雷帕霉素对裸鼠皮下移植胶质瘤VEGF，HIF-1a表达的影响
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摘要
目的探讨雷帕霉素对裸鼠皮下移植胶质瘤肿瘤血管内皮生长因子(vascular endothelial growth factor VEGF)和缺氧诱导因子-1α(hypoxia inducible factor-lαHIF-α)的表达的影响及两个指标的相关性。
方法建立裸鼠皮下移植胶质瘤模型,随机分组后给予：雷帕霉素常规剂量(1.5 mg／kg／d)腹腔注射,对照组给予相同体积二甲基亚砜。用药21 d后处死动物,用免疫组化法检测瘤组织中VEGF和HIF-1α表达水平。
结果与对照组比较,常规剂量雷帕霉素组明显降低了肿瘤VEGF水平以及HIF-1α(P<0.05),且两个指标的表达显著相关(P<0.05)。
结论常规剂量雷帕霉素可抑制肿瘤血管生成,从而抑制肿瘤生长,这为脑胶质瘤切除术后免疫抑制剂的选择提供实验依据。
Objectives we approach the effect of rapamycin to the athymic mouse hypotransplantation tumor which comes from the rats' neurospongioma.And measure the dose of VEGF (vascular endothelial growth factor, VEGF) and HIF-1α(hypoxia inducible factor-1α,HIF-1-α.).And we appraisal the effect of rapamycin to the expression of VEGFand HIF-1 aand their correlation.
Methods we establish the model of the athymic mouse hypotransplantation tumor which comes from the rats neurospongioma. After randomization,we give rapamycin by mouth:the routine dose(1.5 mg/kg/d).The control group is given dimethyl sulfoxide with the same volume.Sacrifice the animals after being given the drugs, measure the dose of VEGF and HIF-1αby immunohistochemistry.
Results compare to the control group,the routine dose group reduce the expression of VEGF and HIF-la(P<0.05).And the two indexs are significantly relative.
Conclusions the routine dose of rapamcin can inhibit the Angiogenesis of mass,and inhibit the growth of mass,which gives the proof of choice of immunodepressant after ectomy of neurospongioma.
方法建立裸鼠皮下移植胶质瘤模型,随机分组后给予：雷帕霉素常规剂量(1.5 mg／kg／d)腹腔注射,对照组给予相同体积二甲基亚砜。用药21 d后处死动物,用免疫组化法检测瘤组织中VEGF和HIF-1α表达水平。
结果与对照组比较,常规剂量雷帕霉素组明显降低了肿瘤VEGF水平以及HIF-1α(P<0.05),且两个指标的表达显著相关(P<0.05)。
结论常规剂量雷帕霉素可抑制肿瘤血管生成,从而抑制肿瘤生长,这为脑胶质瘤切除术后免疫抑制剂的选择提供实验依据。
Objectives we approach the effect of rapamycin to the athymic mouse hypotransplantation tumor which comes from the rats' neurospongioma.And measure the dose of VEGF (vascular endothelial growth factor, VEGF) and HIF-1α(hypoxia inducible factor-1α,HIF-1-α.).And we appraisal the effect of rapamycin to the expression of VEGFand HIF-1 aand their correlation.
Methods we establish the model of the athymic mouse hypotransplantation tumor which comes from the rats neurospongioma. After randomization,we give rapamycin by mouth:the routine dose(1.5 mg/kg/d).The control group is given dimethyl sulfoxide with the same volume.Sacrifice the animals after being given the drugs, measure the dose of VEGF and HIF-1αby immunohistochemistry.
Results compare to the control group,the routine dose group reduce the expression of VEGF and HIF-la(P<0.05).And the two indexs are significantly relative.
Conclusions the routine dose of rapamcin can inhibit the Angiogenesis of mass,and inhibit the growth of mass,which gives the proof of choice of immunodepressant after ectomy of neurospongioma.
引文
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[28]Korkolopoulou P,Patsouris E,Konstantinidou AE,et al.Hypoxia-inducible factor 1 alpha/vascular endothelial growth factor axis in astrocytomas.Associations with microvessel morphometry,proliferation and prognosis.Neuropathol Appl Neurobiol,2004,30(3):267-78.
[29]郭克勤,于如同,高文昌.HIF-1α、 VEGF表达与脑胶质瘤预后的相关性.徐州医学院学报,2003,2(03)：46—50.
[30]KaurB,Khwaja FW, Severson EA, et al. Hypoxia and the hypoxia inducible-factor pathway in glioma growth and angiogenesis[J].Neuro-Oncol,2005,7(2):134～153.
[31]ZagzagD, ZhongH, ScalzittiJM, et al. Expression of hypoxia-in-ducible factor 1 alpha in brain tumors:association with angiogenesis, invasion, and progression[J].Cancer,2000,88(11):2606～2618.
[32]Zhong H, Semenza GL, SimonsJW, et al. Up-regulation of hypoxia-inducible factorl alpha isan early event inprostate carcinogenesis[J].CancerDetect Prev,2004,28(2):88～93.
[33]Gupta K, RadotraBD, BanerjeeAK, et al. Quantitation of angiogenesis and its correlation with vascular endothelial growth factor expression in astrocytic tumors[J].Anal Quant Cytol Histol,2004,26(4):223～229.
[34]Chaudhry IH, O!Donovan DG, Brenchley PE, et al. Vascular endothelial growth factor expression correlateswith tumourgrade and vascularity in gliomas[J]. Histopathology,2001,39(4):409～415.
[35]Goodman,Alice.NEW DIRECTIONS IN THE TREATMENT OF BRAIN TUMORS.Neurology Today,2004,4(9):31.
[36]Kirsch M,Schackert QBlack PM.Anti-angiogenic treatment strategies for malignant brain tumors.J Neurooncol,2000,50(1-2):149-63.
[37]李维方,张光霁,朱诚,等.VEGF反义寡核苷酸抑制C_6胶质瘤细胞VEGF表达的作用和效果.第二军医大学学报,2002(02).
[38]Belozerov,Vladimir E,Van Meir,Erwin GHypoxia inducible factor-1:a novel target for cancer therapy.Anti-Cancer Drugs,2005,16(9):901-909.
[1]Wang GL, Semenza GL. General involvement of hypoxia induciblefactor-1 in transcriptional response to hypoxia[J].ProcNatlAcadSciUSA,1993,90 (9):4304-4308.
[2]Richard K. Oxygen sensing in the hypoxic response pathway:regu2 lation of the hypoxia-inducible transcription factor[J].Genes &Develop,2003,17(21):2614-2623.
[3]Page EL, Robitaille GA, Pouyssegur J, et al. Induction of hypoxiainducible factor-1 alpha by transcriptionaland translationalmech anisms[J].BiolChem,2002,27 (7):48403-48409.
[4]师永红,方伟岗.PI-3K和MEK1/ERK信号通路在碱性纤维母细胞生长因子诱导乳腺癌细胞HIF-1活化中的作用及机制研究[J].中华医学杂志,2004,84(22)：1899-1903.
[5]Scharte M, Han X,Bertges DJ, et al.Cytokines induce HIF-1DNA binding and the expression ofHIF-1-dependent genes incultured ratenterocytes[J].Am J Physiol Gastrointest Liver Physiol,2003,284(3):373-384.
[6]OhhM. Ubiquitin pathway in VHL cancer syndrome[J].Neoplasia,2006,8 (8):623-629.
[7]WengerRH, Stieh1DP,Camenisch G. Integration of oxygen signaling at the consensusHRE[J].Sci STKE,2005,2(3):12-15.
[8]Semenza GL. Developmentof novel therapeutic strategies that targetHIF 1[J].expert opin Ther Targets,2006,10 (2):267-280.
[9]Fyles A,Mibsevic M,Hedley D,et al.Tumor hypoxia has independent predictor impact only in patients with node-negative cervix canced[J].J Clin Oncol,2002,20(3):680-687.
[10]Lallemaln G The hypoxia-inducible factor HIF as a new target in cancer research[J].Bull Ccancer,2002,89(3):257-260.
[11]ErezN,MilyavskyM,EliamR,etal.Expressionof prolyl2hydroxylasel (PHD1/E GLN2) suppresses hypoxia inducible factor21 alphaactivation and inhibits tumor growth[J].Cancer Res,2003,63(24):8777-8783.
[12]Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the HIF pathwayin cancer[J].CurrOpin GenetDev,2001,11(3):293-299.
[13]Haddad JJ. Oxygen sensing and oxidant/redox-related pathways[J]. Biochem BiophysRes commun,2004,316(4):969-977.
[14]An W G,KanekalM, SimonMC, et al. Stabilization ofwild type p53 by hypoxia inducible factorl alpha[J].Nature,1998,393 (6684):401-405.
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[2]Gera JF,MELLINGHOFF IK,Shi Y,et al.AKT activity determines sensitivity to mammalian target of rapamycin(mTOR) inhibitors by regulating cyclin D1 and c-myc expression[J].J Biol Chem,2004,279(4):2737-2746.
[3]Louis DN,Pomeroy SL,Cairncross JG.Focus on central nervous system neoplaCancer Cell,2002,1(2):125-128.
[4]Maher EA,Furnari FB,Bachoo RM,et al.Malignant glioma:genetics and biolof a grave matter.Genes Dev,2001,15(11):1311-1333.
[5]Pulkkanen KJ,Yla-Herttuala S.Gene therapy for malignant glioma:current clinstatus.Mol Ther,2005,12(4):585-598.
[6]Okada H,Pollack IF.Cytokine gene therapy for malignant glioma.Expert OBiol Ther,2004,4(10):1609-1620.
[7]钱志远,黄强.胶质瘤血管发生发展机制研究.中国肿瘤,2005,2(02)：221-225.
[8]Jansen,Marnix,de Witt Hamer,Philip C,Witmer,Antonella N,et al.Curperspectives on antiangiogenesis strategies in the treatment of malignant gliom Brain Research Reviews.45(3),2004.143-163.11.Roguin A,Levy AP.Angiogenesis--an update.Pediatr Endocrinol Rev,2005,2(3):391-398.
[9]Patan S.Vasculogenesis and angiogenesis.Cancer Treat Res,2004,11 (7):3-32.
[10]Patan S.Vasculogenesis and angiogenesis as mechanisms of vascular network formation,growth and remodeling.J Neurooncol,2000,50(1-2):1-15.
[11]Folkman J.Tumor angiogenesis:therapeutic implications.N Engl J Med,1971,285(21):1182-1186.
[12]夏爽,王金环,祁吉.胶质瘤血管生成的研究进展.国外医学.临床放射学分册,2004,3(05)：225-256.
[13]Miyagami M,Katayama Y. Angiogenesis of glioma:evaluation of ultrastructuralcharacteristics of microvessels and tubular bodies(Weibel-Palade)in endothelialcells and immunohistochemical findings with VEGF and p53 protein.Med MolMorphol,2005,38(1):36-42.
[14]Hanahan D,Folkman J.Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.Cell,1996,86(3):353-64.
[15]秦华平,熊光仲,肖惠生.脑胶质瘤中缺氧诱导因子-1α的表达及与肿瘤分级的相关性.中华神经医学杂志,2005,2(04)：53-55.
[16]Semenza GL,Agani F,Booth G,et al.Structural and functional analysis of hypoxia-inducible factor 1.Kidney Int,1997,51(2):553-555.
[17]KaurB,Khwaja FW, Severson EA, et al. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis[J].Neuro-Oncol,2005,7(2):134～153.
[18]ZagzagD, ZhongH, ScalzittiJM, et al.Expression of hypoxia-in-ducible factor 1 alpha in brain tumors:association with angiogenesis, invasion, and progression[J].Cancer,2000,88 (11):2606～2618.
[19]Zhong H, Semenza GL, SimonsJW, et al. Up-regulation of hypoxia inducible factor 1 alpha isan early event inprostate carcinogenesis[J].CancerDetect Prev,2004,28(2):88～93.
[20]Gupta K, RadotraBD, BanerjeeAK, et al. Quantitation of angiogenesis and its correlation with vascular endothelial growth factor expression in astrocytic tumors[J].Anal Quant Cytol Histol,2004,26(4):223～229.
[21]Chaudhry IH, O!Donovan DG, Brenchley PE, et al. Vascular endothelial growth factor expression correlateswith tumourgrade and vascularity in gliomas[J]. Histopathology,2001,39(4):409～415.
[22]Neufeld QCohen T,Gengrinovitch S,et al.Vascular endothelial growth factor (VEGF)and its receptors.FASEB J,1999,13(1):9～22. [23].Carmeliet P,Ferreira V,Breier G,et al.Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.Natur2005,380(6573):435-439.
[24]Olofsson B,Korpelainen E,Pepper MS,et al.Vascular endothelial growth factor B (VEGF-B)binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells.Proc Natl Acad Sci U S A,1998,95(20):11709-11714.
[25]Skobe M,Hawighorst T, Jackson DG,et al.Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis.Nat Med,2001,7(2):192-198.
[26]Stacker SA,Caesar C,Baldwin ME,et al.VEGF-D promotes the metastatic spread of tumor cells via the lymphatics.Nat Med,2001,7(2):186-191.
[27]崔澄,胡建军,杨彦忠.VEGF在肿瘤免疫抑制中的作用及其临床应用前景.白求恩军医学院学报,2005,2(01)：2—8.
[28]Korkolopoulou P,Patsouris E,Konstantinidou AE,et al.Hypoxia-inducible factor 1 alpha/vascular endothelial growth factor axis in astrocytomas.Associations with microvessel morphometry,proliferation and prognosis.Neuropathol Appl Neurobiol,2004,30(3):267-78.
[29]郭克勤,于如同,高文昌.HIF-1α、 VEGF表达与脑胶质瘤预后的相关性.徐州医学院学报,2003,2(03)：46—50.
[30]KaurB,Khwaja FW, Severson EA, et al. Hypoxia and the hypoxia inducible-factor pathway in glioma growth and angiogenesis[J].Neuro-Oncol,2005,7(2):134～153.
[31]ZagzagD, ZhongH, ScalzittiJM, et al. Expression of hypoxia-in-ducible factor 1 alpha in brain tumors:association with angiogenesis, invasion, and progression[J].Cancer,2000,88(11):2606～2618.
[32]Zhong H, Semenza GL, SimonsJW, et al. Up-regulation of hypoxia-inducible factorl alpha isan early event inprostate carcinogenesis[J].CancerDetect Prev,2004,28(2):88～93.
[33]Gupta K, RadotraBD, BanerjeeAK, et al. Quantitation of angiogenesis and its correlation with vascular endothelial growth factor expression in astrocytic tumors[J].Anal Quant Cytol Histol,2004,26(4):223～229.
[34]Chaudhry IH, O!Donovan DG, Brenchley PE, et al. Vascular endothelial growth factor expression correlateswith tumourgrade and vascularity in gliomas[J]. Histopathology,2001,39(4):409～415.
[35]Goodman,Alice.NEW DIRECTIONS IN THE TREATMENT OF BRAIN TUMORS.Neurology Today,2004,4(9):31.
[36]Kirsch M,Schackert QBlack PM.Anti-angiogenic treatment strategies for malignant brain tumors.J Neurooncol,2000,50(1-2):149-63.
[37]李维方,张光霁,朱诚,等.VEGF反义寡核苷酸抑制C_6胶质瘤细胞VEGF表达的作用和效果.第二军医大学学报,2002(02).
[38]Belozerov,Vladimir E,Van Meir,Erwin GHypoxia inducible factor-1:a novel target for cancer therapy.Anti-Cancer Drugs,2005,16(9):901-909.
[1]Wang GL, Semenza GL. General involvement of hypoxia induciblefactor-1 in transcriptional response to hypoxia[J].ProcNatlAcadSciUSA,1993,90 (9):4304-4308.
[2]Richard K. Oxygen sensing in the hypoxic response pathway:regu2 lation of the hypoxia-inducible transcription factor[J].Genes &Develop,2003,17(21):2614-2623.
[3]Page EL, Robitaille GA, Pouyssegur J, et al. Induction of hypoxiainducible factor-1 alpha by transcriptionaland translationalmech anisms[J].BiolChem,2002,27 (7):48403-48409.
[4]师永红,方伟岗.PI-3K和MEK1/ERK信号通路在碱性纤维母细胞生长因子诱导乳腺癌细胞HIF-1活化中的作用及机制研究[J].中华医学杂志,2004,84(22)：1899-1903.
[5]Scharte M, Han X,Bertges DJ, et al.Cytokines induce HIF-1DNA binding and the expression ofHIF-1-dependent genes incultured ratenterocytes[J].Am J Physiol Gastrointest Liver Physiol,2003,284(3):373-384.
[6]OhhM. Ubiquitin pathway in VHL cancer syndrome[J].Neoplasia,2006,8 (8):623-629.
[7]WengerRH, Stieh1DP,Camenisch G. Integration of oxygen signaling at the consensusHRE[J].Sci STKE,2005,2(3):12-15.
[8]Semenza GL. Developmentof novel therapeutic strategies that targetHIF 1[J].expert opin Ther Targets,2006,10 (2):267-280.
[9]Fyles A,Mibsevic M,Hedley D,et al.Tumor hypoxia has independent predictor impact only in patients with node-negative cervix canced[J].J Clin Oncol,2002,20(3):680-687.
[10]Lallemaln G The hypoxia-inducible factor HIF as a new target in cancer research[J].Bull Ccancer,2002,89(3):257-260.
[11]ErezN,MilyavskyM,EliamR,etal.Expressionof prolyl2hydroxylasel (PHD1/E GLN2) suppresses hypoxia inducible factor21 alphaactivation and inhibits tumor growth[J].Cancer Res,2003,63(24):8777-8783.
[12]Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the HIF pathwayin cancer[J].CurrOpin GenetDev,2001,11(3):293-299.
[13]Haddad JJ. Oxygen sensing and oxidant/redox-related pathways[J]. Biochem BiophysRes commun,2004,316(4):969-977.
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