled receptors. Nature 2009; 459(7245): 356-63.
[http://dx.doi.org/10.1038/nature08144] [PMID: 19458711]
[14]
Granier S, Kobilka B. A new era of GPCR structural and chemical biology. Nat Chem Biol 2012; 8(8): 670-3.
[http://dx.doi.org/10.1038/nchembio.1025] [PMID: 22810761]
[15]
Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov 2017; 16(12): 829-42.
[http://dx.doi.org/10.1038/nrd.2017.178] [PMID: 29075003]
[16]
Wootten D, Christopoulos A, Marti-Solano M, Babu MM, Sexton PM. Mechanisms of signalling and biased agonism in G protein-coupled receptors. Nat Rev Mol Cell Biol 2018; 19(10): 638-53.
[http://dx.doi.org/10.1038/s41580-018-0049-3] [PMID: 30104700]
[17]
Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu MM. Molecular signatures of G-protein-coupled receptors. Nature 2013; 494(7436): 185-94.
[http://dx.doi.org/10.1038/nature11896] [PMID: 23407534]
[18]
Hilger D, Masureel M, Kobilka BK. Structure and dynamics of GPCR signaling complexes. Nat Struct Mol Biol 2018; 25(1): 4-12.
[http://dx.doi.org/10.1038/s41594-017-0011-7] [PMID: 29323277]
[19]
Lynch JR, Wang JY. G protein-coupled receptor signaling in stem cells and cancer. Int J Mol Sci 2016; 17(5): 707.
[http://dx.doi.org/10.3390/ijms17050707] [PMID: 27187360]
[20]
de Sousa e Melo F, Kurtova AV, Harnoss JM, et al. A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer. Nature 2017; 543(7647): 676-80.
[http://dx.doi.org/10.1038/nature21713] [PMID: 28358093]
[21]
Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007; 449(7165): 1003-7.
[http://dx.doi.org/10.1038/nature06196] [PMID: 17934449]
[22]
Kundu N, Ma X, Kochel T, et al. Prostaglandin E receptor EP4 is a therapeutic target in breast cancer cells with stem-like properties. Breast Cancer Res Treat 2014; 143(1): 19-31.
[http://dx.doi.org/10.1007/s10549-013-2779-4] [PMID: 24281828]
[23]
Lappano R, Maggiolini M. G protein-coupled receptors: novel targets for drug discovery in cancer. Nat Rev Drug Discov 2011; 10(1): 47-60.
[http://dx.doi.org/10.1038/nrd3320] [PMID: 21193867]
[24]
Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer 2007; 7(2): 79-94.
[http://dx.doi.org/10.1038/nrc2069] [PMID: 17251915]
[25]
V ergnolle N, Wallace JL, Bunnett NW, Hollenberg MD. Protease-activated receptors in inflammation, neuronal signaling and pain. Trends Pharmacol Sci 2001; 22: 146-52.
[http://dx.doi.org/10.1016/S0165-6147(00)01634-5]
[26]
Suen JY, Cotterell A, Lohman RJ, et al. Pathway-selective antagonism of proteinase activated receptor 2. Br J Pharmacol 2014; 171(17): 4112-24.
[http://dx.doi.org/10.1111/bph.12757] [PMID: 24821440]
[27]
Whitehead IP, Zohn IE, Der CJ. Rho GTPase-dependent transformation by G protein-coupled receptors. Oncogene 2001; 20(13): 1547-55.
[http://dx.doi.org/10.1038/sj.onc.1204188] [PMID: 11313901]
[28]
Scott G, Leopardi S, Parker L, Babiarz L, Seiberg M, Han R. The proteinase-activated receptor-2 mediates phagocytosis in a Rho-dependent manner in human keratinocytes. J Invest Dermatol 2003; 121(3): 529-41.
[http://dx.doi.org/10.1046/j.1523-1747.2003.12427.x] [PMID: 12925212]
[29]
Vilardaga J-P, Jean-Alphonse FG, Gardella TJ. Endosomal generation of cAMP in GPCR signaling. Nat Chem Biol 2014; 10(9): 700-6.
[http://dx.doi.org/10.1038/nchembio.1611] [PMID: 25271346]
[30]
Kuna RS, Girada SB, Asalla S, et al. Glucagon-like peptide-1 receptor-mediated endosomal cAMP generation promotes glucose-stimulated insulin secretion in pancreatic β-cells. Am J Physiol Endocrinol Metab 2013; 305(2): E161-70.
[http://dx.doi.org/10.1152/ajpendo.00551.2012] [PMID: 23592482]
[31]
Gutkind JS, Kostenis E. Arrestins as rheostats of GPCR signalling. Nat Rev Mol Cell Biol 2018; 19(10): 615-6.
[http://dx.doi.org/10.1038/s41580-018-0041-y] [PMID: 30026541]
[32]
Heuss C, Gerber U. G-protein-independent signaling by G-protein-coupled receptors. Trends Neurosci 2000; 23(10): 469-75.
[http://dx.doi.org/10.1016/S0166-2236(00)01643-X] [PMID: 11006463]
[33]
Andradas C, Caffarel MM, Pérez-Gómez E, et al. The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK. Oncogene 2011; 30(2): 245-52.
[http://dx.doi.org/10.1038/onc.2010.402] [PMID: 20818416]
[34]
Ge L, Shenoy SK, Lefkowitz RJ, DeFea K. Constitutive protease-activated receptor-2-mediated migration of MDA MB-231 breast cancer cells requires both β-arrestin-1 and -2. J Biol Chem 2004; 279(53): 55419-24.
[http://dx.doi.org/10.1074/jbc.M410312200] [PMID: 15489220]
[35]
Yau MK, Liu L, Fairlie DP. Toward drugs for protease-activated receptor 2 (PAR2). J Med Chem 2013; 56(19): 7477-97.
[http://dx.doi.org/10.1021/jm400638v] [PMID: 23895492]
[36]
Budd DC, Willars GB, McDonald JE, Tobin AB. Phosphorylation of the Gq/11-coupled m3-muscarinic receptor is involved in receptor activation of the ERK-1/2 mitogen-activated protein kinase pathway. J Biol Chem 2001; 276(7): 4581-7.
[http://dx.doi.org/10.1074/jbc.M008827200] [PMID: 11083874]
[37]
Budd DC, Rae A, Tobin AB. Activation of the mitogen-activated protein kinase pathway by a Gq/11-coupled muscarinic receptor is independent of receptor internalization. J Biol Chem 1999; 274(18): 12355-60.
[http://dx.doi.org/10.1074/jbc.274.18.12355] [PMID: 10212206]
[38]
Pi M, Ye R, Nooh MM, et al. Human GPRC6A mediates testosterone-induced ERK and mTORC1 signaling in prostate cancer cells. Mol Pharmacol 2019; 95: 563-72.
[http://dx.doi.org/10.1124/mol.118.115014] [PMID: 30894404]
[39]
Ramachandran R, Noorbakhsh F, Defea K, Hollenberg MD. Targeting proteinase-activated receptors: therapeutic potential and challenges. Nat Rev Drug Discov 2012; 11(1): 69-86.
[http://dx.doi.org/10.1038/nrd3615] [PMID: 22212680]
[40]
Köse M. GPCRs and EGFR - Cross-talk of membrane receptors in cancer. Bioorg Med Chem Lett 2017; 27(16): 3611-20.
[http://dx.doi.org/10.1016/j.bmcl.2017.07.002] [PMID: 28705643]
[41]
Vermeulen L, De Sousa E Melo F, van der Heijden M, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 2010; 12(5): 468-76.
[http://dx.doi.org/10.1038/ncb2048] [PMID: 20418870]
[42]
Reya T, Duncan AW, Ailles L, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003; 423(6938): 409-14.
[http://dx.doi.org/10.1038/nature01593] [PMID: 12717450]
[43]
Wang Y, Krivtsov AV, Sinha AU, et al. The Wnt/β-catenin pathway is required for the development of leukemia stem cells in AML. Science 2010; 327(5973): 1650-3.
[http://dx.doi.org/10.1126/science.1186624] [PMID: 20339075]
[44]
Zhao Z, Lu P, Zhang H, et al. Nestin positively regulates the Wnt/β-catenin pathway and the proliferation, survival and invasiveness of breast cancer stem cells. Breast Cancer Res 2014; 16(4): 408.
[http://dx.doi.org/10.1186/s13058-014-0408-8] [PMID: 25056574]
[45]
Takebe N, Harris PJ, Warren RQ, Ivy SP. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol 2011; 8(2): 97-106.
[http://dx.doi.org/10.1038/nrclinonc.2010.196] [PMID: 21151206]
[46]
Schulte G, Wright SC. Frizzleds as GPCRs–more conventional than we thought! Trends Pharmacol Sci 2018; 39(9): 828-42.
[http://dx.doi.org/10.1016/j.tips.2018.07.001] [PMID: 30049420]
[47]
Janda CY, Waghray D, Levin AM, Thomas C, Garcia KC. Structural basis of Wnt recognition by Frizzled. Science 2012; 337(6090): 59-64.
[http://dx.doi.org/10.1126/science.1222879] [PMID: 22653731]
[48]
Dann CE, Hsieh J-C, Rattner A, Sharma D, Nathans J, Leahy DJ. Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature 2001; 412(6842): 86-90.
[http://dx.doi.org/10.1038/35083601] [PMID: 11452312]
[49]
Katoh M, Katoh M. WNT signaling pathway and stem cell signaling network. Clin Cancer Res 2007; 13(14): 4042-5.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-2316] [PMID: 17634527]
[50]
Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 2017; 169(6): 985-99.
[http://dx.doi.org/10.1016/j.cell.2017.05.016] [PMID: 28575679]
[51]
Boutros M, Paricio N, Strutt DI, Mlodzik M. Dishevelled activates JNK and discriminates between JNK pathways in planar polarity and wingless signaling. Cell 1998; 94(1): 109-18.
[http://dx.doi.org/10.1016/S0092-8674(00)81226-X] [PMID: 9674432]
[52]
Seifert JR, Mlodzik M. Frizzled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility. Nat Rev Genet 2007; 8(2): 126-38.
[http://dx.doi.org/10.1038/nrg2042] [PMID: 17230199]
[53]
Wang HY, Malbon CC. Wnt signaling, Ca2+, and cyclic GMP: visualizing Frizzled functions. Science 2003; 300(5625): 1529-30.
[http://dx.doi.org/10.1126/science.1085259] [PMID: 12791979]
[54]
Dejmek J, Säfholm A, Kamp Nielsen C, Andersson T, Leandersson K. Wnt-5a/Ca2+-induced NFAT activity is counteracted by Wnt-5a/Yes-Cdc42-casein kinase 1α signaling in human mammary epithelial cells. Mol Cell Biol 2006; 26(16): 6024-36.
[http://dx.doi.org/10.1128/MCB.02354-05] [PMID: 16880514]
[55]
Jin X, Jeon H-Y, Joo KM, et al. Frizzled 4 regulates stemness and invasiveness of migrating glioma cells established by serial intracranial transplantation. Cancer Res 2011; 71(8): 3066-75.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-1495] [PMID: 21363911]
[56]
Li G, Su Q, Liu H, et al. Frizzled7 promotes epithelial-to-mesenchymal transition and stemness via activating canonical Wnt/β-catenin pathway in gastric cancer. Int J Biol Sci 2018; 14(3): 280-93.
[http://dx.doi.org/10.7150/ijbs.23756] [PMID: 29559846]
[57]
de Lau W, Barker N, Low TY, et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 2011; 476(7360): 293-7.
[http://dx.doi.org/10.1038/nature10337] [PMID: 21727895]
[58]
Luo W, Rodriguez M, Valdez JM, et al. Lgr4 is a key regulator of prostate development and prostate stem cell differentiation. Stem Cells 2013; 31(11): 2492-505.
[http://dx.doi.org/10.1002/stem.1484] [PMID: 23897697]
[59]
Carmon KS, Gong X, Lin Q, Thomas A, Liu Q. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/β-catenin signaling. Proc Natl Acad Sci USA 2011; 108(28): 11452-7.
[http://dx.doi.org/10.1073/pnas.1106083108] [PMID: 21693646]
[60]
Nakata S, Phillips E, Goidts V. Emerging role for leucine-rich repeat-containing G-protein-coupled receptors LGR5 and LGR4 in cancer stem cells. Cancer Manag Res 2014; 6: 171-80.
[PMID: 24711713]
[61]
Dietrich PA, Yang C, Leung HH, et al. GPR84 sustains aberrant β-catenin signaling in leukemic stem cells for maintenance of MLL leukemogenesis. Blood 2014; 124(22): 3284-94.
[http://dx.doi.org/10.1182/blood-2013-10-532523] [PMID: 25293777]
[62]
Ruiz i Altaba A, Sánchez P, Dahmane N, i Altaba AR. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2002; 2(5): 361-72.
[http://dx.doi.org/10.1038/nrc796] [PMID: 12044012]
[63]
Zhao C, Chen A, Jamieson CH, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 2009; 458(7239): 776-9.
[http://dx.doi.org/10.1038/nature07737] [PMID: 19169242]
[64]
Liu S, Dontu G, Mantle ID, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006; 66(12): 6063-71.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-0054] [PMID: 16778178]
[65]
Memmi EM, Sanarico AG, Giacobbe A, et al. p63 Sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling. Proc Natl Acad Sci USA 2015; 112(11): 3499-504.
[http://dx.doi.org/10.1073/pnas.1500762112] [PMID: 25739959]
[66]
van den Heuvel M, Ingham PW. smoothened encodes a receptor-like serpentine protein required for hedgehog signalling. Nature 1996; 382(6591): 547-51.
[http://dx.doi.org/10.1038/382547a0] [PMID: 8700230]
[67]
Rana R, Carroll CE, Lee H-J, et al. Structural insights into the role of the Smoothened cysteine-rich domain in Hedgehog signalling. Nat Commun 2013; 4: 2965.
[http://dx.doi.org/10.1038/ncomms3965] [PMID: 24351982]
[68]
Muller J-M, Chevrier L, Cochaud S, et al. Hedgehog, Notch and Wnt developmental pathways as targets for anti-cancer drugs. Drug Discov Today Dis Mech 2007; 4: 285-91.
[http://dx.doi.org/10.1016/j.ddmec.2008.05.009]
[69]
Ruiz i Altaba A, Mas C, Stecca B, i Altaba AR. The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol 2007; 17(9): 438-47.
[http://dx.doi.org/10.1016/j.tcb.2007.06.007] [PMID: 17845852]
[70]
Barzi M, Kostrz D, Menendez A, Pons S. Sonic Hedgehog-induced proliferation requires specific Gα inhibitory proteins. J Biol Chem 2011; 286(10): 8067-74.
[http://dx.doi.org/10.1074/jbc.M110.178772] [PMID: 21209076]
[71]
Shimada IS, Hwang S-H, Somatilaka BN, et al. Basal suppression of the sonic hedgehog pathway by the G-protein-coupled receptor Gpr161 restricts medulloblastoma pathogenesis. Cell Rep 2018; 22(5): 1169-84.
[http://dx.doi.org/10.1016/j.celrep.2018.01.018] [PMID: 29386106]
[72]
Mukhopadhyay S, Rohatgi R. G-protein-coupled receptors, Hedgehog signaling and primary cilia. Semin Cell Dev Biol 2014; 33: 63-72.
[http://dx.doi.org/10.1016/j.semcdb.2014.05.002] [PMID: 24845016]
[73]
Mukhopadhyay S, Wen X, Ratti N, et al. The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling. Cell 2013; 152(1-2): 210-23.
[http://dx.doi.org/10.1016/j.cell.2012.12.026] [PMID: 23332756]
[74]
Singh J, Wen X, Scales SJ. The orphan G protein-coupled receptor Gpr175 (Tpra40) enhances Hedgehog signaling by modulating cAMP levels. J Biol Chem 2015; 290(49): 29663-75.
[http://dx.doi.org/10.1074/jbc.M115.665810] [PMID: 26451044]
[75]
Chen Y, Li S, Tong C, et al. G protein-coupled receptor kinase 2 promotes high-level Hedgehog signaling by regulating the active state of Smo through kinase-dependent and kinase-independent mechanisms in Drosophila. Genes Dev 2010; 24(18): 2054-67.
[http://dx.doi.org/10.1101/gad.1948710] [PMID: 20844016]
[76]
Sengupta R, Dubuc A, Ward S, et al. CXCR4 activation defines a new subgroup of Sonic hedgehog-driven medulloblastoma. Cancer Res 2012; 72(1): 122-32.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-1701] [PMID: 22052462]
[77]
Wang Z, Li Y, Banerjee S, Sarkar FH. Emerging role of Notch in stem cells and cancer. Cancer Lett 2009; 279(1): 8-12.
[http://dx.doi.org/10.1016/j.canlet.2008.09.030] [PMID: 19022563]
[78]
Pannuti A, Foreman K, Rizzo P, et al. Targeting Notch to target cancer stem cells. Clin Cancer Res 2010; 16(12): 3141-52.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-2823] [PMID: 20530696]
[79]
McAuliffe SM, Morgan SL, Wyant GA, et al. Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy. Proc Natl Acad Sci USA 2012; 109(43): E2939-48.
[http://dx.doi.org/10.1073/pnas.1206400109] [PMID: 23019585]
[80]
Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation. Nat Commun 2014; 5: 4806.
[81]
Majumder M, Xin X, Liu L, et al. COX-2 induces breast cancer stem cells via EP4/PI3K/AKT/NOTCH/WNT axis. Stem Cells 2016; 34(9): 2290-305.
[http://dx.doi.org/10.1002/stem.2426] [PMID: 27301070]
[82]
Wei Y, Zhang Z, Liao H, et al. Nuclear estrogen receptor-mediated Notch signaling and GPR30-mediated PI3K/AKT signaling in the regulation of endometrial cancer cell proliferation. Oncol Rep 2012; 27(2): 504-10.
[PMID: 22075757]
[83]
Xia P, Xu X-Y. PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application. Am J Cancer Res 2015; 5(5): 1602-9.
[PMID: 26175931]
[84]
Lu L-L, Chen X-H, Zhang G, et al. CCL21 facilitates chemoresistance and cancer stem cell-like properties of colorectal cancer cells through AKT/GSK-3β/Snail signals. Oxid Med Cell Longev 2016; 2016 5874127
[http://dx.doi.org/10.1155/2016/5874127] [PMID: 27057280]
[85]
Zhu H, Guo S, Zhang Y, et al. Proton-sensing GPCR-YAP signalling promotes cancer-associated fibroblast activation of mesenchymal stem cells. Int J Biol Sci 2016; 12(4): 389-96.
[http://dx.doi.org/10.7150/ijbs.13688] [PMID: 27019624]
[86]
Carmon KS, Gong X, Yi J, et al. LGR5 receptor promotes cell-cell adhesion in stem cells and colon cancer cells via the IQGAP1-Rac1 pathway. J Biol Chem 2017; 292(36): 14989-5001.
[http://dx.doi.org/10.1074/jbc.M117.786798] [PMID: 28739799]
[87]
Jiang Y, Yau M-K, Lim J, et al. A potent antagonist of protease-activated Receptor 2 that inhibits multiple signaling functions in human cancer cells. J Pharmacol Exp Ther 2018; 364(2): 246-57.
[http://dx.doi.org/10.1124/jpet.117.245027] [PMID: 29263243]
[88]
Choi HY, Saha SK, Kim K, et al. G protein-coupled receptors in stem cell maintenance and somatic reprogramming to pluripotent or cancer stem cells. BMB Rep 2015; 48(2): 68-80.
[http://dx.doi.org/10.5483/BMBRep.2015.48.2.250] [PMID: 25413305]
[89]
Kumar KK, Burgess AW, Gulbis JM. Structure and function of LGR5: an enigmatic G-protein coupled receptor marking stem cells. Protein Sci 2014; 23(5): 551-65.
[http://dx.doi.org/10.1002/pro.2446] [PMID: 24677446]
[90]
Shimokawa M, Ohta Y, Nishikori S, et al. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature 2017; 545(7653): 187-92.
[http://dx.doi.org/10.1038/nature22081] [PMID: 28355176]
[91]
Tian H, Biehs B, Warming S, et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 2011; 478(7368): 255-9.
[http://dx.doi.org/10.1038/nature10408] [PMID: 21927002]
[92]
Mao XG, Song SJ, Xue XY, et al. LGR5 is a proneural factor and is regulated by OLIG2 in glioma stem-like cells. Cell Mol Neurobiol 2013; 33(6): 851-65.
[http://dx.doi.org/10.1007/s10571-013-9951-6] [PMID: 23793848]
[93]
Yang L, Tang H, Kong Y, et al. LGR5 promotes breast cancer progression and maintains stem-like cells through activation of Wnt/β-catenin signaling. Stem Cells 2015; 33(10): 2913-24.
[http://dx.doi.org/10.1002/stem.2083] [PMID: 26086949]
[94]
Hou H, Kang Y, Li Y, Zeng Y, Ding G, Shang J. miR-33a expression sensitizes Lgr5+ HCC-CSCs to doxorubicin via ABCA1. Neoplasma 2017; 64(1): 81-91.
[http://dx.doi.org/10.4149/neo_2017_110] [PMID: 27881008]
[95]
Jaks V, Barker N, Kasper M, et al. Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat Genet 2008; 40(11): 1291-9.
[http://dx.doi.org/10.1038/ng.239] [PMID: 18849992]
[96]
da Silva-Diz V, Solé-Sánchez S, Valdés-Gutiérrez A, et al. Progeny of Lgr5-expressing hair follicle stem cell contributes to papillomavirus-induced tumor development in epidermis. Oncogene 2013; 32(32): 3732-43.
[http://dx.doi.org/10.1038/onc.2012.375] [PMID: 22945646]
[97]
Nakata S, Campos B, Bageritz J, et al. LGR5 is a marker of poor prognosis in glioblastoma and is required for survival of brain cancer stem-like cells. Brain Pathol 2013; 23(1): 60-72.
[http://dx.doi.org/10.1111/j.1750-3639.2012.00618.x] [PMID: 22805276]
[98]
Liang F, Yue J, Wang J, et al. GPCR48/LGR4 promotes tumorigenesis of prostate cancer via PI3K/Akt signaling pathway. Med Oncol 2015; 32(3): 49.
[http://dx.doi.org/10.1007/s12032-015-0486-1] [PMID: 25636507]
[99]
Yue Z, Yuan Z, Zeng L, et al. LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells. FASEB J 2018; 32(5): 2422-37.
[http://dx.doi.org/10.1096/fj.201700897R] [PMID: 29269400]
[100]
Huang PY, Kandyba E, Jabouille A, et al. Lgr6 is a stem cell marker in mouse skin squamous cell carcinoma. Nat Genet 2017; 49(11): 1624-32.
[http://dx.doi.org/10.1038/ng.3957] [PMID: 28945253]
[101]
Guinot A, Oeztuerk-Winder F, Ventura J-J. miR-17-92/p38α dysregulation enhances Wnt signaling and selects Lgr6+ cancer stem-like cells during lung adenocarcinoma progression. Cancer Res 2016; 76(13): 4012-22.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-3302] [PMID: 27197183]
[102]
Gelmini S, Mangoni M, Serio M, Romagnani P, Lazzeri E. The critical role of SDF-1/CXCR4 axis in cancer and cancer stem cells metastasis. J Endocrinol Invest 2008; 31(9): 809-19.
[http://dx.doi.org/10.1007/BF03349262] [PMID: 18997494]
[103]
Yi T, Zhai B, Yu Y, et al. Quantitative phosphoproteomic analysis reveals system-wide signaling pathways downstream of SDF-1/CXCR4 in breast cancer stem cells. Proc Natl Acad Sci USA 2014; 111(21): E2182-90.
[http://dx.doi.org/10.1073/pnas.1404943111] [PMID: 24782546]
[104]
Kucia M, Reca R, Miekus K, et al. Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis. Stem Cells 2005; 23(7): 879-94.
[http://dx.doi.org/10.1634/stemcells.2004-0342] [PMID: 15888687]
[105]
Balic A, Sørensen MD, Trabulo SM, et al. Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling. Mol Cancer Ther 2014; 13(7): 1758-71.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0948] [PMID: 24785258]
[106]
Chang W-W, Lin R-J, Yu J, et al. The expression and significance of insulin-like growth factor-1 receptor and its pathway on breast cancer stem/progenitors. Breast Cancer Res 2013; 15(3): R39.
[http://dx.doi.org/10.1186/bcr3423] [PMID: 23663564]
[107]
Würth R, Bajetto A, Harrison JK, Barbieri F, Florio T. CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment. Front Cell Neurosci 2014; 8: 144.
[PMID: 24904289]
[108]
Tang X, Li X, Li Z, et al. Downregulation of CXCR7 inhibits proliferative capacity and stem cell-like properties in breast cancer stem cells. Tumour Biol 2016; 37(10): 13425-33.
[http://dx.doi.org/10.1007/s13277-016-5180-1] [PMID: 27460092]
[109]
Ledur PF, Villodre ES, Paulus R, Cruz LA, Flores DG, Lenz G. Extracellular ATP reduces tumor sphere growth and cancer stem cell population in glioblastoma cells. Purinergic Signal 2012; 8(1): 39-48.
[http://dx.doi.org/10.1007/s11302-011-9252-9] [PMID: 21818572]
[110]
Lee B-C, Cheng T, Adams GB, et al. P2Y-like receptor, GPR105 (P2Y14), identifies and mediates chemotaxis of bone-marrow hematopoietic stem cells. Genes Dev 2003; 17(13): 1592-604.
[http://dx.doi.org/10.1101/gad.1071503] [PMID: 12842911]
[111]
Marfia G, Campanella R, Navone SE, et al. Autocrine/paracrine sphingosine-1-phosphate fuels proliferative and stemness qualities of glioblastoma stem cells. Glia 2014; 62(12): 1968-81.
[http://dx.doi.org/10.1002/glia.22718] [PMID: 25042636]
[112]
Schraufstatter IU, Discipio RG, Zhao M, Khaldoyanidi SK. C3a and C5a are chemotactic factors for human mesenchymal stem cells, which cause prolonged ERK1/2 phosphorylation. J Immunol 2009; 182(6): 3827-36.
[http://dx.doi.org/10.4049/jimmunol.0803055] [PMID: 19265162]
[113]
Möhle R, Drost AC. G protein-coupled receptor crosstalk and signaling in hematopoietic stem and progenitor cells. Ann N Y Acad Sci 2012; 1266: 63-7.
[http://dx.doi.org/10.1111/j.1749-6632.2012.06559.x] [PMID: 22901257]
[114]
Kaur G, Kim J, Kaur R, et al. G-protein coupled receptor kinase (GRK)-5 regulates proliferation of glioblastoma-derived stem cells. J Clin Neurosci 2013; 20(7): 1014-8.
[http://dx.doi.org/10.1016/j.jocn.2012.10.008] [PMID: 23693024]
[115]
Ye X, Tam WL, Shibue T, et al. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature 2015; 525(7568): 256-60.
[http://dx.doi.org/10.1038/nature14897] [PMID: 26331542]
[116]
Arakaki AKS, Pan WA, Trejo J. GPCRs in cancer: protease-activated receptors, endocytic adaptors and signaling. Int J Mol Sci 2018; 19(7): 1886.
[http://dx.doi.org/10.3390/ijms19071886] [PMID: 29954076]
[117]
Gurney A, Axelrod F, Bond CJ, et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci USA 2012; 109(29): 11717-22.
[http://dx.doi.org/10.1073/pnas.1120068109] [PMID: 22753465]
[118]
Fukukawa C, Hanaoka H, Nagayama S, et al. Radioimmunotherapy of human synovial sarcoma using a monoclonal antibody against FZD10. Cancer Sci 2008; 99(2): 432-40.
[http://dx.doi.org/10.1111/j.1349-7006.2007.00701.x] [PMID: 18271942]
[119]
Giraudet A-L, Cassier PA, Iwao-Fukukawa C, et al. A first-in-human study investigating biodistribution, safety and recommended dose of a new radiolabeled MAb targeting FZD10 in metastatic synovial sarcoma patients. BMC Cancer 2018; 18(1): 646.
[http://dx.doi.org/10.1186/s12885-018-4544-x] [PMID: 29884132]
[120]
Li HK, Sugyo A, Tsuji AB, et al. α-particle therapy for synovial sarcoma in the mouse using an astatine-211-labeled antibody against frizzled homolog 10. Cancer Sci 2018; 109(7): 2302-9.
[http://dx.doi.org/10.1111/cas.13636] [PMID: 29952132]
[121]
Hsieh J-C, Rattner A, Smallwood PM, Nathans J. Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. Proc Natl Acad Sci USA 1999; 96(7): 3546-51.
[http://dx.doi.org/10.1073/pnas.96.7.3546] [PMID: 10097073]
[122]
Le PN, McDermott JD, Jimeno A. Targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP-54F28. Pharmacol Ther 2015; 146: 1-11.
[http://dx.doi.org/10.1016/j.pharmthera.2014.08.005] [PMID: 25172549]
[123]
Fischer MM, Cancilla B, Yeung VP, et al. WNT antagonists exhibit unique combinatorial antitumor activity with taxanes by potentiating mitotic cell death. Sci Adv 2017; 3(6) e1700090
[http://dx.doi.org/10.1126/sciadv.1700090] [PMID: 28691093]
[124]
Jiang Q, He M, Guan S, et al. MicroRNA-100 suppresses the migration and invasion of breast cancer cells by targeting FZD-8 and inhibiting Wnt/β-catenin signaling pathway. Tumour Biol 2016; 37(4): 5001-11.
[http://dx.doi.org/10.1007/s13277-015-4342-x] [PMID: 26537584]
[125]
Tian F, Mysliwietz J, Ellwart J, Gamarra F, Huber RM, Bergner A. Effects of the Hedgehog pathway inhibitor GDC-0449 on lung cancer cell lines are mediated by side populations. Clin Exp Med 2012; 12(1): 25-30.
[http://dx.doi.org/10.1007/s10238-011-0135-8] [PMID: 21519961]
[126]
Tong W, Qiu L, Qi M, et al. GANT-61 and GDC-0449 induce apoptosis of prostate cancer stem cells through a GLI-dependent mechanism. J Cell Biochem 2018; 119(4): 3641-52.
[http://dx.doi.org/10.1002/jcb.26572] [PMID: 29231999]
[127]
Sims-Mourtada J, Opdenaker LM, Davis J, Arnold KM, Flynn D. Taxane-induced hedgehog signaling is linked to expansion of breast cancer stem-like populations after chemotherapy. Mol Carcinog 2015; 54(11): 1480-93.
[http://dx.doi.org/10.1002/mc.22225] [PMID: 25263583]
[128]
Steg AD, Katre AA, Bevis KS, et al. Smoothened antagonists reverse taxane resistance in ovarian cancer. Mol Cancer Ther 2012; 11(7): 1587-97.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-1058] [PMID: 22553355]
[129]
Huang F-T, Zhuan-Sun Y-X, Zhuang Y-Y, et al. Inhibition of hedgehog signaling depresses self-renewal of pancreatic cancer stem cells and reverses chemoresistance. Int J Oncol 2012; 41(5): 1707-14.
[http://dx.doi.org/10.3892/ijo.2012.1597] [PMID: 22923052]
[130]
Kunstfeld R. Smoothened inhibitors in the treatment of advanced basal cell carcinomas. Curr Opin Oncol 2014; 26(2): 184-95.
[http://dx.doi.org/10.1097/CCO.0000000000000058] [PMID: 24469022]
[131]
Lin TL, Wang QH, Brown P, et al. Self-renewal of acute lymphocytic leukemia cells is limited by the Hedgehog pathway inhibitors cyclopamine and IPI-926. PLoS One 2010; 5(12) e15262
[http://dx.doi.org/10.1371/journal.pone.0015262] [PMID: 21203400]
[132]
Campbell VT, Nadesan P, Ali SA, et al. Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth. Mol Cancer Ther 2014; 13(5): 1259-69.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0731] [PMID: 24634412]
[133]
Fukushima N, Minami Y, Kakiuchi S, et al. Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. Cancer Sci 2016; 107(10): 1422-9.
[http://dx.doi.org/10.1111/cas.13019] [PMID: 27461445]
[134]
Wagner AJ, Messersmith WA, Shaik MN, et al. A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2015; 21(5): 1044-51.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-1116] [PMID: 25388167]
[135]
Ibuki N, Ghaffari M, Pandey M, et al. TAK-441, a novel investigational smoothened antagonist, delays castration-resistant progression in prostate cancer by disrupting paracrine hedgehog signaling. Int J Cancer 2013; 133(8): 1955-66.
[http://dx.doi.org/10.1002/ijc.28193] [PMID: 23564295]
[136]
Babashah S, Sadeghizadeh M, Hajifathali A, et al. Targeting of the signal transducer Smo links microRNA-326 to the oncogenic Hedgehog pathway in CD34+ CML stem/progenitor cells. Int J Cancer 2013; 133(3): 579-89.
[http://dx.doi.org/10.1002/ijc.28043] [PMID: 23341351]
[137]
Junttila MR, Mao W, Wang X, et al. Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer. Sci Transl Med 2015; 7(314): 186.
[http://dx.doi.org/10.1126/scitranslmed.aac7433] [PMID: 26582901]
[138]
Gong X, Azhdarinia A, Ghosh SC, et al. LGR5-targeted antibody–drug conjugate eradicates gastrointestinal tumors and prevents recurrence. Mol Cancer Ther 2016; 15(7): 1580-90.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0114] [PMID: 27207778]
[139]
Cao J, Li C, Wei X, et al. Selective Targeting and eradication of LGR5+ cancer stem cells using RSPO-conjugated doxorubicin liposomes. Mol Cancer Ther 2018; 17(7): 1475-85.
[http://dx.doi.org/10.1158/1535-7163.MCT-17-0694] [PMID: 29695632]
[140]
Fischer MM, Yeung VP, Cattaruzza F, et al. RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations. Sci Rep 2017; 7(1): 15270.
[http://dx.doi.org/10.1038/s41598-017-15704-y] [PMID: 29127379]
[141]
Chartier C, Raval J, Axelrod F, et al. Therapeutic targeting of tumor-derived R-spondin attenuates β-catenin signaling and tumorigenesis in multiple cancer types. Cancer Res 2016; 76(3): 713-23.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-0561] [PMID: 26719531]
[142]
Majumder M, Xin X, Liu L, Girish GV, Lala PK. Prostaglandin E2 receptor EP4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem-like cell functions. Cancer Sci 2014; 105(9): 1142-51.
[http://dx.doi.org/10.1111/cas.12475] [PMID: 24981602]
[143]
Lin MC, Chen SY, He PL, Herschman H, Li HJ. PGE2 /EP4 antagonism enhances tumor chemosensitivity by inducing extracellular vesicle-mediated clearance of cancer stem cells. Int J Cancer 2018; 143(6): 1440-55.
[http://dx.doi.org/10.1002/ijc.31523] [PMID: 29658109]
[144]
Greco SJ, Patel SA, Bryan M, Pliner LF, Banerjee D, Rameshwar P. AMD3100-mediated production of interleukin-1 from mesenchymal stem cells is key to chemosensitivity of breast cancer cells. Am J Cancer Res 2011; 1(6): 701-15.
[PMID: 22016821]
[145]
Dubrovska A, Hartung A, Bouchez LC, et al. CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling. Br J Cancer 2012; 107(1): 43-52.
[http://dx.doi.org/10.1038/bjc.2012.105] [PMID: 22644306]

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