人源性血管抑素对肿瘤血管生成影响的实验研究
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摘要
恶性肿瘤的新生血管形成为肿瘤生长提供了丰富的营养物质,是其生长代谢的重要基础和转移的重要途径。抗肿瘤血管形成、抑制肿瘤血管新生就能抑制肿瘤的生长转移成为肿瘤研究领域中的又一个热点。因此血管抑素(Angiostatin)的强血管抑制作用备受关注,也为肿瘤的治疗带来了新的视点、新方法和新希望。但是血管抑素对血管生成的抑制作用主要表现在哪一血管形成过程及如何作用目前知之不多,所以本研究旨在通过诱导体外培养人脐静脉内皮细胞转变为肿瘤血管内皮后,观察血管抑素对肿瘤血管生成的影响,并探讨其作用的可能机制,探索血管抑素在肿瘤血管抑制治疗中的意义,为肿瘤的防治提供依据。
目的:研究观察人源性具有抑制血管内皮细胞生长活性的血管抑素蛋白对小鼠种植性肺腺癌生长转移的抑制作用及其相关机理。
方法:应用亲和层析法得到纯化的血管抑素;使用Lewis肺癌细胞株接种于C57BL/6N近交系小鼠,建立小鼠皮下移植瘤模型。随机将荷瘤小鼠分为治疗组(高中低剂量)和空白对照组,分别于瘤内注射Angiostatin和无菌生理盐水。观察各组动物的肿瘤生长状况,检测各组肿瘤Angiostatin和微血管密度(MVD),利用免疫组化流式细胞仪行血管内皮细胞分析、检测其生物学活性,接种小鼠并比较肿瘤体积和肿瘤微血管密度(MVD)。
结果:接受血管抑素治疗的小鼠肿瘤肿块重量由治疗前的(1368±1.17)mg减小到治疗后的(148±0.46)mg,,生存期明显延长,未见明显副作用。血管抑素组小鼠肿瘤体积小于对照组( P< 0. 01) ,免疫组化检测显示血管抑素组小鼠肿瘤微血管密度(MVD )低于对照组( P<0. 05)。
结论:Angiostatin可以通过抑制血管生成而在一定程度上抑制肿瘤生长。血管抑素对小鼠种植性肺腺癌的生长有抑制作用,这是血管抑素组肿瘤组织内新生血管形成受到抑制而减少所致;血管抑素能显著抑制C57BL/6N近交系小鼠肺癌Lewis细胞肿瘤肿块生长、转移。
Objective:To investigate Angiostatin from human being can inhibit the activity of ascular endothelial growth vascular STT employed protein on mice planting sex lung adenocarcinoma growth transfer inhibition and related mechanism.
Methods:Applied affinity chromatography method get plasma fiber by trypsin digestion dissolve enzyme original, chromatography column affinity chromatography, dialysis, get the purified vascular STT employed; Users LEWIS inoculation cell lung cancer in C57BL / 6N coefficient mice, establish mice subcutaneous transplant tumor model. Random tumor-burdened mice will be divided into the treatment group (control group) and many doses, respectively on intraperitoneal injection vascular STT employed and sterile saline. Observe each animal behavior, tumor growth, measuring record tumor-burdened rat mass diameter, surial, Detection each tumor blood essels STT employed with microvascular density (MVD), Using immunohistochemistry flow cytometric analysis line endothelial cell analysis, detecting its biological activities, inoculation mice and compare the tumor size and tumor microvascular density (MVD). Another set the untreated control group and observation vascular STT employed side-effects controls, line lung, liver, kidney pathological examination.
Results:Accept vascular STT employed treatment of tumors in mice by mass diameter before treatment (1.368 + 1.17) mg reduced to therapy (148 + 0.46), mg, surial was significantly longer, did not see the obvious side effects. Vascular STT employed mice tumor size less than in control group (P < 0.01), Immunohistochemical detection displayed vascular tumor microvascular employment STT mice density (MVD) lower than that in control group (P < 0. 05).
Conclusion:blood vessels STT employed can inhibit angiogenesis and in a certain extent suppress tumor growth. Vascular STT employed for mice, planting sex lung adenocarcinoma have inhibition of growth, this is a vascular tumor tissue employment STT group within angiogenesis is restrained and by a decrease. Vascular employment STT could significantly inhibit C57BL / 6N coefficient LEWIS cell tumor mass in mice lung cancer growth, transfer.
目的:研究观察人源性具有抑制血管内皮细胞生长活性的血管抑素蛋白对小鼠种植性肺腺癌生长转移的抑制作用及其相关机理。
方法:应用亲和层析法得到纯化的血管抑素;使用Lewis肺癌细胞株接种于C57BL/6N近交系小鼠,建立小鼠皮下移植瘤模型。随机将荷瘤小鼠分为治疗组(高中低剂量)和空白对照组,分别于瘤内注射Angiostatin和无菌生理盐水。观察各组动物的肿瘤生长状况,检测各组肿瘤Angiostatin和微血管密度(MVD),利用免疫组化流式细胞仪行血管内皮细胞分析、检测其生物学活性,接种小鼠并比较肿瘤体积和肿瘤微血管密度(MVD)。
结果:接受血管抑素治疗的小鼠肿瘤肿块重量由治疗前的(1368±1.17)mg减小到治疗后的(148±0.46)mg,,生存期明显延长,未见明显副作用。血管抑素组小鼠肿瘤体积小于对照组( P< 0. 01) ,免疫组化检测显示血管抑素组小鼠肿瘤微血管密度(MVD )低于对照组( P<0. 05)。
结论:Angiostatin可以通过抑制血管生成而在一定程度上抑制肿瘤生长。血管抑素对小鼠种植性肺腺癌的生长有抑制作用,这是血管抑素组肿瘤组织内新生血管形成受到抑制而减少所致;血管抑素能显著抑制C57BL/6N近交系小鼠肺癌Lewis细胞肿瘤肿块生长、转移。
Objective:To investigate Angiostatin from human being can inhibit the activity of ascular endothelial growth vascular STT employed protein on mice planting sex lung adenocarcinoma growth transfer inhibition and related mechanism.
Methods:Applied affinity chromatography method get plasma fiber by trypsin digestion dissolve enzyme original, chromatography column affinity chromatography, dialysis, get the purified vascular STT employed; Users LEWIS inoculation cell lung cancer in C57BL / 6N coefficient mice, establish mice subcutaneous transplant tumor model. Random tumor-burdened mice will be divided into the treatment group (control group) and many doses, respectively on intraperitoneal injection vascular STT employed and sterile saline. Observe each animal behavior, tumor growth, measuring record tumor-burdened rat mass diameter, surial, Detection each tumor blood essels STT employed with microvascular density (MVD), Using immunohistochemistry flow cytometric analysis line endothelial cell analysis, detecting its biological activities, inoculation mice and compare the tumor size and tumor microvascular density (MVD). Another set the untreated control group and observation vascular STT employed side-effects controls, line lung, liver, kidney pathological examination.
Results:Accept vascular STT employed treatment of tumors in mice by mass diameter before treatment (1.368 + 1.17) mg reduced to therapy (148 + 0.46), mg, surial was significantly longer, did not see the obvious side effects. Vascular STT employed mice tumor size less than in control group (P < 0.01), Immunohistochemical detection displayed vascular tumor microvascular employment STT mice density (MVD) lower than that in control group (P < 0. 05).
Conclusion:blood vessels STT employed can inhibit angiogenesis and in a certain extent suppress tumor growth. Vascular STT employed for mice, planting sex lung adenocarcinoma have inhibition of growth, this is a vascular tumor tissue employment STT group within angiogenesis is restrained and by a decrease. Vascular employment STT could significantly inhibit C57BL / 6N coefficient LEWIS cell tumor mass in mice lung cancer growth, transfer.
引文
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[32]孙旭芳,曾水清,王虹等.血管抑素对高氧诱导的视网膜新生血管模型鼠中细胞外信号调节激酶与转录激活蛋白表达的影响[J].中国现代医学杂志, 2006,16(14):2126-2128.
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[2]Folkman J.Tumor angiogenesis:therapeutic implications[J].N Engl J Med, 1997 (285): 1182-1186.
[3]刘保良血管抑素研究进展[M].《临床合理用药杂志》2009,2,24:126-127
[4]吴景文,章翔,付洛安等.原核表达的血管抑素K(1-3)蛋白对脑胶质瘤的生长抑制作用[J].第四军医大学学报,2002,23(23):2155-2159.
[5]王浩华,吕毅,仵正.血管抑素对仓鼠胰腺癌肝脏转移瘤抑制作用的实验研究[J].肝胆外科杂志,2004,12(5):373-375.
[6]房伯俊,李惠翔,谈立松等.人血管抑素的分离纯化及对不同细胞体外增殖的影响[J].郑州大学学报(医学版),2003,38,(1):5154.
[7]张玲.血管抑素对肺癌生物学行为的影响及抑制肿瘤血管形成分子机制的研究[M]中国医科大学博士论文2008-04-01
[8]韦永芳,戴丽军,叶炳飞.重组人血管抑素对荷人CNE-1鼻咽癌裸鼠抑制作用的初步研究[J].广州医学院学报,2004,32(2):8-16.
[9]Gately S, Twardowski PT, Siiaron M, et al. The mechanism of cancer-mediated conversion of plasmingen to the angiogenesis inhibitor angiostatin. Proc Natl Acad Sci USA,1997,94:10868-10872
[10]O’Mahony CA, Seidel A, Albo D, et al. Angiostatin generation by human pancreatic cancer[J]. J Surg Res,1998,77(1):55-58
[11]Sim BK, O'Reilly MS, Liang H, et al.Recombinant human angiostatin protein inhibits experimental primary and metastatic cancer[J].Cancer Res, 1997, 57(7):1329-1334.
[12]Df Moser TL, Stack MS, Asplin I, et al. Angiostatin binds ATP synthase on the surface of human endothelial cells[J]. Proc Natl Acad Sci USA, 1999,96(6):2811-2816
[13]Comelius LA, Nehring LC, Harding E, et al. Matrix metalloproteinases generate angiostatin:effects on neovascularization. J Immunol, 1998, 161 (12): 6845-6852
[14]张玲;张亚嘉;王越中等.血管抑素对人脐静脉内皮细胞及体外微血管模型的作用[J]中国组织工程研究与临床康复, 2007,10(14)
[15]MoserTL, K enan DJ,A shleyT A,et al .Endothelialcell su face FI-FOATP synthase is active in ATP synthesis and is inhibited by angiostatin . Proc-Natl-Acad-Sci-U-S-A, 2001,98 (12):6656-6661.
[16]MoserTL, StackMS,Asplin1, et al .Angiostatin binds ATP synthase on the surface of human endothelial cells[J ].Proc-Natl-Acad-Sci-U-S-A,1999,96 (6):28 11-2816
[17]Arui T, Miles LA, Takada Y. Specific interaction of angiostatin with integrin alpha(v)beta(3) in endothelial cells. J Biol Chem, 2001,276(43): 39562-39568
[18]Redlitz A, Daum G, Sage EH. J Vasc Res, 1999,36(1):28-34
[19]Hari D, Beckett MA, Sukhatme VP, et al. Mol Cell Res Commun, 2000,3(5):277-282
[20]Li H , Lu H ,Criscelli- Fet al . Adenovirus mediated delivery of a uPA/ uPAR antagonist suppressed angiogenesis-dependent tumor growth and dissemina2 tion in mice. Gene Ther ,1998 ,5(8) :1105-1113.
[21]Brooks P C ,Clark RA ,Cheresh D A. Requirement of vascular integrinαvβ3 for angiogenesis. Science ,1994 ,264(5158) :569-571.
[22]Yancopoulos GD ,Klagsbrun M, Folkman J . Vasculogenesis , angiogenesis , and growth factors :ephrins enter the fray at the border. Cell ,1998 ,93 (5) : 661-664.
[23]张均克,邓耀祖.血管新生研究进展.江汉大学学报(自然科学版),2005,33(2):90-96.
[24]Nadeem WA,David SA.Angiostatin selectively inhibits signaling by hepatocyte growth factor in Endothelial and muscle cells[J].blood,2003, 101,1857-1863.
[25]Wahl ML,Kenan DJ,Gonzalez-Gonow M,et al.Angiostatin’s molecular mechanism;aspects of specificity and regulation elucidated[J].I Cell Biochem,2005,96:242-261.
[26]Holly HA,Christie WO,Hallie KA,et al.Angiostatin 4.5-mediated Apoptosis of Vascular Endothelial cell[J].Cancer Research,2003,63: 4275-4280.
[27]Dudani AK,Bentchavtchavadze M,Porter S,et al. Angiostatin and plasminogen share binding to endothelial cell surface actin[J].Biochem cell biol,2005,83(1):28-35.
[28]陶永辉,张莲芳,金坚.Angiostatin作用靶点的初步研究[J].中国药理学通报, 2006,22(9):1084-1088.
[29]Mousuni M,Takehiko T,Biao S,et al.Plasmin-induced Migration Requiers Signaling through Protease-activated receptor 1 and Integrin a9b1[J]. J. Bio. Chem, 2004, 279(36):37528-37534.
[30]Takehiko T,Mousumi M,Lindsey A,et al.Plasmin-induced Migration of Endothelial Cells .J. Biol.Chem,2002,277(37):33564-33570.
[31]Soff RA.Angiostatin and angiostatin-related proteins[J].Cancer Metast Rev, 2000,19:97-107.
[32]孙旭芳,曾水清,王虹等.血管抑素对高氧诱导的视网膜新生血管模型鼠中细胞外信号调节激酶与转录激活蛋白表达的影响[J].中国现代医学杂志, 2006,16(14):2126-2128.
[33]Thysnovsky B,levchenko T,Mansson G,et al.Angiomotin:an angiotatinbinding protein that regulates endothelial cell migration and tube formation[J].J Cell Biol,2001,152:1247-1254.
[34]Tammy MO,Daniel KE,Timothy AS,et al.Endothelial cell surface F1-Fo ATP synthase is active in ATP synthesis and is inhibited by angiostatin [J]. PNAS, 2001, 98(12):6656-6661.
[35]Mauceri HJ, Hanna NN, Beckett MA, et al. Combined effects of angiostatin and ionzing radiation in antitumour therapy[J]. Nature. 1998,394(6):287-291
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