Abstract
Chemokines, which have chemotactic abilities, are comprised of a family of small cytokines with 8-10 kilodaltons. Chemokines work in immune cells by trafficking and regulating cell proliferation, migration, activation, differentiation, and homing. CXCR-4 is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1, also known as CXCL12), which has been found to be expressed in more than 23 different types of cancers. Recently, the SDF-1/CXCR-4 signaling pathway has emerged as a potential therapeutic target for human tumor because of its critical role in tumor initiation and progression by activating multiple signaling pathways, such as ERK1/2, ras, p38 MAPK, PLC/ MAPK, and SAPK/ JNK, as well as regulating cancer stem cells. CXCL12/CXCR4 antagonists have been produced, which have shown encouraging results in anti-cancer activity. Here, we provide a brief overview of the CXCL12/CXCR4 axis as a molecular target for cancer treatment. We also review the potential utility of targeting CXCL12/CXCR4 axis in combination of immunotherapy and/or chemotherapy based on up-to-date literature and ongoing research progress.
Keywords: Cancer, cancer stem cell, immunotherapy, CXCR4, CXCL12, chemokine, kilodaltons.
[http://dx.doi.org/10.1067/mai.2003.1594] [PMID: 12789214]
[http://dx.doi.org/10.1016/j.yexcr.2011.10.012] [PMID: 22036649]
[http://dx.doi.org/10.1016/j.yexcr.2010.10.020] [PMID: 21040721]
[http://dx.doi.org/10.1515/BC.2009.144] [PMID: 19804363]
[http://dx.doi.org/10.3390/ijms17050643] [PMID: 27136535]
[http://dx.doi.org/10.1189/jlb.3MR0915-431RR] [PMID: 26908826]
[http://dx.doi.org/10.1200/JCO.1999.17.9.2692] [PMID: 10561343]
[http://dx.doi.org/10.1016/S1074-7613(00)80165-X] [PMID: 10714678]
[PMID: 10699158]
[http://dx.doi.org/10.1038/nri3049] [PMID: 21866172]
[http://dx.doi.org/10.7150/thno.4922] [PMID: 23382783]
[http://dx.doi.org/10.1038/35065016] [PMID: 11242036]
[http://dx.doi.org/10.1182/blood.V99.8.2703] [PMID: 11929756]
[http://dx.doi.org/10.1038/onc.2015.139] [PMID: 25961926]
[http://dx.doi.org/10.5732/cjc.009.10404] [PMID: 20346226]
[PMID: 26347749]
[http://dx.doi.org/10.1074/jbc.M508234200] [PMID: 16107333]
[http://dx.doi.org/10.11622/smedj.2016057] [PMID: 26996902]
[http://dx.doi.org/10.1016/j.it.2007.05.007] [PMID: 17560169]
[http://dx.doi.org/10.1073/pnas.91.6.2305] [PMID: 8134392]
[http://dx.doi.org/10.1634/stemcells.2004-0342] [PMID: 15888687]
[http://dx.doi.org/10.1016/j.bbamem.2006.11.002] [PMID: 17169327]
[http://dx.doi.org/10.1016/j.biopha.2006.06.004] [PMID: 16828253]
[http://dx.doi.org/10.1074/jbc.M111.277038] [PMID: 21730065]
[http://dx.doi.org/10.1016/j.cytogfr.2012.08.007] [PMID: 22989616]
[http://dx.doi.org/10.1007/s10555-010-9256-x] [PMID: 20839032]
[http://dx.doi.org/10.1074/jbc.275.4.2479] [PMID: 10644702]
[http://dx.doi.org/10.1074/jbc.M207294200] [PMID: 12370187]
[http://dx.doi.org/[DOI: 10.1016/j.cllc.2016.12.005] [PMID: 28073681]
[http://dx.doi.org/10.1186/1476-4598-13-58] [PMID: 24629239]
[http://dx.doi.org/10.1159/000345353] [PMID: 23257686]
[http://dx.doi.org/10.1007/s11060-010-0111-2] [PMID: 20157762]
[http://dx.doi.org/10.1093/carcin/bgl129] [PMID: 16840440]
[http://dx.doi.org/10.1158/1541-7786.MCR-07-0054] [PMID: 17699109]
[http://dx.doi.org/10.1038/sj.bjc.6604726] [PMID: 18941460]
[http://dx.doi.org/10.1023/A:1025905008934] [PMID: 14635796]
[http://dx.doi.org/10.1074/jbc.M300609200] [PMID: 12690099]
[http://dx.doi.org/10.1038/cdd.2011.89] [PMID: 21720384]
[http://dx.doi.org/10.1096/fasebj.13.13.1699] [PMID: 10506573]
[http://dx.doi.org/10.1111/j.1365-2567.2004.01863.x] [PMID: 15147562]
[http://dx.doi.org/10.1007/s10585-008-9210-2] [PMID: 18814042]
[PMID: 15831676]
[http://dx.doi.org/10.1172/JCI12629] [PMID: 11489936]
[http://dx.doi.org/10.1158/0008-5472.CAN-05-1293] [PMID: 16267013]
[http://dx.doi.org/10.1158/0008-5472.CAN-04-1303] [PMID: 16061624]
[http://dx.doi.org/10.1016/j.ccr.2004.09.027] [PMID: 15542430]
[http://dx.doi.org/10.1371/journal.pone.0047287] [PMID: 23082154]
[http://dx.doi.org/10.3892/or.2013.2254] [PMID: 23443279]
[http://dx.doi.org/10.1158/1541-7786.MCR-07-0117] [PMID: 18337451]
[http://dx.doi.org/10.1016/j.yexcr.2005.04.024] [PMID: 15921680]
[http://dx.doi.org/10.1016/S1534-5807(03)00321-6] [PMID: 14602072]
[http://dx.doi.org/10.1074/jbc.M503790200] [PMID: 15870067]
[http://dx.doi.org/10.1158/0008-5472.CAN-04-3309] [PMID: 15805285]
[http://dx.doi.org/10.1007/s00018-010-0388-5] [PMID: 20473547]
[http://dx.doi.org/10.1186/1476-4598-8-62] [PMID: 19671192]
[http://dx.doi.org/10.1016/j.canlet.2005.06.021] [PMID: 16046252]
[http://dx.doi.org/10.1016/j.bbrc.2007.05.182] [PMID: 17559806]
[http://dx.doi.org/10.1016/j.humpath.2014.05.012] [PMID: 25086956]
[http://dx.doi.org/10.3892/mmr.2015.3518] [PMID: 25815440]
[http://dx.doi.org/10.1038/nrc1388] [PMID: 15229479]
[http://dx.doi.org/10.1002/path.3029] [PMID: 21989643]
[http://dx.doi.org/10.1007/s13277-016-5016-z] [PMID: 27079871]
[PMID: 25688243]
[http://dx.doi.org/10.4161/cbt.9.6.11233] [PMID: 20147779]
[PMID: 26356032]
[http://dx.doi.org/10.18632/oncotarget.3217] [PMID: 25669980]
[http://dx.doi.org/10.1016/j.semcancer.2003.10.003] [PMID: 15246052]
[http://dx.doi.org/10.1152/ajplung.00321.2011] [PMID: 22345572]
[http://dx.doi.org/10.1016/j.bcp.2007.08.025] [PMID: 17904532]
[http://dx.doi.org/10.1186/1471-2407-12-480] [PMID: 23075330]
[http://dx.doi.org/10.3892/etm.2011.235] [PMID: 22977534]
[http://dx.doi.org/10.1371/journal.pone.0088176] [PMID: 24505417]
[PMID: 17016644]
[http://dx.doi.org/10.1158/0008-5472.CAN-14-3781] [PMID: 26141860]
[http://dx.doi.org/10.1158/1078-0432.CCR-05-0537] [PMID: 16322285]
[http://dx.doi.org/10.3892/ol.2014.1979] [PMID: 24932250]
[http://dx.doi.org/10.1158/1541-7786.MCR-12-0334] [PMID: 24025971]
[http://dx.doi.org/10.1016/j.jtcvs.2008.07.039] [PMID: 19258077]
[http://dx.doi.org/10.18632/oncoscience.117] [PMID: 25897429]
[http://dx.doi.org/10.1016/j.cell.2011.09.024] [PMID: 22000009]
[http://dx.doi.org/10.1016/j.tig.2008.10.012] [PMID: 19054589]
[http://dx.doi.org/10.1016/j.yexcr.2010.02.045] [PMID: 20211171]
[http://dx.doi.org/10.1371/journal.pone.0122439] [PMID: 25775124]
[http://dx.doi.org/10.1007/s12185-010-0654-1] [PMID: 20697855]
[http://dx.doi.org/10.1038/nrc865] [PMID: 12154349]
[http://dx.doi.org/10.1164/rccm.200301-071OC] [PMID: 12626353]
[http://dx.doi.org/10.1007/s10620-011-1922-5] [PMID: 21960286]
[http://dx.doi.org/10.1016/j.trsl.2014.12.006] [PMID: 25620615]
[http://dx.doi.org/10.4149/neo_2013_082] [PMID: 23906298]
[http://dx.doi.org/10.1038/sj.onc.1209505] [PMID: 16568088]
[PMID: 18575756]
[http://dx.doi.org/10.18632/oncotarget.10786] [PMID: 27462860]
[http://dx.doi.org/10.1016/j.bbadis.2009.02.010] [PMID: 19254761]
[http://dx.doi.org/10.1155/2016/1740936]
[http://dx.doi.org/10.1186/s13058-016-0712-6] [PMID: 27220421]
[http://dx.doi.org/10.1007/s12013-014-9844-4] [PMID: 24549856]
[http://dx.doi.org/10.1111/resp.12094] [PMID: 23586700]
[http://dx.doi.org/10.1097/JTO.0b013e31826bfbc6] [PMID: 23154562]
[PMID: 26592827]
[http://dx.doi.org/10.1158/0008-5472.CAN-10-0881] [PMID: 21118965]
[http://dx.doi.org/10.1016/j.canlet.2012.08.021] [PMID: 22935675]
[http://dx.doi.org/10.2174/187152010790909308] [PMID: 20184538]
[http://dx.doi.org/10.1152/physrev.00046.2011] [PMID: 23073628]
[http://dx.doi.org/10.5966/sctm.2015-0048] [PMID: 26136504]
[http://dx.doi.org/10.1016/B978-0-12-800092-2.00010-1] [PMID: 25081533]
[http://dx.doi.org/10.1177/1535370213480714] [PMID: 23598979]
[PMID: 24228135]
[http://dx.doi.org/10.1002/path.4086] [PMID: 22899341]
[http://dx.doi.org/10.1111/cas.12045] [PMID: 23066953]
[http://dx.doi.org/10.3892/or.2015.4057] [PMID: 26081992]
[http://dx.doi.org/10.1186/1476-4598-11-73] [PMID: 23009336]
[http://dx.doi.org/10.1038/sj.bjc.6605668] [PMID: 20424609]
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2808] [PMID: 25934888]
[http://dx.doi.org/10.1158/1078-0432.CCR-12-0370] [PMID: 23444212]
[http://dx.doi.org/10.1371/journal.pone.0038996] [PMID: 22768056]
[http://dx.doi.org/10.1016/j.ccr.2014.01.008] [PMID: 24525231]
[PMID: 19763051]
[http://dx.doi.org/10.1158/0008-5472.CAN-14-3265] [PMID: 26122848]
[http://dx.doi.org/10.3892/or.2015.3956] [PMID: 25955300]
[http://dx.doi.org/10.1158/0008-5472.CAN-13-2136] [PMID: 24607842]
[PMID: 26675547]
[http://dx.doi.org/10.18632/oncotarget.5626] [PMID: 26486080]
[http://dx.doi.org/10.1371/journal.pone.0079798] [PMID: 24278179]
[http://dx.doi.org/10.18632/oncotarget.13214] [PMID: 27835894]
[http://dx.doi.org/10.1097/JTO.0000000000000563] [PMID: 26020124]
[PMID: 28000861]
[http://dx.doi.org/10.1007/s13277-016-5016-z] [PMID: 27079871]
[http://dx.doi.org/10.1016/j.semcancer.2003.10.010] [PMID: 15246048]
[http://dx.doi.org/10.1016/j.semcancer.2003.10.001] [PMID: 15246050]
[http://dx.doi.org/10.1517/13543784.2012.656197] [PMID: 22283809]
[http://dx.doi.org/10.2174/138161210794455003] [PMID: 21158728]
[http://dx.doi.org/10.1038/onc.2012.37] [PMID: 22370645]
[http://dx.doi.org/10.1007/s11010-011-0860-z] [PMID: 21553023]
[http://dx.doi.org/10.1073/pnas.0905653106] [PMID: 19805294]
[http://dx.doi.org/10.1007/s13277-015-4690-6] [PMID: 26715265]
[http://dx.doi.org/10.1016/j.canlet.2012.08.014] [PMID: 22906416]
[PMID: 27242955]
[PMID: 26798578]
[http://dx.doi.org/10.1016/j.jtcvs.2012.07.031] [PMID: 22925564]
[http://dx.doi.org/10.1021/jm049429h] [PMID: 15658852]
[http://dx.doi.org/10.1016/j.bmcl.2012.01.134] [PMID: 22365757]
[http://dx.doi.org/10.1016/S0014-5793(03)00824-X] [PMID: 12935890]
[http://dx.doi.org/10.2174/157489212801820039]
[http://dx.doi.org/10.1016/j.febslet.2012.08.011] [PMID: 22992418]
[http://dx.doi.org/10.1128/AAC.00013-07] [PMID: 17452489]
[http://dx.doi.org/10.1097/QAI.0b013e3181627566] [PMID: 18362694]
[http://dx.doi.org/10.1016/j.bcp.2008.12.014] [PMID: 19161986]
[PMID: 19363221]
[http://dx.doi.org/10.1038/nrd2819] [PMID: 19180104]
[http://dx.doi.org/10.1038/bjc.2013.124] [PMID: 23538388]
[http://dx.doi.org/10.1371/journal.pone.0034038] [PMID: 22485156]
[http://dx.doi.org/10.1016/j.jmgm.2015.05.004] [PMID: 26080355]
[http://dx.doi.org/10.1128/AAC.01293-09] [PMID: 19949058]
[http://dx.doi.org/10.1128/AAC.01727-08] [PMID: 19451305]
[PMID: 23267887]
[http://dx.doi.org/10.1158/1078-0432.CCR-12-2333] [PMID: 23213054]
[http://dx.doi.org/10.1073/pnas.1220580110] [PMID: 23509246]
[http://dx.doi.org/10.1016/j.jss.2012.09.035] [PMID: 23117118]
[http://dx.doi.org/10.1245/s10434-014-3705-7]
[http://dx.doi.org/10.1038/onc.2013.448] [PMID: 24141785]
[http://dx.doi.org/10.1016/j.biopha.2016.04.060] [PMID: 27470356]
[http://dx.doi.org/10.18632/oncotarget.11176] [PMID: 27517626]
[http://dx.doi.org/10.1158/0008-5472.CAN-03-3958] [PMID: 15205345]
[http://dx.doi.org/10.1016/j.jtcvs.2010.11.056] [PMID: 21463876]
[http://dx.doi.org/10.1021/jm070679i] [PMID: 17958344]
[http://dx.doi.org/10.1371/journal.pone.0027042] [PMID: 22069486]
[http://dx.doi.org/10.1182/blood-2011-10-383406] [PMID: 22308295]
[http://dx.doi.org/[doi: 10.18632/oncotarget.13238]
[PMID: 27669438]
[http://dx.doi.org/10.1039/C4IB00015C] [PMID: 24675873]
[http://dx.doi.org/10.1002/ijc.25665] [PMID: 20830712]
[http://dx.doi.org/10.1007/s10549-014-3053-0] [PMID: 25030358]
[http://dx.doi.org/10.1038/ncb1741] [PMID: 18568019]
[http://dx.doi.org/10.1007/s12033-014-9796-3] [PMID: 25150396]
[http://dx.doi.org/10.1016/j.bbrc.2007.09.007] [PMID: 17889832]
[http://dx.doi.org/10.1016/j.biopha.2015.08.013] [PMID: 26349988]
[http://dx.doi.org/10.1056/NEJMoa1200694] [PMID: 22658128]
[http://dx.doi.org/10.2217/imt-2015-0029] [PMID: 27140411]
[http://dx.doi.org/10.1126/scitranslmed.aad7118] [PMID: 26936508]
[http://dx.doi.org/10.1056/NEJMoa1200690] [PMID: 22658127]
[http://dx.doi.org/10.1002/bdrb.21176] [PMID: 27062127]
[http://dx.doi.org/10.1056/NEJMoa1003466] [PMID: 20525992]
[http://dx.doi.org/10.1053/j.seminoncol.2015.05.008] [PMID: 26320062]
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0002] [PMID: 24778314]
[http://dx.doi.org/10.1056/NEJMoa1103849] [PMID: 21830940]
[PMID: 27298832]
[http://dx.doi.org/10.1158/2326-6066.CIR-15-0106] [PMID: 25968457]
[http://dx.doi.org/10.1056/NEJMoa1501824] [PMID: 25891174]
[http://dx.doi.org/10.1126/science.aaa1348] [PMID: 25765070]
[http://dx.doi.org/10.1056/NEJMoa1504627] [PMID: 26028407]
[http://dx.doi.org/10.1371/journal.pone.0130142] [PMID: 26086854]
[http://dx.doi.org/10.1016/j.ccr.2005.04.023] [PMID: 15894267]
[http://dx.doi.org/10.1073/pnas.1320318110] [PMID: 24277834]
[http://dx.doi.org/10.1002/hep.27665] [PMID: 25529917]
[http://dx.doi.org/10.1038/sj.onc.1207097] [PMID: 14603250]
[http://dx.doi.org/10.1016/j.exphem.2010.11.010] [PMID: 21138752]
[http://dx.doi.org/10.1038/cgt.2015.55] [PMID: 26494555]
[http://dx.doi.org/10.1158/0008-5472.CAN-04-1844] [PMID: 15574767]
[http://dx.doi.org/10.1593/neo.12324] [PMID: 22952424]
[http://dx.doi.org/10.1038/bjc.2014.1] [PMID: 24448360]
[http://dx.doi.org/10.1016/j.jss.2008.06.044] [PMID: 19482312]
[http://dx.doi.org/10.1007/s10585-010-9321-4] [PMID: 20229045]
[http://dx.doi.org/10.1186/1471-2490-14-12] [PMID: 24472670]
[PMID: 12499259]
[http://dx.doi.org/10.1021/bi5011927] [PMID: 25407882]
[http://dx.doi.org/10.2147/IJN.S112204] [PMID: 27660448]
[http://dx.doi.org/10.1007/s10147-011-0222-6] [PMID: 21455623]
[http://dx.doi.org/10.1002/ijc.25966] [PMID: 21448932]
[http://dx.doi.org/10.1371/journal.pone.0026943] [PMID: 22066019]
[http://dx.doi.org/10.1016/j.bcp.2010.07.045] [PMID: 20699088]
[PMID: 27725861]
[http://dx.doi.org/10.1371/journal.pone.0058426] [PMID: 23484027]
[http://dx.doi.org/10.18632/oncotarget.2112] [PMID: 25115391]
[http://dx.doi.org/10.1021/jm100786g] [PMID: 21105715]
[http://dx.doi.org/10.1007/s00109-010-0669-3] [PMID: 20798912]
[http://dx.doi.org/10.1371/journal.pone.0023741] [PMID: 21912642]
[http://dx.doi.org/10.1002/cmdc.201200582] [PMID: 23468189]