SDF-1/CXCR4与血液系统恶性肿瘤的关系研究进展(2)

　　淋巴瘤

　　Bertolini等［7］将分别用CXCR4抗体和SDF-1抗体孵育过的淋巴瘤细胞株Namalwa，用经腹腔和经静脉二种方式注入小鼠建立了肿瘤模型，结果发现在腹腔注射组中注射了经孵育过的Namalwa细胞的小鼠比注射未孵育过的Namalwa细胞小鼠的体内肿瘤体积小,重量轻,以CXCR4抗体的作用最明显。而在静脉注射组中发现，所有注射未孵育过的Namalwa细胞的小鼠在36天内死亡,注射经SDF-1抗体孵育过的Namalwa细胞的小鼠在60天内死亡。而83%的注射CXCR4抗体孵育过的Namalwa细胞小鼠仍然存活，在150天内未发病，对此类小鼠的注射24小时后的外周血检测显示，32%-47%的Namalwa细胞表达凋亡标志物-膜联蛋白V,提示CXCR4抗体能有效地促使淋巴瘤细胞凋亡。为了证实CXCR4抗体治疗非霍奇金淋巴瘤的可行性,Bertolini等［7］还做了有关CXCR4抗体毒性实验,结果证实体内实验和尸检中均未发现其毒性作用。研究表明，EB病毒在Burkitt淋巴瘤、霍奇金病、B细胞淋巴组织增生性疾病的发病机制中发挥着重要作用［24］。其中,仅经腹腔注射EBV(+)患者外周血单个核细胞的SCID小鼠长出 EBV(+)的人B细胞淋巴瘤(hu/SCID),且肿瘤多向高表达SDF-1的腹膜、肝脏和淋巴结处转移,其机制尚不清楚，推测SDF-1/CXCR4在淋巴瘤的生长和转移过程中起着积极作用。Piovan等［25］在体内对hu/SCID肿瘤细胞CXCR4的表达情况进行研究发现，hu/SCID肿瘤细胞可分为CD23low和 CD23int 2种亚型。CD23low细胞表面大量表达功能性的CXCR4受体,而CD23int细胞则以分泌 SDF-1为主。在SDF-1的刺激作用下CD23int细胞可向CD23low细胞转变。这一结果提示SDF-1/CXCR4轴在维持此二型细胞的稳态中起了关键的作用,很好地促进了hu/SCID肿瘤的生长。用SDF-1抗体或小分子CXCR4拮抗剂TC14012均能显著抑制hu/SCID肿瘤细胞的增殖。随着近年来RNA干扰技术的兴起和发展， Lapteva等［26］报道了用干扰性小分子RNA（siRNA）干扰乳腺癌细胞MDA-MB-231的CXCR4表达，结果发现乳腺癌细胞的侵袭力和黏附力明显下降，肿瘤生长缓慢，并且进一步证明缺乏CXCR4表达的乳腺癌细胞不能在SCID小鼠体内生长，此研究结果提示CXCR4对体内肿瘤生长和转移起着重要的作用，有可能作为乳腺癌治疗的靶点。总之,SDF-1/CXCR4在许多生理和病理过程中都发挥着重要的效应。随着其在血液系统肿瘤生长、浸润和耐药过程中作用机制的研究深入，SDF-1/CXCR4可能成为血液系统肿瘤治疗上的新靶点。

【参考文献】
  　　1 De-La-Luz-Sierra M, Yang F, Narazaki M, et al. Differential processing of stromal-derived factor-1alpha and stromal-derived factor-1beta explains functional diversity. Blood, 2004; 103: 2452-2459

　　2 Sadir R, Imberty A, Baleux F, et al. Heparan sulfate/heparin oligosaccharides protect stromal cell-derived factor-1 (SDF-1)/CXCL12 against proteolysis induced by CD26/dipeptidyl peptidase Ⅳ. J Biol Chem, 2004; 279: 43854-43860

　　3 Mohle R, Schittenhelm M, Failenschmid C, et al. Functional response of leukaemic blasts to stromal cell-derived factor-1 correlates with preferential expression of the chemokine receptor CXCR4 in acute myelomonocytic and lymphoblastic leukaemia. Br J Haematol, 2000; 110: 563-572

　　4 曾东风,孔佩艳,陈幸华等. SDF-1及其受体CXCR4在急性白血病与淋巴瘤表达的初步研究.中国实验血液学杂志,2005; 13: 274-277

　　5 刘峥嵘,孔慧,张秋堂. 在急性淋巴细胞白血病的表达及其意义. 中国实验血液学杂志,2004;12: 441-444

　　6 Crazzolara R, Kreczy A, Mann G, et al. High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia. Br J Haematol,2001;115: 545-553

　　7 Barretina J, Junca J, Liano A, et al. CXCR4 and SDF-1 expression in B-cell chronic lymphocytic leukemia and stage of the disease. Ann Hematol, 2003; 82: 500-505

　　8 Durig J, Rosenthal C, Elmaagacli A,et al. Biological effects of stromal-derived factor-1 alpha on normal and CML CD34+ haemopoietic cells.Leukemia, 2000;14:1652-1660

　　9 Bertolini F, Dell′ Agnola C, Mancuso P, et al. CXCR4 neutralization,a novel therape- utic approach for non-Hodgkin′ s lymphoma.Cancer Res, 2002; 62: 3106-3112

　　10 Hopken UE, Foss HD, Meyer D, et al. Up-regulation of the chemokine receptor CRR7 in classical but not in lymphocyte predominant Hodgkin disease correlates with distinct dissemination of neoplastic cells in lymphoid organs. Blood, 2002; 99: 1109-1116

　　11 Moller C, Stromberg T, Juremalm M, et al. Expression and function of chemokine receptors in human multiple myeloma.Leukemia, 2003; 17: 203-210

　　12 Matsuda M, Morita Y, Hanamoto H, et al. CD34+ progenitors from MDS patients are unresponsive to SDF-1, despite high levels of SDF-1 in bone marrow plasma. Leukemia, 2004; 18: 1038-1040

　　13 Rombouts E, Pavic B, Lowenberg B, et al. Reration between CXCR4 expression, FLT3 mutations, and unfavorable prognosis of adult myeloid leukemia. Blood, 2004; 104: 550 -557

　　14 Schneider P, Vasse M, AL Bayati A, et al. Is high expression of the chemokine receptor CXCR-4 of predicative value for early relapse in childhood acute lymphoblastic leukaemia? Br J Haematol, 2002; 119: 579-580

　　15 Ishibe N, Albitar M, Jilani IB, et al. CXCR4 expression is associated with survival in familial chronic lymphocytic leukemia,but CD38 expression is not. Blood, 2002; 100: 1100-1101

　　16 Matsunaga T, Takemoto N, Sato T, et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat Med, 2003;9: 1158-1165

　　17 Burger JA, Kipps TJ. Chemokine receptors and stromal cells in the homing and homeostasis of chronic lymphocytic leukemia B cells. Leuk Lymphhoma, 2002; 43: 461-466

　　18 Lataillade JJ, Clay D, Bourin P, et al. Stromal cell-erived factor 1 regulates primitive hematopoiesis by suppressing apoptosis and by promoting G0/G1 transition in CD34+ cells: evidence for an autocrine/paracrine mechanism. Blood, 2002; 99: 1117 -1129

　　19 魏力, 孔佩艳, 陈幸华等. 抗CXCR4单克隆抗体对细胞HL-60粘附性及Bcl-2、Fas蛋白表达的影响. 中国实验血液学杂志, 2004; 12: 436-440

　　20 Tavor S, Petit I, Porozov S, et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice.Cancer Res, 2004; 64: 2817-2824

　　21 Ponomaryov T, Peled A, Petit I, et al. Induction of the chemokine stromol-derived factor-1 following DNA damage inproves human stem cell function.J Clin Invest, 2000; 106: 1331-1339

　　22 Juarez J, Bradstock KF, Gottlieb DJ, et al. Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemia cells in vitro. Leukemia, 2003; 17: 1294-1300

　　23 魏力,孔佩艳,陈幸华等.抗CXCR4单克隆抗体12G5对阿糖胞苷杀伤HL-60细胞效应的影响.中国实验血液学杂志,2005; 13: 269-273

　　24 Rickinson AB, Kieff E. Epstein-Barr vinus. In: Fields BN,Knipe DM,Howley PM, eds. Fields virology. Philadelphia, PA: Lippincott-Raven. 2001: 2511-2627

　　25 Piovan E, Tosello V, Indraccolo S, et al. Chemokine receptor expression in EBV associated lymphoproliferation in hu/SCID mice: implications for CXCL12/CXCR4 axis in lymphoma generation. Blood, 2005; 105: 931-939

　　26 Lapteva N, Yang AG, Sanders DE, et al. CXCR4 knockdown by small interfering RNA abrogates breast tumor growth in vivo. Cancer Gene Ther, 2005; 12: 84-89

共2页: 上一页 [1] 2