Emerging targets in malignancy management: role of the CXCL12/CXCR4 axis

Emerging targets in malignancy management: role of the CXCL12/CXCR4 axis. (GCB)-DLBCL, but not in ABC-DLBCL; and in individuals with an IPI of 2, but not in those with an IPI>2. The lack of prognostic significance of CXCR4 in ABC-DLBCL was likely due to the activation of p53 tumor suppressor attenuating CXCR4 signaling. Furthermore, concurrent CXCR4+ and translocation showed dismal results resembling but self-employed of double-hit Masitinib ( AB1010) DLBCL. Gene manifestation profiling suggested that alterations in the tumor microenvironment and immune responses, improved tumor proliferation and survival, and the dissemination of CXCR4+ tumor cells to distant organs or cells were underlying molecular mechanisms responsible for the CXCR4+ connected poor prognosis. DLBCL, compared the gene manifestation profiles and protein manifestation of biomarkers between CXCR4+ and CXCR4? DLBCLs, and evaluated the prognostic value of CXCR4 manifestation. We also tested the effect of the high-affinity CXCL12/CXCR4 inhibitor BTK140 (4F-benzoyl-TN14003) on DLBCL cells mRNA significantly. (G) CXCR4 cell surface manifestation correlated with decreased mRNA levels, both in GCB- and ARHGEF11 ABC-DLBCL. (H-I) CXCR4 manifestation correlated with significantly poorer OS and PFS in the overall DLBCL cohort. (J-K) CXCR4 manifestation correlated with significantly poorer PFS (but not OS) in GCB-DLBCL. (L-M) CXCR4 manifestation correlated with significantly poorer OS (but not PFS) in ABC-DLBCL. (N-O) CXCR4 manifestation correlated with significantly poorer survival in DLBCL individuals with a low IPI, but not in DLBCL individuals with a high IPI. CXCR4 cell surface manifestation and mRNA levels were higher in the ABC than GCB subtype, whereas mRNA levels did not differ significantly between the two organizations (Numbers 1E-F, Supplemental Number 1C). CXCR4 manifestation recognized via IHC was significantly correlated with CXCR4 mRNA levels (< .0001, Supplemental Figure 1D), and intriguingly, significantly correlated with lower mRNA levels (Figure ?(Number1G1G). Clinicopathologic features of individuals with CXCR4 manifestation Clinically, CXCR4+ group experienced higher proportion of male individuals and individuals with heavy tumors than the CXCR4? group, and tended to have higher rate of recurrence of >1 extranodal involvement (mutations, Myc overexpression and less regularly indicated BLIMP-1 or nuclear RelB. In comparison, CXCR4+ ABC-DLBCLs compared to CXCR4? ABC-DLBCLs experienced a higher percentage of individuals with a high Ki-67 index, p53, Myc, Bcl-2, PI3K manifestation and lower event of translocations and nuclear p50 manifestation (Table ?(Table22). Table 1 Clinical features of individuals with CXCR4+ and CXCR4? manifestation in overall, GCB-DLBCL and ABC-DLBCL Masitinib ( AB1010) ideals Masitinib ( AB1010) as CR vs additional reactions. Few clinical features of particular cases were not available. Table 2 Pathological features of individuals with CXCR4+ and CXCR4? manifestation in overall, GCB-DLBCL and ABC-DLBCL mutationsNo94(74)241(80.9).0729(61.7)133(78.7).01765(81.3)105(83.3).70Yes33(26)57(19.1)18(38.3)36(21.3)15(18.8)21(16.7)translocationNo83(85.6)198(91.7).1125(80.6)102(87.9).3758(87.9)95(96).067Yes14(14.4)18(8.3)6(19.4)14(12.1)8(12.1)4(4)translocationNo101(83.5)227(82.2).8929(67.4)107(70.4).7172(92.3)119(97.5).16Yes20(16.5)49(17.8)14(32.6)45(29.6)6(7.7)3(2.5)translocationNo73(83)150(64.4).001332(82.1)95(73.1).2641(69.5)54(52.9).04Yes15(17)83(35.6)7(17.9)35(26.9)18(30.5)48(47.1)p53 overexpression< 20%71(57.3)195(67.7).04429(63)104(63.8)1.0042(53.8)91(72.8).0065 20%53(42.7)93(32.3)17(37)59(36.2)36(46.2)34(27.2)Myc overexpression< 70%73(57.9)221(72.5).004431(60.8)126(78.3).01742(56)93(65).24 70%53(42.1)84(27.5)20(39.2)35(21.7)33(44)50(35)Bcl-2 overexpression< 70%48(35.8)175(53.7).000724(47.1)108(60).1124(28.9)65(45.1).017 70%86(64.2)151(46.3)27(52.9)72(40)59(71.1)79(54.9)GCET1 overexpression< 50%84(63.2)219(67.6).3821(40.4)89(49.7).2763(77.8)129(89.6).019 50%49(36.8)105(32.4)31(59.6)90(50.3)18(22.2)15(10.4)FOXP1 overexpression< 60%33(24.4)151(46.3)< .000126(50)118(65.6).057(8.4)33(22.6).0065 60%102(75.6)175(53.7)26(50)62(34.4)76(91.6)113(77.4)MUM1 overexpression< 30%43(31.9)181(55.7)< .000134(65.4)137(76.1).159(10.8)44(30.3).006 30%92(68.1)144(44.3)18(34.6)43(23.9)74(89.2)101(69.7)PI3K overexpression< 70%80(61.5)233(73.7).01236(73.5)130(73.4)1.0044(54.3)103(74.6).0028 70%50(38.5)83(26.3)1326.5%47(26.6)37(45.7)35(25.4)BLIMP-1 expression< 10%97(75.2)233(72.6).6447(95.9)144(80.9).00850(62.5)88(62)1.00 10%32(24.8)88(27.4)2(4.1)34(19.1)30(37.5)54(38)p50Negative74(57.4)135(44.4).01634(66.7)93(54.7).1540(51.3)42(31.3).0054Positive55(42.6)169(55.6)17(33.3)77(45.3)38(48.7)92(68.7)p52Negative100(77.5)210(67.7).0538(77.6)114(67.1).2162(77.5)96(68.6).17Positive29(22.5)100(32.3)11(22.4)56(32.9)18(22.5)44(31.4)p65Negative60(45.8)129(40.7).3422(44)65(37.8).5138(46.9)61(42.7).58Positive71(54.2)188(59.3)28(56)107(62.2)43(53.1)82(57.3)RelBNegative117(92.1)253(82.4).0146(95.8)143(83.6).0371(89.9)109(80.7).08Positive10(7.9)54(17.6)2(4.2)28(16.4)8(10.1)26(19.3)c-RelNegative89(68.5)208(69.3).9131(62)121(72.9).1658(72.5)87(64.9).29Positive41(31.5)92(30.7)19(38)45(27.1)22(27.5)47(35.1) Open in a separate window CXCR4 manifestation was associated with significantly poorer survival CXCR4+ DLBCL individuals had significantly poorer overall survival (OS) (mRNA levels in nodal vs main extranodal individuals). Although CXCR4 cell surface manifestation invariably correlated with lower mRNA levels in both nodal and extranodal sites (Number ?(Number2C),2C), CXCR4+ manifestation correlated with significantly poorer OS and PFS only in nodal DLBCLs (Numbers 2E-H) no matter extranodal involvement status (Supplemental Number 1F). In contrast, CXCR4 surface manifestation was negatively correlated with mRNA levels only in individuals without BM involvement (Number ?(Figure2D).2D). However, the prognostic significance of CXCR4 in nodal DLBCL was shown in both organizations either with or without BM involvement at analysis (Numbers 2I-L). Collectively, these data suggested the Masitinib ( AB1010) prognostic significance of CXCR4 manifestation is self-employed of BM or extranodal involvement, and reduction of mRNA levels in the primary sites. Open in a separate window Number 2 Manifestation and prognostic significance of CXCR4 in nodal and extranodal DLBCL(A-B) CXCR4 cell surface and mRNA manifestation levels in.