侵袭性垂体腺瘤中cyclin E、cdk2和p27~（kip1）的表达
摘要
目的:探讨细胞周期相关蛋白cyclin E、cdk2和p27kip1在侵袭性垂体腺瘤中的表达,三者的表达有无相关性,以及它们的表达与垂体腺瘤呈侵袭性生长的生物学行为是否具有相关性,以期为侵袭性垂体腺瘤的诊断、临床治疗和预后判断提供帮助。
方法:58例新鲜切除的垂体腺瘤标本每例分成三份,一份送病理科行常规病理检查,一份立即放入4%的多聚甲醛液中固定用于免疫组化检测,另一份立即放入-80℃冰箱冻存或立即提取蛋白用于免疫印迹检测。使用兔抗cyclin E、兔抗cdk2和兔抗p27kip1三种抗体,采用免疫组织化学法(Immunohistochemistry,IHC)和western印迹法(western blotting,WB)检测垂体腺瘤中cyclin E、cdk2和p27kip1蛋白的表达情况。
结果:Cyclin E和cdk2在侵袭组中的表达均明显高于非侵袭组(P均<0.05),而p27kip1在侵袭组中的表达明显低于非侵袭组(P<0.05);cyclin E和cdk2在垂体腺瘤中的表达呈正相关(P<0.05),两者与p27kip1的表达均呈负相关(P均<0.05);cyclin E和cdk2的表达与垂体腺瘤的侵袭性均呈正相关(P均<0.05),p27kip1的表达与垂体腺瘤的侵袭性呈负相关(P<0.05)。
结论: Cyclin E和cdk2的过度表达及p27kip1的低表达与侵袭性垂体腺瘤的发生、发展、增殖显著相关,三者可能成为判断垂体腺瘤的侵袭性和预后的指标。
Objective: To study on the expressions of cell cycle associated protein cyclin E, cdk2 and p27kip1 in invasive pituitary adenomas, and to investigate whether there exist correlations among the expressions of the three proteins and between the expressions of the three proteins and the invasiveness of invasive pituitary adenomas.
Methods: 58 cases of fresh resected pituitary adenomas were collected, each sample was divided into three parts, one for routine detection in the department of pathology; one for Immunohistochemistry by immediately dipping into 4% paraformaldehyde, and the last one for Western blotting analysis by storing in ultra low temperature refrigerator or extracting its proteins immediately. Immunohistochemical analysis and Western blotting analysis using anti-cyclin E, anti-cdk2 and anti-p27kip1 antibodies were performed to detect the expressions of cyclin E, cdk2 and p27kip1 in pituitary adenomas.
Results: The expressions of cyclin E and cdk2 in invasive pituitary adenomas were both significantly higher than that in noninvasive pituitary adenomas (both P<0.05), but the expression of p27kip1 in invasive group was significantly lower than that in noninvasive group (P<0.05). There was positive correlation between the expression of cyclin E and cdk2 in pituitary adenomas (P<0.05), and negative correlation between the expression of the former two and p27kip1 (both P<0.05); there was positive correlation between the expression of cyclin E and cdk2 and the invasiveness of pituitary adenomas (both P<0.05), and negative correlation between the expression of p27kip1 and the invasiveness of pituitary adenomas (P<0.05).
Conclusions: The overexpressions of cyclin E and cdk2 and the lower expression of p27kip1 were significantly associated with the invasiveness of pituitary adenomas, cyclin E, cdk2 and p27kip1 proteins may be valuable prognostic factors for pituitary adenoma.
方法:58例新鲜切除的垂体腺瘤标本每例分成三份,一份送病理科行常规病理检查,一份立即放入4%的多聚甲醛液中固定用于免疫组化检测,另一份立即放入-80℃冰箱冻存或立即提取蛋白用于免疫印迹检测。使用兔抗cyclin E、兔抗cdk2和兔抗p27kip1三种抗体,采用免疫组织化学法(Immunohistochemistry,IHC)和western印迹法(western blotting,WB)检测垂体腺瘤中cyclin E、cdk2和p27kip1蛋白的表达情况。
结果:Cyclin E和cdk2在侵袭组中的表达均明显高于非侵袭组(P均<0.05),而p27kip1在侵袭组中的表达明显低于非侵袭组(P<0.05);cyclin E和cdk2在垂体腺瘤中的表达呈正相关(P<0.05),两者与p27kip1的表达均呈负相关(P均<0.05);cyclin E和cdk2的表达与垂体腺瘤的侵袭性均呈正相关(P均<0.05),p27kip1的表达与垂体腺瘤的侵袭性呈负相关(P<0.05)。
结论: Cyclin E和cdk2的过度表达及p27kip1的低表达与侵袭性垂体腺瘤的发生、发展、增殖显著相关,三者可能成为判断垂体腺瘤的侵袭性和预后的指标。
Objective: To study on the expressions of cell cycle associated protein cyclin E, cdk2 and p27kip1 in invasive pituitary adenomas, and to investigate whether there exist correlations among the expressions of the three proteins and between the expressions of the three proteins and the invasiveness of invasive pituitary adenomas.
Methods: 58 cases of fresh resected pituitary adenomas were collected, each sample was divided into three parts, one for routine detection in the department of pathology; one for Immunohistochemistry by immediately dipping into 4% paraformaldehyde, and the last one for Western blotting analysis by storing in ultra low temperature refrigerator or extracting its proteins immediately. Immunohistochemical analysis and Western blotting analysis using anti-cyclin E, anti-cdk2 and anti-p27kip1 antibodies were performed to detect the expressions of cyclin E, cdk2 and p27kip1 in pituitary adenomas.
Results: The expressions of cyclin E and cdk2 in invasive pituitary adenomas were both significantly higher than that in noninvasive pituitary adenomas (both P<0.05), but the expression of p27kip1 in invasive group was significantly lower than that in noninvasive group (P<0.05). There was positive correlation between the expression of cyclin E and cdk2 in pituitary adenomas (P<0.05), and negative correlation between the expression of the former two and p27kip1 (both P<0.05); there was positive correlation between the expression of cyclin E and cdk2 and the invasiveness of pituitary adenomas (both P<0.05), and negative correlation between the expression of p27kip1 and the invasiveness of pituitary adenomas (P<0.05).
Conclusions: The overexpressions of cyclin E and cdk2 and the lower expression of p27kip1 were significantly associated with the invasiveness of pituitary adenomas, cyclin E, cdk2 and p27kip1 proteins may be valuable prognostic factors for pituitary adenoma.
引文
[1] 王忠诚. 神经外科学[M]. 武汉: 湖北科学技术出版社. 2000, 489-490
[2] 任祖渊. 垂体腺瘤诊断和治疗现状[J]. 中国神经肿瘤杂志. 2006; 4(1): 1-4
[3] Blevins LS Jr, Verity DK, Allen G.. Aggressive pituitary tumors [J]. Oncology. 1998, 12(9): 1307-1312
[4] Anthony P, Heaney, Gregory A, et al. Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis [J]. Nature Medicine. 1999, 5(1): 1317-1321
[5] 冯作化. 医学分子生物学[M]. 北京: 人民卫生出版社. 2005, 146-147
[6] Arooz T, Yam CH, Siu WY, et al. On the concentrations of cyclins and cyclin-dependent kinases in extracts of cultured human cells [J]. Biochemistry. 2000, 39(31):9494-9501
[7] Coqueret O. Linking cyclins to transcriptional control [J]. Gene. 2002, 299(1-2): 35-55
[8] Sasaki T, Katayose Y, Suzuki M, et al. Adenovirus expressing mutant p27kip1 enhanced apoptosis against cholangiocarcinoma than adenovirus-p27kip1 wild type[J]. Hepatogastroenterology. 2004, 51(55): 68-75
[9] Ye L, Zhang HY, Wang H, et al. Effects of transforming growth factor beta 1 on the growth of rhabdomyosarcoma cell line RD [J]. Chin Med J. 2005, 118(8): 678-686
[10] Sanz Gonzalez SM, Melero Fernandez de Mera R, Malek NP, et al. Atheroma development in apolipoprotein E-null mice is not regulated by phosphorylation of p27(Kip1) on threonine 187[J]. J Cell Biochem. 2006, 97(4): 735-743
[11] Wilson CB. A decade of pituitary microsurgery: The Herbert Olivercrona lecture [J]. J Neurosurg. 1984, 61(5): 814-833
[12] Knosp E, Steiner E, Kitz K, et al. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings [J]. Neurosurgery. 1993 Oct, 33(4): 610-7. discussion 617-618
[13] Jefferson G.. Extrasellar extensions of pituitary adenomas [J]. Proc R Soc Med.1940, 33: 433-458
[14] Scheithauer BW, Kovacs KT, Laws ER, et al. Pathology of invasive pituitary tumors with special reference to functional classification [J]. Neurosurg. 1986, 65(6): 733-744
[15] Selman WR, Laws ER, Scheithauer BW, et al. The occurrence of dural invasion in pituitary adenomas [J]. Neurosurg. 1986, 64(3): 402-407
[16] YU R, MELMED S. Oncogene activation in pituitary tumors[J]. Brain Pathol, 2001, l1(3): 328-341
[17] ZHANG X, HORWITZ G A, HEANEY A P, et a1. Pituitary tumor transforming gene(PTTG)expression in pituitary adenomas[J]. J Clin Endocrinol Metab, 1999, 84(2): 761-767
[18] Blevins LS Jr, Verity DK, Allen G.. Aggressive pituitary tumors [J]. Oncology. 1998, 12(9): 1307-1312
[19] Anthony P, Heaney, Gregory A, et al. Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis [J]. Nature Medicine. 1999, 5(1): 1317-1321
[20] PAEZ-PEREDA M, KUCHENBAUER F, ARZT E, et al. Regulation of pituitary hormones and cell proliferation by components of the extracellular matrix[J]. Braz J Med Biol Res, 2005, 38(10): 1487-1494
[21] MALIK M T, KAKAR S S. Regulation of angiogenesis and invasion by human pituitary tumor transforming gene(PTTG) through increased expression and secretion of matrix metalloproteinase-2(MMP-2)[J]. Mol Cancer, 2006 , 5(1): 61
[22] LIU W, MATSUMOTO Y, OKADA M, et al. Matrix metalloproteinase 2 an d 9 expression correlated with cavernous sinus invasion of pituitary adenomas [J]. J Med Invest, 2005, 52(3-4): 151-158
[23] KORBONITS M, CHITNIS M M, GUEORGUIEV M, et al. Leptin in pituitary adenomas–a novel paracrine regulatory system [J]. Pituitary, 2001, 4(1-2):49-55
[24] 毕晓峰, 杜其航, 穆庆岭, 等. Cyclin E 的表达与胆管癌神经浸润及预后关系的研究[J]. 山东大学学报(医学版), 2007, 45(10): 1059-1062
[25] 张国顺, 高国芬, 林尚泽. 鼻咽癌中细胞周期蛋白 E 与细胞周期蛋白依赖性激酶抑制因子 p27kip1的相关性分析[J]. 贵阳医学院学报, 2007, 32(6): 622-628
[26] 兰军良, 王海波. 细胞周期素 E、p27kip1 多参数测定在胃癌早期诊断中的应用[J]. 山西医药杂志, 2007, 36(11): 968-969
[27] 何春年, 徐翠清, 赵焕芬, 等. 在子宫颈上皮内瘤变和鳞癌组织中 cyclin E、Rb基因表达的研究[J]. 中国组织化学与细胞化学杂志, 2007, 16(3): 330-335
[28] Ponce-Castaneda M. p27kipl: chromosomal mapping to 12p12—12p13.I and absence of mutations in human tumors[J]. Cancer Res, 1995, 55(6): 1211—1214
[29] Wingate, H; Zhang, N; McGarhen, M J; et al. The tumor-specific hyperactive forms of cyclin E are resistant to inhibition by p21 and p27 [J]. J-Biol-Chem. 2005; 280(15): 15148-57
[30] Deb-Basu, D; Karlsson, A; Li, Q; et al. MYC can enforce cell cycle transit from G1 to S and G2 to S, but not mitotic cellular division, independent of p27-mediated inihibition of cyclin E/CDK2[J]. Cell-Cycle. 2006; 5(12): 1348-55
[31] Halevy O, Novitch BG, Spicer DB, et a1. Correlation of ter2 minal cell cycle arrest of skeletal muscle with induction of P21 by myoD[J]. Science, 1995, 267(5200): 1018—1021
[32] Fujisda S, Inuzuka M, Tanaka N, et a1. Expression of p27 is associated with Bax expression and spontaneous apoptosis in o2ral and oropharyugeal carcirnoma[J]. Carcer Int J, 1999, 84(3): 315—320
[33] Kim YT, Zhao M. Aberrant cell cycle regulation in cervical carcinoma [J]. Yonsei Med J. 2005, 46(5): 597-613
[34] Sui L, Dong Y, Ohno M, et al. Implication of malignancy and prognosis of p27(kip1), cyclin E, and Cdk2 expression in epithelial ovarian tumors[J]. Gynecol Oncol. 2001; 83(1): 56-63
[35] Jordan S, Lidhar K, Korbonits M, et al. Cyclin D and cyclin E expression in normal and adenomatous pituitary [J]. Eur J Endocrinol. 2000;143(1):R1-6
[1] Folberg R, Hendrix MJ, Maniotis AJ. Vasculogenic mimicry and tumor angingenesis[J]. Am J Pathol. 2000, 156(3): 361-381
[2] 戴如飞, 刘宁, 朱凤仪, 等. 血管内皮生长因子和P53及细胞增殖核抗原蛋白表达与垂体腺瘤复发的关系[J]. 中华检验医学杂志. 2004, 27(7): 431-433
[3] Chen L, Liu YS, Wang LS, et al. Expression of pituitary tumor transforming gene, endostatin, and basic fibroblast growth factor mRNAs in invasive pituitary adenomas[J]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2004, 29(6): 651-666
[4] Zhou R, Skalli O. TGF-alpha differentially regulates GFAP, vimentin, and nestin gene expression in U一373 MG glioblastoma cells: correlation with cell shape and motility [J]. Exp Cell Res. 2000, 254(2) :269-278
[5] Kim KY, Jeong SY, Won J, et al. Induction of angiogenesis by expression of soluble type II transforming growth factor-β receptor in mouse hepatoma[J]. J Biol Chem. 2001, 276(42): 38781-38786
[6] Goth MI, Hubina E, Raptis S, et al. Physiological and Pathological Angiogenesis in the Endocrine System [J]. Microsc Res Tech. 2003, 60: 98-106
[7] Renner U, Lohrer P, Schaaf L, et a1. Transforming growth factor-βstimulatesvascular endothelial growth factor production by folliculostellate pituitary cells[J]. Endocrinology. 2002, 143: 3759-3765
[8] 郭常利, 吴瑜, 王兰, 等. PCNA、P16、TGF-β1蛋白表达与垂体腺瘤侵袭性的关系[J]. 中国临床神经科学. 2001, 9(3): 237-239
[9] Ezzat S, Asa SL. Mechanisms of Disease: The Pathogenesis of Pituitary Tumors [J]. Nat Clin Pract Endocrinol Metab. 2006, 2(4): 220-230
[10] Kong YG, Ren ZY, Su CB, et al. Elevated soluble epidermal growth factor receptor level in pituitary adenoma and carcinoma[J]. Chin Med Sci J. 2004, 19(3): 199-202
[11] Miranti CK, Brugge JS. Sensing the environment:a historical perspective on integrin signal transduction[J]. Nat Cell Biol. 2002, 4(4): E83-E90
[12] Lee JW, Juliano R. Mitogenic signal transduction by integrin and growth factor receptor -mediated pathways [J]. Mol Cells. 2004, 17(2): 188-202
[13] 万锋, 舒凯, 雷霆, 等. 整合素β1、局灶黏附激酶的表达与垂体瘤的侵袭性[J]. 中国临床神经外科杂志. 2002, 7(5): 265-267
[14] Wang HL, Zhang SL, Lu YM, et al. Effect of Hepatocyte Growth Factor on Invasion of Ovarian Cancer Cell Line SKOV3 and Its Signal Transduction Pathway[J]. Ai Zheng. 2006,25(5): 570-575
[15] Moser TL, Sharon MS, Asplin L, et a1. Angiogenesis bind ATP synthase on the surface of human endothelial cells [J]. Proc Natl Acad Sci USA. 1999, 96(6): 2811-2816
[16] Moser TL, Kenan DJ, Ashley TA, et a1. Endothelial cell surface F1-FO ATP synthase is active in ATP synthesis and is inhibited by angiostatin[J]. Proc Natl Acad Sci USA. 2001, 98(12): 6656-6661
[17] Mendel DB, Laird AD, Smolich BD, et a1. Development of SU5416,a selective small molecule inhibitor of VEGF receptor tyrosine kinase activity,as an anti-angiogenesis agent[J]. Anticancer Drug Des. 2000, 15(1): 29-41
[18] Carter SK. Clinical strategy for the development of angiogenesis inhibitors [J]. Oncologist. 2000, 5(Suppl 1): 51-54
[19] Tomita T. Matrix metalloproteinases and tissue inhibitors of metallo-proteinases inthyroid C-cells and medullary thyroid carcinomas [J]. Histo-pathology. 1997, 31(2): 150-156
[20] Lode HN, Moehler T, Xiang R, et a1. Synergy between an antiangiogenic integrin alpha antagonist and an antibody-cytokine fusion protein eradicates spontaneous tumor metastases [J]. Proc Natl Acad Sci USA. 1999, 96(4): 1591-1596
[2] 任祖渊. 垂体腺瘤诊断和治疗现状[J]. 中国神经肿瘤杂志. 2006; 4(1): 1-4
[3] Blevins LS Jr, Verity DK, Allen G.. Aggressive pituitary tumors [J]. Oncology. 1998, 12(9): 1307-1312
[4] Anthony P, Heaney, Gregory A, et al. Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis [J]. Nature Medicine. 1999, 5(1): 1317-1321
[5] 冯作化. 医学分子生物学[M]. 北京: 人民卫生出版社. 2005, 146-147
[6] Arooz T, Yam CH, Siu WY, et al. On the concentrations of cyclins and cyclin-dependent kinases in extracts of cultured human cells [J]. Biochemistry. 2000, 39(31):9494-9501
[7] Coqueret O. Linking cyclins to transcriptional control [J]. Gene. 2002, 299(1-2): 35-55
[8] Sasaki T, Katayose Y, Suzuki M, et al. Adenovirus expressing mutant p27kip1 enhanced apoptosis against cholangiocarcinoma than adenovirus-p27kip1 wild type[J]. Hepatogastroenterology. 2004, 51(55): 68-75
[9] Ye L, Zhang HY, Wang H, et al. Effects of transforming growth factor beta 1 on the growth of rhabdomyosarcoma cell line RD [J]. Chin Med J. 2005, 118(8): 678-686
[10] Sanz Gonzalez SM, Melero Fernandez de Mera R, Malek NP, et al. Atheroma development in apolipoprotein E-null mice is not regulated by phosphorylation of p27(Kip1) on threonine 187[J]. J Cell Biochem. 2006, 97(4): 735-743
[11] Wilson CB. A decade of pituitary microsurgery: The Herbert Olivercrona lecture [J]. J Neurosurg. 1984, 61(5): 814-833
[12] Knosp E, Steiner E, Kitz K, et al. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings [J]. Neurosurgery. 1993 Oct, 33(4): 610-7. discussion 617-618
[13] Jefferson G.. Extrasellar extensions of pituitary adenomas [J]. Proc R Soc Med.1940, 33: 433-458
[14] Scheithauer BW, Kovacs KT, Laws ER, et al. Pathology of invasive pituitary tumors with special reference to functional classification [J]. Neurosurg. 1986, 65(6): 733-744
[15] Selman WR, Laws ER, Scheithauer BW, et al. The occurrence of dural invasion in pituitary adenomas [J]. Neurosurg. 1986, 64(3): 402-407
[16] YU R, MELMED S. Oncogene activation in pituitary tumors[J]. Brain Pathol, 2001, l1(3): 328-341
[17] ZHANG X, HORWITZ G A, HEANEY A P, et a1. Pituitary tumor transforming gene(PTTG)expression in pituitary adenomas[J]. J Clin Endocrinol Metab, 1999, 84(2): 761-767
[18] Blevins LS Jr, Verity DK, Allen G.. Aggressive pituitary tumors [J]. Oncology. 1998, 12(9): 1307-1312
[19] Anthony P, Heaney, Gregory A, et al. Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis [J]. Nature Medicine. 1999, 5(1): 1317-1321
[20] PAEZ-PEREDA M, KUCHENBAUER F, ARZT E, et al. Regulation of pituitary hormones and cell proliferation by components of the extracellular matrix[J]. Braz J Med Biol Res, 2005, 38(10): 1487-1494
[21] MALIK M T, KAKAR S S. Regulation of angiogenesis and invasion by human pituitary tumor transforming gene(PTTG) through increased expression and secretion of matrix metalloproteinase-2(MMP-2)[J]. Mol Cancer, 2006 , 5(1): 61
[22] LIU W, MATSUMOTO Y, OKADA M, et al. Matrix metalloproteinase 2 an d 9 expression correlated with cavernous sinus invasion of pituitary adenomas [J]. J Med Invest, 2005, 52(3-4): 151-158
[23] KORBONITS M, CHITNIS M M, GUEORGUIEV M, et al. Leptin in pituitary adenomas–a novel paracrine regulatory system [J]. Pituitary, 2001, 4(1-2):49-55
[24] 毕晓峰, 杜其航, 穆庆岭, 等. Cyclin E 的表达与胆管癌神经浸润及预后关系的研究[J]. 山东大学学报(医学版), 2007, 45(10): 1059-1062
[25] 张国顺, 高国芬, 林尚泽. 鼻咽癌中细胞周期蛋白 E 与细胞周期蛋白依赖性激酶抑制因子 p27kip1的相关性分析[J]. 贵阳医学院学报, 2007, 32(6): 622-628
[26] 兰军良, 王海波. 细胞周期素 E、p27kip1 多参数测定在胃癌早期诊断中的应用[J]. 山西医药杂志, 2007, 36(11): 968-969
[27] 何春年, 徐翠清, 赵焕芬, 等. 在子宫颈上皮内瘤变和鳞癌组织中 cyclin E、Rb基因表达的研究[J]. 中国组织化学与细胞化学杂志, 2007, 16(3): 330-335
[28] Ponce-Castaneda M. p27kipl: chromosomal mapping to 12p12—12p13.I and absence of mutations in human tumors[J]. Cancer Res, 1995, 55(6): 1211—1214
[29] Wingate, H; Zhang, N; McGarhen, M J; et al. The tumor-specific hyperactive forms of cyclin E are resistant to inhibition by p21 and p27 [J]. J-Biol-Chem. 2005; 280(15): 15148-57
[30] Deb-Basu, D; Karlsson, A; Li, Q; et al. MYC can enforce cell cycle transit from G1 to S and G2 to S, but not mitotic cellular division, independent of p27-mediated inihibition of cyclin E/CDK2[J]. Cell-Cycle. 2006; 5(12): 1348-55
[31] Halevy O, Novitch BG, Spicer DB, et a1. Correlation of ter2 minal cell cycle arrest of skeletal muscle with induction of P21 by myoD[J]. Science, 1995, 267(5200): 1018—1021
[32] Fujisda S, Inuzuka M, Tanaka N, et a1. Expression of p27 is associated with Bax expression and spontaneous apoptosis in o2ral and oropharyugeal carcirnoma[J]. Carcer Int J, 1999, 84(3): 315—320
[33] Kim YT, Zhao M. Aberrant cell cycle regulation in cervical carcinoma [J]. Yonsei Med J. 2005, 46(5): 597-613
[34] Sui L, Dong Y, Ohno M, et al. Implication of malignancy and prognosis of p27(kip1), cyclin E, and Cdk2 expression in epithelial ovarian tumors[J]. Gynecol Oncol. 2001; 83(1): 56-63
[35] Jordan S, Lidhar K, Korbonits M, et al. Cyclin D and cyclin E expression in normal and adenomatous pituitary [J]. Eur J Endocrinol. 2000;143(1):R1-6
[1] Folberg R, Hendrix MJ, Maniotis AJ. Vasculogenic mimicry and tumor angingenesis[J]. Am J Pathol. 2000, 156(3): 361-381
[2] 戴如飞, 刘宁, 朱凤仪, 等. 血管内皮生长因子和P53及细胞增殖核抗原蛋白表达与垂体腺瘤复发的关系[J]. 中华检验医学杂志. 2004, 27(7): 431-433
[3] Chen L, Liu YS, Wang LS, et al. Expression of pituitary tumor transforming gene, endostatin, and basic fibroblast growth factor mRNAs in invasive pituitary adenomas[J]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2004, 29(6): 651-666
[4] Zhou R, Skalli O. TGF-alpha differentially regulates GFAP, vimentin, and nestin gene expression in U一373 MG glioblastoma cells: correlation with cell shape and motility [J]. Exp Cell Res. 2000, 254(2) :269-278
[5] Kim KY, Jeong SY, Won J, et al. Induction of angiogenesis by expression of soluble type II transforming growth factor-β receptor in mouse hepatoma[J]. J Biol Chem. 2001, 276(42): 38781-38786
[6] Goth MI, Hubina E, Raptis S, et al. Physiological and Pathological Angiogenesis in the Endocrine System [J]. Microsc Res Tech. 2003, 60: 98-106
[7] Renner U, Lohrer P, Schaaf L, et a1. Transforming growth factor-βstimulatesvascular endothelial growth factor production by folliculostellate pituitary cells[J]. Endocrinology. 2002, 143: 3759-3765
[8] 郭常利, 吴瑜, 王兰, 等. PCNA、P16、TGF-β1蛋白表达与垂体腺瘤侵袭性的关系[J]. 中国临床神经科学. 2001, 9(3): 237-239
[9] Ezzat S, Asa SL. Mechanisms of Disease: The Pathogenesis of Pituitary Tumors [J]. Nat Clin Pract Endocrinol Metab. 2006, 2(4): 220-230
[10] Kong YG, Ren ZY, Su CB, et al. Elevated soluble epidermal growth factor receptor level in pituitary adenoma and carcinoma[J]. Chin Med Sci J. 2004, 19(3): 199-202
[11] Miranti CK, Brugge JS. Sensing the environment:a historical perspective on integrin signal transduction[J]. Nat Cell Biol. 2002, 4(4): E83-E90
[12] Lee JW, Juliano R. Mitogenic signal transduction by integrin and growth factor receptor -mediated pathways [J]. Mol Cells. 2004, 17(2): 188-202
[13] 万锋, 舒凯, 雷霆, 等. 整合素β1、局灶黏附激酶的表达与垂体瘤的侵袭性[J]. 中国临床神经外科杂志. 2002, 7(5): 265-267
[14] Wang HL, Zhang SL, Lu YM, et al. Effect of Hepatocyte Growth Factor on Invasion of Ovarian Cancer Cell Line SKOV3 and Its Signal Transduction Pathway[J]. Ai Zheng. 2006,25(5): 570-575
[15] Moser TL, Sharon MS, Asplin L, et a1. Angiogenesis bind ATP synthase on the surface of human endothelial cells [J]. Proc Natl Acad Sci USA. 1999, 96(6): 2811-2816
[16] Moser TL, Kenan DJ, Ashley TA, et a1. Endothelial cell surface F1-FO ATP synthase is active in ATP synthesis and is inhibited by angiostatin[J]. Proc Natl Acad Sci USA. 2001, 98(12): 6656-6661
[17] Mendel DB, Laird AD, Smolich BD, et a1. Development of SU5416,a selective small molecule inhibitor of VEGF receptor tyrosine kinase activity,as an anti-angiogenesis agent[J]. Anticancer Drug Des. 2000, 15(1): 29-41
[18] Carter SK. Clinical strategy for the development of angiogenesis inhibitors [J]. Oncologist. 2000, 5(Suppl 1): 51-54
[19] Tomita T. Matrix metalloproteinases and tissue inhibitors of metallo-proteinases inthyroid C-cells and medullary thyroid carcinomas [J]. Histo-pathology. 1997, 31(2): 150-156
[20] Lode HN, Moehler T, Xiang R, et a1. Synergy between an antiangiogenic integrin alpha antagonist and an antibody-cytokine fusion protein eradicates spontaneous tumor metastases [J]. Proc Natl Acad Sci USA. 1999, 96(4): 1591-1596