粘附分子抑制剂幻灯片.ppt

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1、粘附分子抑制剂第1页，共20页，编辑于2022年，星期一background knowledgeNatalizumab：a recombinant humanized IgG4 monoclonal antibody,which binds integrin-a4,in MM;integrin:cell surface receptors that mediate both cell-cell and cell-extra cellular matrix adhesion;fibronectin:strong adhesive components for MM cells via inter

2、action of a variety of integrins including integrin-a4。第2页，共20页，编辑于2022年，星期一MM细胞的粘附过程骨髓基质细胞促进MM细胞增殖整合蛋白MM 细胞第3页，共20页，编辑于2022年，星期一SummaryIntegrin-a4 expression in the MM bone marrow microenvironment；Natalizumab inhibits MM cell adhesion to fibronectin,endothelial cells；Natalizumab inhibits MM cell ad

3、hesion to BMSCsas well as MM cell proliferation triggered by MM-BMSC adhesion；Natalizumab inhibits MM-BMSC-induced secretion of VEGF and angiogenesis；Natalizumab inhibits VEGF-and IGF-1-triggered MM cell migration on fibronectin；Natalizumab inhibits MM cell growth in a murine model of MMNatalizumab

4、sensitizes MM cells attached to BMSCs and endothelial cells to bortezomib.第4页，共20页，编辑于2022年，星期一NO.1 Integrin-a4 expression in the MMbone marrow microenvironmentAll of theMM cell lines expressed integrin-a4；ITGA4 was significantly upregulated in plasma tumour cells derived from MM patients versus pla

5、sma cells from healthy donors；neither endothelial cells nor primary BMSCs or BMSC cell lines expressed integrin-a4。第5页，共20页，编辑于2022年，星期一NO.2 Natalizumab inhibits MM cell adhesion to fibronectin,and endothelial cells第6页，共20页，编辑于2022年，星期一nodulus：1.Pretreatment with Natalizumab inhibits MM cell adhesio

6、n to fibronectin(A)or endothelial cells(B);2.pretreatment with Natalizumab decreased K562a4,but not K562,cell adhesion to fibronectin(C);3.Natalizumab disrupted the binding of already adherent MM cells(D-F).第7页，共20页，编辑于2022年，星期一NO.3 Natalizumab inhibits MM cell adhesion to BMSCs as well as MM cell p

7、roliferation triggered by MM-BMSC adhesion第8页，共20页，编辑于2022年，星期一nodulus：1.Natalizumab inhibited adhesion to BMSCs of non-binding MM(A);2.Natalizumab also inhibited adhesion to BMSCs of already adherent MM(B);3.increased MM cell proliferation triggered by MM-BMSC adhesion was inhibited by Natalizumab(

8、C).第9页，共20页，编辑于2022年，星期一NO.4 Natalizumab inhibits MM-BMSC-induced secretion of VEGF and angiogenesis第10页，共20页，编辑于2022年，星期一nodulus:1.Natalizumab significantly inhibited MM-BMSC-triggered increases of VEGF secretion(A);2.endothelial cell tubule formation triggered by supernatants derived from Natalizu

9、mab-,treated MM-BMSC co-cultures(5 h),was markedly inhibited(B-C).第11页，共20页，编辑于2022年，星期一NO.5 Natalizumab inhibits VEGF-and IGF-1-triggered MM cell migration on fibronectin第12页，共20页，编辑于2022年，星期一nodulus:1.Natalizumab abrogates both VEGF-as well as IGF-1-triggered MM(MM.1S,OPM2)cell migration on fibron

10、ectin(A,B)；2.Natalizumab abrogates phosphorylation of both PKC and integrin-a4 which induced by costimulation with either IGF-1 or VEGF and fibronectin（C,D）.第13页，共20页，编辑于2022年，星期一NO.6 Natalizumab inhibits MM cell growth in a murine model of MM第14页，共20页，编辑于2022年，星期一nodulus:1.the levels of ShuIL-6R in

11、 MM is downregulated which is treated buy Natalizumab(A);2.Natalizumab increased animal survival(B);3.Natalizumab also downregulated expression of human VEGF and Ki67 and H&E(C);4.tumour angiogenesis of MM which is pretreated by Nab is lower than those non-treated by it(D).第15页，共20页，编辑于2022年，星期一NO.7

12、 Natalizumab sensitizes MM cells attached to BMSCs and endothelial cells to bortezomib第16页，共20页，编辑于2022年，星期一nodulus:Natalizumab synergistically enhanced sensitivity of tumour cells to bortezomib in both MM-BMSC and MM-EC co-cultures as well as to dexamethasone(this experiment didnt show)第17页，共20页，编辑

13、于2022年，星期一conclusion inhibite adhesion of MM cells to BMSC or HUVECNabblock the proliferative effect of MMchemosensitize MM cells to bortezomibblock the angiogenesis induced by VEGFinhibite tumour growth,VEGF secretion,and angiogenesis in murine model of human MM in the human BM microenvironmentBloc

14、k MM cell migration第18页，共20页，编辑于2022年，星期一Discussionintegrin-a4 may be an attractive target for the treatment of the disease at its early stages;a potential therapeutic role for the SAM inhibitor Natalizumab which specifically targets integrin-a4 in MM;whether maintenance therapy with Natalizumab in combination with low dose bortezomib or dexamethasone after conventional therapies prevents or delays the progression of minimal residual disease.第19页，共20页，编辑于2022年，星期一第20页，共20页，编辑于2022年，星期一