請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/40836完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 郭明良(Min-Liang Kuo) | |
| dc.contributor.author | Wan-Ching Chung | en |
| dc.contributor.author | 鍾宛瑾 | zh_TW |
| dc.date.accessioned | 2021-06-14T17:02:40Z | - |
| dc.date.available | 2018-07-28 | |
| dc.date.copyright | 2008-09-11 | |
| dc.date.issued | 2008 | |
| dc.date.submitted | 2008-07-28 | |
| dc.identifier.citation | 1. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407(6801):249-57.
2. Carmeliet P. Angiogenesis in life, disease and medicine. Nature 2005;438(7070):932-6. 3. Carmeliet P, Tessier-Lavigne M. Common mechanisms of nerve and blood vessel wiring. Nature 2005;436(7048):193-200. 4. Matsumoto T, Claesson-Welsh L. VEGF receptor signal transduction. Sci STKE 2001;2001(112):RE21. 5. Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 2007;8(6):464-78. 6. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. Faseb J 1999;13(1):9-22. 7. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 1989;246(4935):1309-12. 8. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989;246(4935):1306-9. 9. Myoken Y, Kayada Y, Okamoto T, Kan M, Sato GH, Sato JD. Vascular endothelial cell growth factor (VEGF) produced by A-431 human epidermoid carcinoma cells and identification of VEGF membrane binding sites. Proc Natl Acad Sci U S A 1991;88(13):5819-23. 10. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9(6):669-76. 11. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 1991;266(18):11947-54. 12. Feng D, Nagy JA, Dvorak HF, Dvorak AM. Ultrastructural studies define soluble macromolecular, particulate, and cellular transendothelial cell pathways in venules, lymphatic vessels, and tumor-associated microvessels in man and animals. Microsc Res Tech 2002;57(5):289-326. 13. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983;219(4587):983-5. 14. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 2006;7(5):359-71. 15. Masson-Gadais B, Houle F, Laferriere J, Huot J. Integrin alphavbeta3, requirement for VEGFR2-mediated activation of SAPK2/p38 and for Hsp90-dependent phosphorylation of focal adhesion kinase in endothelial cells activated by VEGF. Cell Stress Chaperones 2003;8(1):37-52. 16. Poltorak Z, Cohen T, Sivan R, Kandelis Y, Spira G, Vlodavsky I, Keshet E, Neufeld G. VEGF145, a secreted vascular endothelial growth factor isoform that binds to extracellular matrix. J Biol Chem 1997;272(11):7151-8. 17. Lei J, Jiang A, Pei D. Identification and characterization of a new splicing variant of vascular endothelial growth factor: VEGF183. Biochim Biophys Acta 1998;1443(3):400-6. 18. Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 1992;267(36):26031-7. 19. Yi T, Yi Z, Cho SG, Luo J, Pandey MK, Aggarwal BB, Liu M. Gambogic acid inhibits angiogenesis and prostate tumor growth by suppressing vascular endothelial growth factor receptor 2 signaling. Cancer Res 2008;68(6):1843-50. 20. Quinn TP, Peters KG, De Vries C, Ferrara N, Williams LT. Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci U S A 1993;90(16):7533-7. 21. Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 1994;269(43):26988-95. 22. Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 2007;6(4):273-86. 23. Gimbrone MA, Jr., Cotran RS, Folkman J. Human vascular endothelial cells in culture. Growth and DNA synthesis. J Cell Biol 1974;60(3):673-84. 24. Langer R, Folkman J. Polymers for the sustained release of proteins and other macromolecules. Nature 1976;263(5580):797-800. 25. Gimbrone MA, Jr., Cotran RS, Leapman SB, Folkman J. Tumor growth and neovascularization: an experimental model using the rabbit cornea. J Natl Cancer Inst 1974;52(2):413-27. 26. Auerbach R, Arensman R, Kubai L, Folkman J. Tumor-induced angiogenesis: lack of inhibition by irradiation. Int J Cancer 1975;15(2):241-5. 27. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285(21):1182-6. 28. Ausprunk DH, Falterman K, Folkman J. The sequence of events in the regression of corneal capillaries. Lab Invest 1978;38(3):284-94. 29. Maeshima Y, Sudhakar A, Lively JC, Ueki K, Kharbanda S, Kahn CR, Sonenberg N, Hynes RO, Kalluri R. Tumstatin, an endothelial cell-specific inhibitor of protein synthesis. Science 2002;295(5552):140-3. 30. O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994;79(2):315-28. 31. Frater-Schroder M, Risau W, Hallmann R, Gautschi P, Bohlen P. Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Proc Natl Acad Sci U S A 1987;84(15):5277-81. 32. Folkman J. Endogenous angiogenesis inhibitors. Apmis 2004;112(7-8):496-507. 33. Nyberg P, Xie L, Kalluri R. Endogenous inhibitors of angiogenesis. Cancer Res 2005;65(10):3967-79. 34. Zhang Y, Kensler TW, Cho CG, Posner GH, Talalay P. Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc Natl Acad Sci U S A 1994;91(8):3147-50. 35. Timar J, Dome B, Fazekas K, Janovics A, Paku S. Angiogenesis-dependent diseases and angiogenesis therapy. Pathol Oncol Res 2001;7(2):85-94. 36. Romanque P, Piguet AC, Dufour JF. Targeting vessels to treat hepatocellular carcinoma. Clin Sci (Lond) 2008;114(7):467-77. 37. Bruix J. Treatment of hepatocellular carcinoma. Hepatology 1997;25(2):259-62. 38. Yamagoe S, Yamakawa Y, Matsuo Y, Minowada J, Mizuno S, Suzuki K. Purification and primary amino acid sequence of a novel neutrophil chemotactic factor LECT2. Immunol Lett 1996;52(1):9-13. 39. Yamagoe S, Mizuno S, Suzuki K. Molecular cloning of human and bovine LECT2 having a neutrophil chemotactic activity and its specific expression in the liver. Biochim Biophys Acta 1998;1396(1):105-13. 40. Nagai H, Hamada T, Uchida T, Yamagoe S, Suzuki K. Systemic expression of a newly recognized protein, LECT2, in the human body. Pathol Int 1998;48(11):882-6. 41. Hiraki Y, Inoue H, Kondo J, Kamizono A, Yoshitake Y, Shukunami C, Suzuki F. A novel growth-promoting factor derived from fetal bovine cartilage, chondromodulin II. Purification and amino acid sequence. J Biol Chem 1996;271(37):22657-62. 42. Shukunami C, Kondo J, Wakai H, Takahashi K, Inoue H, Kamizono A, Hiraki Y. Molecular cloning of mouse and bovine chondromodulin-II cDNAs and the growth-promoting actions of bovine recombinant protein. J Biochem 1999;125(3):436-42. 43. Kameoka Y, Yamagoe S, Hatano Y, Kasama T, Suzuki K. Val58Ile polymorphism of the neutrophil chemoattractant LECT2 and rheumatoid arthritis in the Japanese population. Arthritis Rheum 2000;43(6):1419-20. 44. Yamagoe S, Akasaka T, Uchida T, Hachiya T, Okabe T, Yamakawa Y, Arai T, Mizuno S, Suzuki K. Expression of a neutrophil chemotactic protein LECT2 in human hepatocytes revealed by immunochemical studies using polyclonal and monoclonal antibodies to a recombinant LECT2. Biochem Biophys Res Commun 1997;237(1):116-20. 45. Sato Y, Watanabe H, Kameyama H, Kobayashi T, Yamamoto S, Takeishi T, Hirano K, Oya H, Nakatsuka H, Watanabe T, Kokai H, Yamagoe S, Suzuki K, Oya K, Kojima K, Hatakeyama K. Changes in serum LECT 2 levels during the early period of liver regeneration after adult living related donor liver transplantation. Transplant Proc 2004;36(8):2357-8. 46. Saito T, Okumura A, Watanabe H, Asano M, Ishida-Okawara A, Sakagami J, Sudo K, Hatano-Yokoe Y, Bezbradica JS, Joyce S, Abo T, Iwakura Y, Suzuki K, Yamagoe S. Increase in hepatic NKT cells in leukocyte cell-derived chemotaxin 2-deficient mice contributes to severe concanavalin A-induced hepatitis. J Immunol 2004;173(1):579-85. 47. Uchida T, Nagai H, Gotoh K, Kanagawa H, Kouyama H, Kawanishi T, Mima S, Yamagoe S, Suzuki K. Expression pattern of a newly recognized protein, LECT2, in hepatocellular carcinoma and its premalignant lesion. Pathol Int 1999;49(2):147-51. 48. Xiao D, Singh SV. Phenethyl isothiocyanate inhibits angiogenesis in vitro and ex vivo. Cancer Res 2007;67(5):2239-46. 49. Lamy S, Ruiz MT, Wisniewski J, Garde S, Rabbani SA, Panchal C, Wu JJ, Annabi B. A prostate secretory protein94-derived synthetic peptide PCK3145 inhibits VEGF signalling in endothelial cells: implication in tumor angiogenesis. Int J Cancer 2006;118(9):2350-8. 50. Crum R, Szabo S, Folkman J. A new class of steroids inhibits angiogenesis in the presence of heparin or a heparin fragment. Science 1985;230(4732):1375-8. 51. Nguyen M, Shing Y, Folkman J. Quantitation of angiogenesis and antiangiogenesis in the chick embryo chorioallantoic membrane. Microvasc Res 1994;47(1):31-40. 52. Miles AA, Miles EM. Vascular reactions to histamine, histamine-liberator and leukotaxine in the skin of guinea-pigs. J Physiol 1952;118(2):228-57. 53. Flamme I, von Reutern M, Drexler HC, Syed-Ali S, Risau W. Overexpression of vascular endothelial growth factor in the avian embryo induces hypervascularization and increased vascular permeability without alterations of embryonic pattern formation. Dev Biol 1995;171(2):399-414. 54. Witte L, Hicklin DJ, Zhu Z, Pytowski B, Kotanides H, Rockwell P, Bohlen P. Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. Cancer Metastasis Rev 1998;17(2):155-61. 55. Banerjee S, Dowsett M, Ashworth A, Martin LA. Mechanisms of disease: angiogenesis and the management of breast cancer. Nat Clin Pract Oncol 2007;4(9):536-50. 56. Folkman J. Tumor suppression by p53 is mediated in part by the antiangiogenic activity of endostatin and tumstatin. Sci STKE 2006;2006(354):pe35. 57. Griscelli F, Li H, Bennaceur-Griscelli A, Soria J, Opolon P, Soria C, Perricaudet M, Yeh P, Lu H. Angiostatin gene transfer: inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest. Proc Natl Acad Sci U S A 1998;95(11):6367-72. 58. Folkman J, D'Amore PA. Blood vessel formation: what is its molecular basis? Cell 1996;87(7):1153-5. 59. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86(3):353-64. 60. Hori A, Sasada R, Matsutani E, Naito K, Sakura Y, Fujita T, Kozai Y. Suppression of solid tumor growth by immunoneutralizing monoclonal antibody against human basic fibroblast growth factor. Cancer Res 1991;51(22):6180-4. 61. O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997;88(2):277-85. 62. Hanahan D, Christofori G, Naik P, Arbeit J. Transgenic mouse models of tumour angiogenesis: the angiogenic switch, its molecular controls, and prospects for preclinical therapeutic models. Eur J Cancer 1996;32A(14):2386-93. 63. Skobe M, Rockwell P, Goldstein N, Vosseler S, Fusenig NE. Halting angiogenesis suppresses carcinoma cell invasion. Nat Med 1997;3(11):1222-7. 64. Satchi-Fainaro R, Mamluk R, Wang L, Short SM, Nagy JA, Feng D, Dvorak AM, Dvorak HF, Puder M, Mukhopadhyay D, Folkman J. Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin. Cancer Cell 2005;7(3):251-61. 65. Ryeom S, Baek KH, Rioth MJ, Lynch RC, Zaslavsky A, Birsner A, Yoon SS, McKeon F. Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth. Cancer Cell 2008;13(5):420-31. 66. Karkkainen MJ, Petrova TV. Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 2000;19(49):5598-605. 67. Hong KH, Yoo SA, Kang SS, Choi JJ, Kim WU, Cho CS. Hypoxia induces expression of connective tissue growth factor in scleroderma skin fibroblasts. Clin Exp Immunol 2006;146(2):362-70. 68. Dai X, Cui SG, Wang T, Liu Q, Song HJ, Wang R. Endogenous opioid peptides, endomorphin-1 and -2 and deltorphin I, stimulate angiogenesis in the CAM assay. Eur J Pharmacol 2008;579(1-3):269-75. 69. Carmeliet P, Collen D. Molecular basis of angiogenesis. Role of VEGF and VE-cadherin. Ann N Y Acad Sci 2000;902:249-62; discussion 62-4. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/40836 | - |
| dc.description.abstract | 血管新生與癌症發展有密切的關聯，血管新生是一種生理過程，主要作用來自於血管最內層的內皮細胞。當內皮細胞受到血管新生物質的活化而產生細胞增生、移動、萌芽並進一步重組形成新的血管，藉此提供腫瘤生長所需之養分。若能找出抑制血管新生作用之蛋白分子，對於癌症治療將有重大突破。實驗室先前研究利用生物晶片技術(microarray)，找到調控肝癌血管侵犯表現的基因 (leukocyte cell-derived chemotaxin 2，LECT2)。分析127名肝癌病人發現LECT2表現量與腫瘤大小呈現逆相關，進一步以動物實驗與雞胚胎卵黃囊試驗法(chicken chorioallantoic membrane，CAM assay)，發現LECT2具有抑制肝癌腫瘤生成與血管形成之作用。故本實驗欲探討LECT2是否會標的血管內皮細胞，影響血管新生物質誘發血管新生的作用，進一步廣泛性的探討LECT2於多種癌細胞株之血管新生的角色。
本研究以VEGF165為誘發因子，結果顯示LECT2重組蛋白能減少VEGF165所誘發血管內皮生長因子接受器2 (VEGFR2) 磷酸化而抑制下游ERK及AKT的訊息傳遞途徑，使內皮細胞的增生、移動與新生血管的能力下降。此外，CAM assay 與小黑鼠體內血管新生的實驗(Matrigel Plug assay)，同樣觀察到LECT2重組蛋白抑制VEGF165所誘發血管生成。在血管滲透的研究發現，無論在in vitro或in vivo實驗模式皆證明LECT2重組蛋白可以降低VEGF165所誘發的血管滲透作用。收集不同種類癌細胞株的細胞培養液與LECT2重組蛋白處理於內皮細胞，結果顯示LECT2重組蛋白能抑制SK-Hep1肝癌細胞、A549肺癌細胞、MCF-7乳癌細胞以及B16F1小鼠黑色素瘤細胞之血管新生。進一步在B16F1細胞株穩定表現LECT2，結果發現可抑制腫瘤血管增生、降低腫瘤血管密度以達到抑制腫瘤生長的效果。 本研究首先證實LECT2可以直接影響內皮細胞，抑制VEGF165所誘發之血管生成，同時減少腫瘤血管新生之現象。由本研究之結果，更明確闡述LECT2在抗血管新生的角色上所具有的生物效應與作用機轉，此結果對於腫瘤的臨床治療與應用勢必具相當大的潛力與期待，未來進一步將LECT2發展成為蛋白質類藥物，以應用在抗血管新生作用的癌症治療上。 | zh_TW |
| dc.description.abstract | Angiogenesis is a process of new blood vessel formation which has essential roles in development, reproduction and repair. In our previous studies, several that the leukocyte cell-derived chemotaxin 2 (LECT2) gene expression was down-regulated with vascular invasion. The levels of LECT2 are clearly correlated with regulating tumor size and overall survival of HCC patients. Using CAM assay, we found that LECT2-transfected cells conditioned media exhibited extremely low angiogenic activity as compared to control cells. This result suggesting that LECT2 may down-regulate certain angiogenic factors. Hence we proposed to investigate the molecular mechanism underlying LECT2 mediated anti-angiogenic factors-induced angiogenesis in vitro and in vivo. Further, we also observed report the expression of LECT2 in others cancer cells.
In this study we evaluated the function of recombinant human LECT2 (rLECT2) proteins on angiogenesis by using human umbilical vein endothelial cells (HUVEC). We demonstrated a selective and significant inhibition of VEGF165 mediated angiogenic activity in HUVEC by rLECT2 protein through inhibiting the VEGF165-induced proliferation, migration and tube formation. The rLECT2 protein also suppressed VEGF165-induced angiogenesis in CAM assay and matrigel plug assay. Both in vitro and in vivo, we found that LECT2 suppressed the VEGF165-induced vascular permeability. Our results demonstrated that rLECT2 protein could reduce the VEGF165-induced VEGFR-2 phosphorylation and inhibited the expression of downstream ERK and AKT phosphorylation in HUVEC. In addition, rLECT2 protein reduced cancer cell conditioned media-induced tube formation in HUVEC and LECT2 also decreased tumor growth of melanoma cells. In conclusion, we for the first time found that LECT2 played an important role in anti-angiogenesis. Moreover the LECT2 might have broad therapeutic applications in diseases characterized by excessive angiogenesis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-14T17:02:40Z (GMT). No. of bitstreams: 1 ntu-97-R95447002-1.pdf: 2503081 bytes, checksum: fb4d97a073867eb2eda682a10a8f9080 (MD5) Previous issue date: 2008 | en |
| dc.description.tableofcontents | 中文摘要2
Abstract3 Introduction4 Materials and Methods8 Results16 •Purification of recombinant human LECT2 (rLECT2) proteins16 •rLECT2 protein reduced angiogenic factors-induced migration in HUVEC 16 •rLECT2 protein extremely inhibited VEGF165-induced tube formation in HUVEC 16 •rLECT2 protein inhibited VEGF165-induced HUVEC proliferation17 •rLECT2 protein inhibited VEGF165-induced migration in HUVEC17 •rLECT2 protein reduced the VEGF165-induced tube formation in HUVEC17 •rLECT2 protein suppressed VEGF165-induced angiogenesis in CAM assay 18 •rLECT2 protein inhibited VEGF165-induced angiogenesis in Matrigel plag assay18 •rLECT2 protein suppressed VEGF165-stimulated vascular permeability in vitro and in vivo19 •rLECT2 protein inhibited VEGF165-induced VEGFR-2 phosphorylation in HUVEC19 •rLECT2 protein reduced cancer cell conditioned medium-induced tube formation in HUVEC20 •Ectopic expression of LECT2 in B16 melanoma cells21 Discussion22 Reference 27 Figure and figure legends33 | |
| dc.language.iso | en | |
| dc.subject | 血管新生 | zh_TW |
| dc.subject | 內皮細胞 | zh_TW |
| dc.subject | 白血球趨化蛋白2 | zh_TW |
| dc.subject | leukocyte cell-derived chemotaxin 2 | en |
| dc.subject | angiogenesis | en |
| dc.subject | endothelial cells | en |
| dc.title | 探討Leukocyte Cell-Derived Chemotaxin 2 (LECT2) 對於血管內皮生長因子誘發血管新生之影響 | zh_TW |
| dc.title | Effects of Leukocyte Cell-Derived Chemotaxin 2 (LECT2) on VEGF165-Induced Angiogenesis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 96-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 夏興國(Shine-Gwo Shiah),朱家瑜(Chia-Yu Chu) | |
| dc.subject.keyword | 血管新生,內皮細胞,白血球趨化蛋白2, | zh_TW |
| dc.subject.keyword | angiogenesis,endothelial cells,leukocyte cell-derived chemotaxin 2, | en |
| dc.relation.page | 50 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2008-07-29 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-97-1.pdf 未授權公開取用 | 2.44 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。