Ki-67、PCNA、MMP-9在垂体腺瘤中的表达与垂体腺瘤侵袭性及复发的关系研究
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摘要
目的:a.研究核增殖抗原Ki-67、PCNA、基质金属蛋白酶-9(MMP-9)在垂体腺瘤中的表达;b.研究Ki-67、PCNA与MMP-9在垂体腺瘤中表达的相互关系;c.通过研究侵袭性、非侵袭性及复发性垂体腺瘤组织中Ki-67、PCNA、MMP-9的表达差异,为垂体腺瘤的治疗提供指导。
材料与方法:1.收集我院2002年1月—2008年3月临床资料完整的垂体腺瘤患者手术标本86例,为研究对象,均经10%的中性甲醛固定、石蜡包埋。回顾这些病例的详细临床资料,本文研究采用Hardy-Wilson及Knosp分级、分期标准,结合术中切除的硬膜及瘤周垂体组织经病理证实肿瘤细胞浸润,判断垂体腺瘤的侵袭性,将肿瘤标本分为非侵袭性组(44例)、侵袭性组(42例),其中侵袭性组中复发9例。
2.采用免疫组化SP法分别检测两组垂体腺瘤组织石蜡切片中核增殖抗原Ki-67、PCNA、MMP-9的表达;
3.统计分析垂体腺瘤组织中Ki-67、PCNA、MMP-9的表达在两组病例中的差异,研究Ki-67、PCNA、MMP-9在垂体腺瘤中表达的相互关系,并进一步分析它们与垂体腺瘤侵袭性及复发的关系。
结果:1、Ki-67、PCNA在86例垂体腺瘤组织中表达与患者性别无关,与肿瘤大小有关,大腺瘤或巨腺瘤表达明显高于小腺瘤。非侵袭和侵袭性腺瘤组中,Ki-67LI值为1.83±0.85和3.36±1.17;PCNA阳性表达率分别为22.73%(10/44)和57.14%(24/42),经统计学t检验和X~2,Ki-67及PCNA在侵袭性组表达明显高于非侵袭性组(P＜0.01)。
2、MMP-9在垂体腺瘤组织中表达与患者性别无关,与肿瘤大小有关,大腺瘤或巨腺瘤表达明显高于小腺瘤。非侵袭和侵袭性组中,MMP-9阳性表达率分别为47.73%(21/44)和73.81%(31/42)。经统计学X~2检验,MMP-9侵袭性组表达明显高于非侵袭性组(P＜0.01)。
3、侵袭性腺瘤复发组与非复发组中及复发组复发前后PCNA阳性表达率分别为55.56%,57.58%和66.67%,无明显统计学差异(p＞0.05)。在侵袭性腺瘤复发组复发前后,Ki-67LI值分别为3.52±1.23,3.58±0.67,无明显统计学差异(p＞0.05);复发组Ki-67LI值3.52±1.23,明显高于非复发组Ki-67LI值3.32±1.06,有统计学意义(P＜0.01).在侵袭性腺瘤复发组复发前后与非复发组中,MMP-9阳性表达率分别为88.89%,100%和69.70%,经统计学X2检验,MMP-9在侵袭性腺瘤复发组复发前后与非复发组中有显著差异(P＜0.01)。
4.Ki-67、PCNA及MMP-9在垂体腺瘤中表达呈正相关,在垂体腺瘤的侵袭性生长及复发中起协同作用。
结论:1.Ki-67、PCNA细胞核增殖抗原在侵袭性垂体腺瘤中表达明显高于非侵袭性腺瘤,提示Ki-67、PCNA可以作为判断垂体腺瘤侵袭性的重要标记物。
2.Ki-67LI值3%可以作为区分非侵袭性和侵袭性垂体腺瘤的Ki-67阈值,Ki-67LI值越高,预示侵袭性垂体腺瘤易复发。
3.侵袭性垂体腺瘤MMP-9蛋白表达较非侵袭性腺瘤显著增高,MMP-9蛋白表达复发组明显高于非复发组,且复发后较复发前表达明显增高,提示MMP-9在垂体腺瘤的侵袭性生长及肿瘤复发中扮演重要作用。
4.Ki-67、PCNA及MMP-9在垂体腺瘤中表达呈正相关,在垂体腺瘤的侵袭性生长及复发中起协同作用,三者结合可作为判断垂体腺瘤侵袭性及预后的重要参考指标。
Objective:In our study,we observe the expression of the Ki-67,PCNA antigen and MMP-9 in pituitary adenoma tissues.We observe the expression of theKi-67,PCNA antigen and MMP-9 in invasive pituitary adenoma and noninvasive pituitary adenoma,we compare the expression difference of Ki-67,PCNA antigen and MMP-9 between two groups, analysis the relationship with the invasion of pituitary adenomas.
Methods:1.86 pituitary adenomas specimens removed in our department were collected, all fixed with 10%neutral formalin and then paraffin embedded.Every case history was detailedly reviewed,and all specimens were divided into invasive group(42 cases)and noninvasive group(44 cases)by adopting Hardy-Wilson and Knosp standard.
2.It was examined by immunohistochemistry of SP methods that expression of Ki-67,PCNA antigen and MMP-9 in these slices of specimens.
3.Finally we discuss the correlation between expression of Gal-3 and Ki-67 antigen,and then analyze the relationship between expression of Ki-67,PCNA antigen and MMP-9 with invasiveness of the pituitary adenomas.
Results:1.The expression of Ki-67 and PCNA is no significant relationship with the sex in 86 pituitary adenoma,There is significant difference with diameter of the tumor,the expression of macroadenoma is higher than the small adenoma.The positive expression fig of Ki-67L1 in non-invasive pituitary adenomas andinvasive pituitary adenomas is 1.83±0.85,3.36±1.17 respectively.The positive expression rate of PCNA in non-invasive pituitary adenomas and invasive pituitary adenomas is 22.73%(10/44),57.14%(24/42) respectively.There is significant difference between 2 groups(p＜0.01).
2.The expression of MMP-9 is no significant relationship with the sex in 86 pituitary adenoma,There is significant difference with diameter of the tumor,the expression of macroadenoma is higher to the small adenoma.The positive expression rate of MMP-9 in non-invasive pituitary adenomas and invasive pituitary adenomas is 47.73%(21/44),73.81%(31/42)respectively.There is significant difference between 2 groups(p＜0.01).
3.The positive expression rate of PCNA in recur-invasive pituitary adenomas,non recur-invasive pituitary adenomas and afterwards recur-invasive pituitary adenomas is 55.56%, 57.58%,66.67%respectively.There is no significant difference between 3 groups(p＞0.05). The positive expression fig of Ki-67LI is 3.52±1.23,3.58±0.67 respectively.There is significant difference between 2 groups(p＜0.01).The positive expression rate of MMP-9 is 88.89%,100%,69.70%respectively.There is significant difference between 3 groups(p＜0.01).
4.There is a significant correlation between expression level of Ki-67、PCNA and MMP-9.
Conclusions:1.The expression of Ki-67 and PCNA in invasive pituitary adenomas is higher than that in non-invasive pituitary adenomas,the expression quantity is increased with invasion extent,indicate the Ki-67 and PCNA might be parameter in judgement invasion of pituitary adenoma.
2.The value 3%of Ki-67 may be threshold value to distinguish non-invasive pituitary adenomas andinvasive pituitary adenomas,the value is higher,indicate that andinvasive pituitary adenomas is easy recurrence.
3.The expression of MMP-9 is higher in invasive pituitary adenoma to non-invasive pituitary adenomas,The expression of MMP-9 is higher in recur pituitary adenoma to non recur pituitary adenoma.MMP-9 plays an important role in invasive growth and recur of pituitary adenoma.
4.There is a significant correlation between the expression of Ki-67,PCNA and MMP-9 in pituitary ademona,plays an cooperative effect invasive growth and recur of pituitary adenoma,the Ki-67,PCNA and MMP-9 might be parameter in judgement invasion and prognosis of pituitary adenoma.
材料与方法:1.收集我院2002年1月—2008年3月临床资料完整的垂体腺瘤患者手术标本86例,为研究对象,均经10%的中性甲醛固定、石蜡包埋。回顾这些病例的详细临床资料,本文研究采用Hardy-Wilson及Knosp分级、分期标准,结合术中切除的硬膜及瘤周垂体组织经病理证实肿瘤细胞浸润,判断垂体腺瘤的侵袭性,将肿瘤标本分为非侵袭性组(44例)、侵袭性组(42例),其中侵袭性组中复发9例。
2.采用免疫组化SP法分别检测两组垂体腺瘤组织石蜡切片中核增殖抗原Ki-67、PCNA、MMP-9的表达;
3.统计分析垂体腺瘤组织中Ki-67、PCNA、MMP-9的表达在两组病例中的差异,研究Ki-67、PCNA、MMP-9在垂体腺瘤中表达的相互关系,并进一步分析它们与垂体腺瘤侵袭性及复发的关系。
结果:1、Ki-67、PCNA在86例垂体腺瘤组织中表达与患者性别无关,与肿瘤大小有关,大腺瘤或巨腺瘤表达明显高于小腺瘤。非侵袭和侵袭性腺瘤组中,Ki-67LI值为1.83±0.85和3.36±1.17;PCNA阳性表达率分别为22.73%(10/44)和57.14%(24/42),经统计学t检验和X~2,Ki-67及PCNA在侵袭性组表达明显高于非侵袭性组(P＜0.01)。
2、MMP-9在垂体腺瘤组织中表达与患者性别无关,与肿瘤大小有关,大腺瘤或巨腺瘤表达明显高于小腺瘤。非侵袭和侵袭性组中,MMP-9阳性表达率分别为47.73%(21/44)和73.81%(31/42)。经统计学X~2检验,MMP-9侵袭性组表达明显高于非侵袭性组(P＜0.01)。
3、侵袭性腺瘤复发组与非复发组中及复发组复发前后PCNA阳性表达率分别为55.56%,57.58%和66.67%,无明显统计学差异(p＞0.05)。在侵袭性腺瘤复发组复发前后,Ki-67LI值分别为3.52±1.23,3.58±0.67,无明显统计学差异(p＞0.05);复发组Ki-67LI值3.52±1.23,明显高于非复发组Ki-67LI值3.32±1.06,有统计学意义(P＜0.01).在侵袭性腺瘤复发组复发前后与非复发组中,MMP-9阳性表达率分别为88.89%,100%和69.70%,经统计学X2检验,MMP-9在侵袭性腺瘤复发组复发前后与非复发组中有显著差异(P＜0.01)。
4.Ki-67、PCNA及MMP-9在垂体腺瘤中表达呈正相关,在垂体腺瘤的侵袭性生长及复发中起协同作用。
结论:1.Ki-67、PCNA细胞核增殖抗原在侵袭性垂体腺瘤中表达明显高于非侵袭性腺瘤,提示Ki-67、PCNA可以作为判断垂体腺瘤侵袭性的重要标记物。
2.Ki-67LI值3%可以作为区分非侵袭性和侵袭性垂体腺瘤的Ki-67阈值,Ki-67LI值越高,预示侵袭性垂体腺瘤易复发。
3.侵袭性垂体腺瘤MMP-9蛋白表达较非侵袭性腺瘤显著增高,MMP-9蛋白表达复发组明显高于非复发组,且复发后较复发前表达明显增高,提示MMP-9在垂体腺瘤的侵袭性生长及肿瘤复发中扮演重要作用。
4.Ki-67、PCNA及MMP-9在垂体腺瘤中表达呈正相关,在垂体腺瘤的侵袭性生长及复发中起协同作用,三者结合可作为判断垂体腺瘤侵袭性及预后的重要参考指标。
Objective:In our study,we observe the expression of the Ki-67,PCNA antigen and MMP-9 in pituitary adenoma tissues.We observe the expression of theKi-67,PCNA antigen and MMP-9 in invasive pituitary adenoma and noninvasive pituitary adenoma,we compare the expression difference of Ki-67,PCNA antigen and MMP-9 between two groups, analysis the relationship with the invasion of pituitary adenomas.
Methods:1.86 pituitary adenomas specimens removed in our department were collected, all fixed with 10%neutral formalin and then paraffin embedded.Every case history was detailedly reviewed,and all specimens were divided into invasive group(42 cases)and noninvasive group(44 cases)by adopting Hardy-Wilson and Knosp standard.
2.It was examined by immunohistochemistry of SP methods that expression of Ki-67,PCNA antigen and MMP-9 in these slices of specimens.
3.Finally we discuss the correlation between expression of Gal-3 and Ki-67 antigen,and then analyze the relationship between expression of Ki-67,PCNA antigen and MMP-9 with invasiveness of the pituitary adenomas.
Results:1.The expression of Ki-67 and PCNA is no significant relationship with the sex in 86 pituitary adenoma,There is significant difference with diameter of the tumor,the expression of macroadenoma is higher than the small adenoma.The positive expression fig of Ki-67L1 in non-invasive pituitary adenomas andinvasive pituitary adenomas is 1.83±0.85,3.36±1.17 respectively.The positive expression rate of PCNA in non-invasive pituitary adenomas and invasive pituitary adenomas is 22.73%(10/44),57.14%(24/42) respectively.There is significant difference between 2 groups(p＜0.01).
2.The expression of MMP-9 is no significant relationship with the sex in 86 pituitary adenoma,There is significant difference with diameter of the tumor,the expression of macroadenoma is higher to the small adenoma.The positive expression rate of MMP-9 in non-invasive pituitary adenomas and invasive pituitary adenomas is 47.73%(21/44),73.81%(31/42)respectively.There is significant difference between 2 groups(p＜0.01).
3.The positive expression rate of PCNA in recur-invasive pituitary adenomas,non recur-invasive pituitary adenomas and afterwards recur-invasive pituitary adenomas is 55.56%, 57.58%,66.67%respectively.There is no significant difference between 3 groups(p＞0.05). The positive expression fig of Ki-67LI is 3.52±1.23,3.58±0.67 respectively.There is significant difference between 2 groups(p＜0.01).The positive expression rate of MMP-9 is 88.89%,100%,69.70%respectively.There is significant difference between 3 groups(p＜0.01).
4.There is a significant correlation between expression level of Ki-67、PCNA and MMP-9.
Conclusions:1.The expression of Ki-67 and PCNA in invasive pituitary adenomas is higher than that in non-invasive pituitary adenomas,the expression quantity is increased with invasion extent,indicate the Ki-67 and PCNA might be parameter in judgement invasion of pituitary adenoma.
2.The value 3%of Ki-67 may be threshold value to distinguish non-invasive pituitary adenomas andinvasive pituitary adenomas,the value is higher,indicate that andinvasive pituitary adenomas is easy recurrence.
3.The expression of MMP-9 is higher in invasive pituitary adenoma to non-invasive pituitary adenomas,The expression of MMP-9 is higher in recur pituitary adenoma to non recur pituitary adenoma.MMP-9 plays an important role in invasive growth and recur of pituitary adenoma.
4.There is a significant correlation between the expression of Ki-67,PCNA and MMP-9 in pituitary ademona,plays an cooperative effect invasive growth and recur of pituitary adenoma,the Ki-67,PCNA and MMP-9 might be parameter in judgement invasion and prognosis of pituitary adenoma.
引文
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1.Turner.H.E.,Nagy Z,Esiri MM,et al.Role of matrix metalloproteinase 9 in pituitary tumor behavior[J].Clinical Endocrinology and metabolism,2000;85(8):2931-295.
2.Kawamoto H,Vozumi T,Kawammoto K,et al.Type Ⅳ Collagenase activity and cavernous sinus in human pituitary ademomas[J].Acta Neurochir,1996;138:390-395.
3.Itoh Y,Nagase H.Matrix metalloproteinases in cancer[J].Essays Biochem,2002;38:21.
4.Krainem,KoremS.Matrix metalloproteinases and the thyroid[J].Thyroid,2000,10(12):1061-1069.
5.Velasco G,Pendas A M,Fueyo A,etal.Cloning and characterization of human MMP 23,a new matrix metalloproteinase predominantly expressed in reproductive tissue and lacking conserved domains in other family members[J].J BiolChem,1999,274(8):4570-4576.
6.Visse R,Hideaki N.Matrix metalloproteinases and tissue inhibitors of metalloproteinases structure,function,and biochemistry[J].Circ Res,2003,92:827.
7.Preston A.Matrix metalloproteinases[J].Cal Biochem,2002,2(5):56-58.
8.JohnsonN,Abonen M,Kahari M,etal.Matrix Metallo -Proteinase in tumor invasion.CMLS Cell Mol Life Sei,2000,57(1):5-15.
9.Visse R,Hideaki N.Matrix metalloproteinases and tissue inhibitors of metalloproteinases structure,function,and biochemistry[J].Circ Res,2003,92:827.
10.陈晓锋,顾振纶,梁中琴,等.基质金属蛋白酶与肿瘤侵袭和转移研究进展[J].中国药理学通报,2001,17(3):253.
11.Alper O,Bergmann-Leitner ES,Bennell TA,et al.Epidemanl growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells[J].Natl cancer Inst,2001,93(18):1375.
12.Mark DS,Werb Z.ECM proteinases[A].Thomas K,Ronal V.Guidebook to the extracellular matrix,anchor,and an hesion proteins[M].ed 2.New York:Oxford University Press Inc,1999.505-509.
13.Hidalgo M,Eckhardt SG.Development of matixm etalloproteinase inhibitors in cancer therapy[J].Nail Cancer,2001,93(3):178-193.
14.Bode W,Femandez Catalan C,Crams F,et al.Insights in to MMPoTIMP interactions.Ann NY Acad Sci,1999,878(1):73-91.
15.Hojo Y,Ikeda U,Takahashi M,et al.Matrix metalloproteinase-1 expression by interaction between moncytes and vascular endothelial cells[J].J Mol Cell Cardiol,2000,32(8):1459.
16.Sternlicht MD,Coussens LM,Vu TH,et al.Biolog and regulation of the matrix metalloproteinases[A]Clendenirm NJ,Appelt K.Matrix metalloproteinase inhibitors in cancer therapy[M].Totowa:Human Press Inc,2001.1-37.
17.Haas TL,Madri JA.Extracellular matrix-driven matrix metalloproteinase production in endothelial cells:implication forangiogenesis.Trends Cardiovase Med 1999,9(3-4):70-77.
18.Yano H,Hara A,Murase S,et al.Expression of hepatocyte growth factor and matrix metalloproteinase-2 in human glioma.Brain Tumor.Pathol,2001,18(1):7-12.
19.Rodrigyez-Manzaneque JC,Lane TF,Ortega MA,et al.Thrombospondin-1 suppresses spontaneous turn or growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor.Proc Acad Sci USA,2001,98(22):1248-1249.
20.Charoenrat P,Modjtahedi H,Rhys P,et al.Epidermal growth factor-like ligands differentially up-regulate matrix metalloproteinase 9 in head and neck squammous carcinoma cells.Cancer Res,2000;60(4):1121-1128.
21.Mareelo Paez Pereda,M.Fernanda Ledda,Vietoria Goldberg,etal.Highlevels of matrix metalloProteinases regulate Proliferation and hormone seeretion in Pituitary cells[J].Clinical Endoerinology and Metabolism,2000:85(1):263-269.
22.张建民,牛涣江,等.侵袭性垂体腺瘤基质金属蛋白酶的表达及其与微血管密度的相关性[J].实用肿瘤杂志,2003,18(3):212-215.
23.王翦,刘运生,等.MMPs及TIMP在垂体腺瘤中的表达与侵袭性关系[J].中南大学学报(医学版),2004,29(6):647-650.
24.Yokoyama S,Hirano H,Moroki K,et al.Are nonfunctioning pituitary adenomas extenging into the cavernous sinus aggressive and/or invasive ? Neurosurgy 2001,49(4):857-62; discussion 862-3.
25.Edith Beaulieu, Zarin kachra,Nathalie Mousseau,et al.Matrix metalloproteinases and their inhibitors in human pituitary tumors.Neurosurgery, 1999:45(6): 1432-1441.
26.Nemunaitis J,Pool C,Primrose J,et al, Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on Serum tumor markers in advanced cancer : selection of a biologically active and tolerable dose for longer-term studies.Clin Cancer Ras,1998,4(J):1101-1109.
1.马文斌,池田秀敏,吉本高志.多激素分泌性垂体泌乳素腺瘤的激素分泌谱及克隆分析[J].中华神经外科杂志,2006,22(6):334-337.
2.章翔,于小强.重视侵袭性垂体腺瘤的基础研究[J].中华神经外科疾病研究杂志,2008,7(2):97-99.
3.Bates AS,Farrel WE,Bicknell EJ,et al.Allelic deletion in pituitary adenomas reflects aggressive biological activity and has potential value as a prognostic marker[J].Clin Endocrinol Metab;1997,82(3):818-824.
4.Nam DH,Song SY,Park K,et al.Clinical significance of molecular genetic changes in sporadic invasive pituitary adenomas[J].Exp Mol Med,2001,33(3):111-116.
5.Gurlek A,Karavitaki N,Ansorge O,et al.What are the markers of aggressiveness in prolactinomas?Changes in cell biology,extracellular matrix components,Angio genesis and genetics[J].Eur J Endocrinol,2007,156(2):143-153.
6.Jacob T,Deepthi K,Naibedya C.The emerging role of pituitary tumor-transforming gene in tumorigenesis[J].Clin Med Res,2006,4(2):130-137.
7.Zhang X,Horwitx GA,Prezant TR,et al.Structure,expression,and function of human pituitary tumor-transforming gene(PTTG)[J].Mol Endocrinol,1999,13(1):156-166.
8.Yu R,Melmed S.Oncogene activation in pituitary tumor[J].Brain Pathol,2001,11(3):328-341.
9.A Lania,G Mantovani,A Spada.Genetics of pituitary tumors:focus on G-protein mutations[J].Experimental Biology and Medicine,2003,228(9):1004-1017.
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11.张振强,张巨波。垂体腺瘤中凋亡抑制基因survivin的表达和bcl-2、p63相关性的研究[J].河南大学学报(医学版),2004,23(4):15-18.
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25. Itoh Y, Nagase H. Matrix metalloproteinases in cancer [J].Essays Biochem,2002;38:21
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37.Yano H,Hara A,Murase S,et al.Expression of hepatocyte growth factor and matrix metalloproteinase-2 in human glioma.Brain Tumor Pathol,2001,18(1):7-12.
38.Rodrigyez-Manzaneque JC,Lane TF,Ortega MA,et al.Thrombospondin-1 suppresses spontaneous turn or growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor.Proc Acad Sci USA,2001,98(22):1248-1249.
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42.王翦,刘运生,等.MMPs及TIMP在垂体腺瘤中的表达与侵袭性关系[J].中南大学学报(医学版),2004,29(6):647-650.
43.张建民,牛涣江,等.侵袭性垂体腺瘤基质金属蛋白酶的表达及其与微血管密度的相关性[J].实用肿瘤杂志,2003,18(3):212-215.
44.Laquerriere A,Jun J,Tiollier J,et al.Experimental evaluation of bi-layered human collagen as a dural substitute.J Neurosurg.1993,78:487.
45.李爱军,王道奎,等.PTTG、MMPs、VEGF在侵袭性垂体腺瘤中的表达及其意义[J].中国临床神经外科杂志,2007,12(7):418-421.
1.Turner.H.E.,Nagy Z,Esiri MM,et al.Role of matrix metalloproteinase 9 in pituitary tumor behavior[J].Clinical Endocrinology and metabolism,2000;85(8):2931-295.
2.Kawamoto H,Vozumi T,Kawammoto K,et al.Type Ⅳ Collagenase activity and cavernous sinus in human pituitary ademomas[J].Acta Neurochir,1996;138:390-395.
3.Itoh Y,Nagase H.Matrix metalloproteinases in cancer[J].Essays Biochem,2002;38:21.
4.Krainem,KoremS.Matrix metalloproteinases and the thyroid[J].Thyroid,2000,10(12):1061-1069.
5.Velasco G,Pendas A M,Fueyo A,etal.Cloning and characterization of human MMP 23,a new matrix metalloproteinase predominantly expressed in reproductive tissue and lacking conserved domains in other family members[J].J BiolChem,1999,274(8):4570-4576.
6.Visse R,Hideaki N.Matrix metalloproteinases and tissue inhibitors of metalloproteinases structure,function,and biochemistry[J].Circ Res,2003,92:827.
7.Preston A.Matrix metalloproteinases[J].Cal Biochem,2002,2(5):56-58.
8.JohnsonN,Abonen M,Kahari M,etal.Matrix Metallo -Proteinase in tumor invasion.CMLS Cell Mol Life Sei,2000,57(1):5-15.
9.Visse R,Hideaki N.Matrix metalloproteinases and tissue inhibitors of metalloproteinases structure,function,and biochemistry[J].Circ Res,2003,92:827.
10.陈晓锋,顾振纶,梁中琴,等.基质金属蛋白酶与肿瘤侵袭和转移研究进展[J].中国药理学通报,2001,17(3):253.
11.Alper O,Bergmann-Leitner ES,Bennell TA,et al.Epidemanl growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells[J].Natl cancer Inst,2001,93(18):1375.
12.Mark DS,Werb Z.ECM proteinases[A].Thomas K,Ronal V.Guidebook to the extracellular matrix,anchor,and an hesion proteins[M].ed 2.New York:Oxford University Press Inc,1999.505-509.
13.Hidalgo M,Eckhardt SG.Development of matixm etalloproteinase inhibitors in cancer therapy[J].Nail Cancer,2001,93(3):178-193.
14.Bode W,Femandez Catalan C,Crams F,et al.Insights in to MMPoTIMP interactions.Ann NY Acad Sci,1999,878(1):73-91.
15.Hojo Y,Ikeda U,Takahashi M,et al.Matrix metalloproteinase-1 expression by interaction between moncytes and vascular endothelial cells[J].J Mol Cell Cardiol,2000,32(8):1459.
16.Sternlicht MD,Coussens LM,Vu TH,et al.Biolog and regulation of the matrix metalloproteinases[A]Clendenirm NJ,Appelt K.Matrix metalloproteinase inhibitors in cancer therapy[M].Totowa:Human Press Inc,2001.1-37.
17.Haas TL,Madri JA.Extracellular matrix-driven matrix metalloproteinase production in endothelial cells:implication forangiogenesis.Trends Cardiovase Med 1999,9(3-4):70-77.
18.Yano H,Hara A,Murase S,et al.Expression of hepatocyte growth factor and matrix metalloproteinase-2 in human glioma.Brain Tumor.Pathol,2001,18(1):7-12.
19.Rodrigyez-Manzaneque JC,Lane TF,Ortega MA,et al.Thrombospondin-1 suppresses spontaneous turn or growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor.Proc Acad Sci USA,2001,98(22):1248-1249.
20.Charoenrat P,Modjtahedi H,Rhys P,et al.Epidermal growth factor-like ligands differentially up-regulate matrix metalloproteinase 9 in head and neck squammous carcinoma cells.Cancer Res,2000;60(4):1121-1128.
21.Mareelo Paez Pereda,M.Fernanda Ledda,Vietoria Goldberg,etal.Highlevels of matrix metalloProteinases regulate Proliferation and hormone seeretion in Pituitary cells[J].Clinical Endoerinology and Metabolism,2000:85(1):263-269.
22.张建民,牛涣江,等.侵袭性垂体腺瘤基质金属蛋白酶的表达及其与微血管密度的相关性[J].实用肿瘤杂志,2003,18(3):212-215.
23.王翦,刘运生,等.MMPs及TIMP在垂体腺瘤中的表达与侵袭性关系[J].中南大学学报(医学版),2004,29(6):647-650.
24.Yokoyama S,Hirano H,Moroki K,et al.Are nonfunctioning pituitary adenomas extenging into the cavernous sinus aggressive and/or invasive ? Neurosurgy 2001,49(4):857-62; discussion 862-3.
25.Edith Beaulieu, Zarin kachra,Nathalie Mousseau,et al.Matrix metalloproteinases and their inhibitors in human pituitary tumors.Neurosurgery, 1999:45(6): 1432-1441.
26.Nemunaitis J,Pool C,Primrose J,et al, Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on Serum tumor markers in advanced cancer : selection of a biologically active and tolerable dose for longer-term studies.Clin Cancer Ras,1998,4(J):1101-1109.
1.马文斌,池田秀敏,吉本高志.多激素分泌性垂体泌乳素腺瘤的激素分泌谱及克隆分析[J].中华神经外科杂志,2006,22(6):334-337.
2.章翔,于小强.重视侵袭性垂体腺瘤的基础研究[J].中华神经外科疾病研究杂志,2008,7(2):97-99.
3.Bates AS,Farrel WE,Bicknell EJ,et al.Allelic deletion in pituitary adenomas reflects aggressive biological activity and has potential value as a prognostic marker[J].Clin Endocrinol Metab;1997,82(3):818-824.
4.Nam DH,Song SY,Park K,et al.Clinical significance of molecular genetic changes in sporadic invasive pituitary adenomas[J].Exp Mol Med,2001,33(3):111-116.
5.Gurlek A,Karavitaki N,Ansorge O,et al.What are the markers of aggressiveness in prolactinomas?Changes in cell biology,extracellular matrix components,Angio genesis and genetics[J].Eur J Endocrinol,2007,156(2):143-153.
6.Jacob T,Deepthi K,Naibedya C.The emerging role of pituitary tumor-transforming gene in tumorigenesis[J].Clin Med Res,2006,4(2):130-137.
7.Zhang X,Horwitx GA,Prezant TR,et al.Structure,expression,and function of human pituitary tumor-transforming gene(PTTG)[J].Mol Endocrinol,1999,13(1):156-166.
8.Yu R,Melmed S.Oncogene activation in pituitary tumor[J].Brain Pathol,2001,11(3):328-341.
9.A Lania,G Mantovani,A Spada.Genetics of pituitary tumors:focus on G-protein mutations[J].Experimental Biology and Medicine,2003,228(9):1004-1017.
10.Shimon I,Hinton DR,Weiss MH,et al.Prolactinomas express human heparin-binding secretary transforming gene(hst)protein product:marker of tumor invasiveness[J].Clin Endocrinol,1998,48(1):23-29.
11.张振强,张巨波。垂体腺瘤中凋亡抑制基因survivin的表达和bcl-2、p63相关性的研究[J].河南大学学报(医学版),2004,23(4):15-18.
12.Asa SL,Ezzat S.The cytogenesis and pathogenesis of pituitary adenomas[J].Endocrine Rev,1998,19(6):798-827.
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