進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-2104201113355400
論文名稱(中文) 肝纖維化在促進肝癌生長的角色
論文名稱(英文) The Role of Liver Fibrosis in Enhancing Hepatoma Growth
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 99
學期 2
出版年 100
研究生(中文) 楊明臻
研究生(英文) Ming-Chen Yang
學號 s5895136
學位類別 博士
語文別 中文
論文頁數 103頁
口試委員 召集委員-楊倍昌
口試委員-胡承波
口試委員-陳立宗
口試委員-凌斌
口試委員-陳玉玲
指導教授-黎煥耀
中文關鍵字 肝纖維化  肝癌  星狀細胞  上皮間質轉換  刀豆素 
英文關鍵字 Liver fibrosis  Hepatoma  Hepatic stellate cells  Epithelial-mesenchymal transition  Concanavalin A 
學科別分類
中文摘要 肝癌目前位居國人十大癌症死因第二位,發生的原因與肝炎病毒的高感染率有相當密切的關係,在長期慢性肝炎的狀況下容易演變為肝纖維化,而嚴重的肝纖維化會變成肝硬化,加速肝癌的發生,在流行病學上肝炎-肝硬化-肝癌的關連性已被證實,然而肝纖維化與肝癌生長相互作用的分子機制尚不清楚,因此本研究即是針對肝纖維化在促進肝癌生長的角色做探討。利用藥物(Thioacetamide, TAA)引發肝纖維化,結合移植肝腫瘤細胞株(ML1)長成肝腫瘤的方式,建立一個能夠觀察肝纖維化及肝腫瘤細胞生長的平台,探討其相互作用的關係。經過不同實驗條件的測試,包括先引發肝纖維化、後引發肝纖維化及持續引發肝纖維化的三種動物模式,發現有肝纖維化誘發的情況下都會增加肝腫瘤細胞的生長。在肝纖維化結合肝腫瘤細胞的情況下肝臟中細胞激素(IFN-、IL-4、IL-6)含量下降,CD3+ T 細胞比例下降,利用組織免疫螢光染色發現在肝纖維化小鼠腫瘤中CD4+及CD8+ T細胞浸潤數目減少,如果以抗體剔除CD8+ T細胞,則腫瘤數目增加,顯示CD8+ T細胞參與抑制腫瘤的生長,但若剔除CD4+ T細胞,則腫瘤生長被抑制,浸潤至腫瘤的CD8+ T細胞也增加;而調節性T細胞會受肝纖維化誘導而產生,在肝纖維化的腫瘤內比例也增加,因此我們推論肝纖維化的環境透過增加調節性T細胞來抑制免疫反應而導致腫瘤生長加快。星狀細胞(hepatic stellate cell, HSC)在肝纖維化的過程已知扮演重要的角色,因此我們也探討星狀細胞參與在肝纖維化促進肝腫瘤細胞生長的角色,在肝纖維化合併肝腫瘤的小鼠肝組織切片中發現星狀細胞附近的組織有E-cadherin表現量下降的現象,如果將ML1合併大鼠星狀細胞株HSC-T6種植在背部,發現ML1更容易轉移到肺部,且轉移至肺的腫瘤中有上皮-間質轉換(epithelial-mesenchymal transition, EMT)的現象。為了進一步證實其中的機制,我們將HSC-T6的培養液加入ML1細胞,發現會引發ML1腫瘤細胞進行EMT,使上皮細胞特徵如E-cadherin表現減弱,轉變成為類似間質細胞的形態,並增加ML1移動的能力。利用質譜儀分析HSC-T6培養液中的成分,發現含大量的膠原蛋白。如果以siRNA降低HSC-T6第一型膠原蛋白的表現,可以降低星狀細胞培養液引起的上皮-間質轉換,若是加入第一型膠原蛋白會引發ML1細胞E-cadherin表現下降,顯示星狀細胞會經由分泌第一型膠原蛋白使ML1進行EMT。另外也嘗試利用刀豆素(Concanavalin A)來治療肝纖維化合併肝腫瘤的小鼠,Con A具有治療肝腫瘤的效果是透過引發免疫反應以及肝腫瘤細胞自噬(autophagy)的現象,我們更進一步發現Con A可以與內皮細胞作用,引發血管滲漏的現象,且對於肝纖維化合併肝腫瘤的小鼠也有治療效果。
英文摘要 Hepatocellular carcinoma (HCC) has the second highest mortality rate in Taiwan. The high prevalence of HCC is related to high infection rate of hepatitis viruses, especially HBV and HCV. The epidemiological studies have shown that persisting chronic hepatitis lead to liver fibrosis, cirrhosis, finally hepatocellular carcinoma formation. However, the mechanisms involved in the interaction between fibrosis and hepatoma are still unclear. The purpose of present study is to investigate whether fibrosis can enhance hepatoma growth and its possible mechanisms. First, we setup an in situ model by transplanting hepatoma cell line ML1 in BALB/c mice to form tumors in liver, combined with giving thioacetamide (TAA) to induce liver fibrosis. By creating a liver fibrosis and hepatoma co-existing animal model, we can evaluate the interaction between liver fibrosis and tumor growth. The result showed that comparing to hepatoma only mice, hepatoma and liver fibrosis co-existing group has more tumor nodules, and shorter surviving time, indicating that liver fibrotic induction will enhance the liver tumor growth and mortality. The cytokines including IFN-, IL-4, IL-6 and many other cytokines were decreased in fibrotic mice. The intrahepatic leukocyte was altered, the tumor infiltrating CD4+ and CD8+ T cells were decreased. The CD8+ T cell depletion increased the nodule numbers, whereas CD4+ T cell depletion decreased the tumor nodule numbers, suggesting that CD8+ T cells are the effector cells to tumor and CD4+ T cells will regulate the anti-tumor effect. Furthermore, regulatory T cells (Treg) with Foxp3 expression was found to increase in fibrotic liver combined with hepatoma growth. We conclude that regulatory CD4+ T cell contributed to the enhancement of heaptoma growth after fibrotic induction by downregulating the anti-tumor immune responses. The hepatic stellate cell (HSC) is known to play an important role in liver fibrosis, but its interaction with hepatoma cells is still unclear. The immunohistochemistry staining of TAA-ML1 liver tissue section showed that E-cadherin of tumor was down-regulated around HSC. In a subcutaneous tumor animal model, HSC combined with ML1 induces more metastatic tumor nodule in lung than ML1 alone. Furthermore, we found that the conditioned medium of HSC cell line HSC-T6 can trigger ML1 to undergo epithelial-mesenchymal transition (EMT), which makes ML1 loss epithelial marker E-cadherin, transform its morphology into mesenchymal-like, and enhance the migration activity. This suggests that HSC can induce ML1 to undergo EMT. The component in HSC conditioned medium was further analyzed. Collagen type I was found to be one of the major compound in conditioned medium of HSC-T6 by proteomic analysis. When collagen type I was knockdown in HSC-T6, its induction of EMT on ML1 cells was decreased. The collagen type I treated ML1 can induce EMT, suggesting that collagen type I contribute to HSC-induced EMT in ML1 cell. Finally, the therapeutic effect of Concanavalin A (Con A) on fibrosis combined with hepatoma mice was evaluated. We have reported that Con A can activate immune response and induce tumor cell autophagic death to inhibit hepatoma growth in vivo. We further found that Con A can bind to endothelial cell and induce endothelial cell damage. It can also partially inhibit hepatoma cell growth in fibrosis combined with hepatoma mice.
論文目次 考試合格證明 II
中文摘要 III
英文摘要 V
致謝 VII
總目錄 IX
圖目錄 XI
研究背景 1
研究目標 10
研究材料及方法 11
I. 實驗材料 11
抗體 11
試劑 13
塑膠耗材、玻璃製品 16
儀器 17
II. 實驗方法 18
細胞培養 19
實驗動物 19
小鼠肝纖維化及肝腫瘤動物模式 19
天狼星紅染色 20
傷口癒合分析 21
淋巴細胞生長及活化測試 21
肝組織中白血球分離 21
螢光免疫組織染色 22
細胞激素偵測 22
CD4/CD8細胞剔除實驗 23
細胞週期分析 23
小鼠背部腫瘤轉移模式 23
細胞轉染 23
羥脯氨酸含量測定 24
血漿滲出試驗 24
刀豆素結合試驗 24
西方墨點法 25
星狀細胞培養液收取 25
反轉錄聚合酶鏈式反應 25
實驗結果 28
肝纖維化及肝腫瘤小鼠模式之建立 28
免疫反應在肝纖維化促進肝腫瘤生長的角色 30
星狀細胞在肝纖維化促進肝腫瘤轉移的角色 34
刀豆素做為治療肝纖維化及肝腫瘤的治療藥物 38
討論 42
肝纖維化及肝腫瘤小鼠模式之建立 42
免疫反應在肝纖維化促進肝腫瘤生長的角色 43
星狀細胞在肝纖維化促進肝腫瘤轉移的角色 44
其他可能的作用機制 49
刀豆素做為治療肝纖維化及肝腫瘤的治療藥物 50
結論 52
參考文獻 53
圖 61
作者簡歷 102
參考文獻 1. Atzori L, Poli G, Perra A. Hepatic stellate cell: a star cell in the liver. Int J Biochem Cell Biol; 41:1639-42. 2009
2. Winau F, Hegasy G, Weiskirchen R, Weber S, Cassan C, Sieling PA, Modlin RL, Liblau RS, Gressner AM, Kaufmann SH. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity; 26:117-29. 2007
3. Yu MC, Chen CH, Liang X, Wang L, Gandhi CR, Fung JJ, Lu L, Qian S. Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice. Hepatology; 40:1312-21. 2004
4. Jiang G, Yang HR, Wang L, Wildey GM, Fung J, Qian S, Lu L. Hepatic stellate cells preferentially expand allogeneic CD4+ CD25+ FoxP3+ regulatory T cells in an IL-2-dependent manner. Transplantation; 86:1492-502. 2008
5. Lau AH, Thomson AW. Dendritic cells and immune regulation in the liver. Gut; 52:307-14. 2003
6. Selmi C, Mackay IR, Gershwin ME. The immunological milieu of the liver. Semin Liver Dis; 27:129-39. 2007
7. Klugewitz K, Adams DH, Emoto M, Eulenburg K, Hamann A. The composition of intrahepatic lymphocytes: shaped by selective recruitment? Trends Immunol; 25:590-4. 2004
8. Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology; 43:S54-62. 2006
9. Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology; 130:435-52. 2006
10. Muhanna N, Abu Tair L, Doron S, Amer J, Azzeh M, Mahamid M, Friedman S, Safadi R. Amelioration of hepatic fibrosis by NK cell activation. Gut; 60:90-8. 2011
11. Gale RP, Sparkes RS, Golde DW. Bone marrow origin of hepatic macrophages (Kupffer cells) in humans. Science; 201:937-8. 1978
12. Groux H, Bigler M, de Vries JE, Roncarolo MG. Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J Exp Med; 184:19-29. 1996
13. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, Lang R, Iredale JP. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest; 115:56-65. 2005
14. Syn WK, Oo YH, Pereira TA, Karaca GF, Jung Y, Omenetti A, Witek RP, Choi SS, Guy CD, Fearing CM, Teaberry V, Pereira FE, Adams DH, Diehl AM. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology; 51:1998-2007. 2010
15. Ishikawa S, Ikejima K, Yamagata H, Aoyama T, Kon K, Arai K, Takeda K, Watanabe S. CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice. J Hepatol 2010.
16. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol; 214:199-210. 2008
17. Shi Z, Wakil AE, Rockey DC. Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses. Proc Natl Acad Sci U S A; 94:10663-8. 1997
18. Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest; 117:539-48. 2007
19. Marquez M, Fernandez-Gutierrez C, Montes-de-Oca M, Blanco MJ, Brun F, Rodriguez-Ramos C, Giron-Gonzalez JA. Chronic antigenic stimuli as a possible explanation for the immunodepression caused by liver cirrhosis. Clin Exp Immunol; 158:219-29. 2009
20. Safadi R, Ohta M, Alvarez CE, Fiel MI, Bansal M, Mehal WZ, Friedman SL. Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes. Gastroenterology; 127:870-82. 2004
21. Novobrantseva TI, Majeau GR, Amatucci A, Kogan S, Brenner I, Casola S, Shlomchik MJ, Koteliansky V, Hochman PS, Ibraghimov A. Attenuated liver fibrosis in the absence of B cells. J Clin Invest; 115:3072-82. 2005
22. Rajkovic IA, Williams R. Abnormalities of neutrophil phagocytosis, intracellular killing and metabolic activity in alcoholic cirrhosis and hepatitis. Hepatology; 6:252-62. 1986
23. Morizane T, Watanabe T, Tsuchimoto K, Tsuchiya M. Impaired T cell function and decreased natural killer activity in patients with liver cirrhosis and their significance in the development of hepatocellular carcinoma. Gastroenterol Jpn; 15:226-32. 1980
24. Guarner C, Runyon BA, Young S, Heck M, Sheikh MY. Intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats with ascites. J Hepatol; 26:1372-8. 1997
25. Holdstock G, Ershler WB, Krawitt EL. Demonstration of non-specific B-cell stimulation in patients with cirrhosis. Gut; 23:724-8. 1982
26. Bralet MP, Regimbeau JM, Pineau P, Dubois S, Loas G, Degos F, Valla D, Belghiti J, Degott C, Terris B. Hepatocellular carcinoma occurring in nonfibrotic liver: epidemiologic and histopathologic analysis of 80 French cases. Hepatology; 32:200-4. 2000
27. Stroffolini T, Andreone P, Andriulli A, Ascione A, Craxi A, Chiaramonte M, Galante D, Manghisi OG, Mazzanti R, Medaglia C, Pilleri G, Rapaccini GL, Simonetti RG, Taliani G, Tosti ME, Villa E, Gasbarrini G. Characteristics of hepatocellular carcinoma in Italy. J Hepatol; 29:944-52. 1998
28. Okuda H. Hepatocellular carcinoma development in cirrhosis. Best Pract Res Clin Gastroenterol; 21:161-73. 2007
29. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology; 127:S35-50. 2004
30. Gang Z, Qi Q, Jing C, Wang C. Measuring microenvironment mechanical stress of rat liver during diethylnitrosamine induced hepatocarcinogenesis by atomic force microscope. Microsc Res Tech; 72:672-8. 2009
31. Kornek M, Raskopf E, Tolba R, Becker U, Klockner M, Sauerbruch T, Schmitz V. Accelerated orthotopic hepatocellular carcinomas growth is linked to increased expression of pro-angiogenic and prometastatic factors in murine liver fibrosis. Liver Int; 28:509-18. 2008
32. Kuriyama S, Yamazaki M, Mitoro A, Tsujimoto T, Kikukawa M, Tsujinoue H, Nakatani T, Toyokawa Y, Yoshiji H, Fukui H. Hepatocellular carcinoma in an orthotopic mouse model metastasizes intrahepatically in cirrhotic but not in normal liver. Int J Cancer; 80:471-6. 1999
33. Faouzi S, Le Bail B, Neaud V, Boussarie L, Saric J, Bioulac-Sage P, Balabaud C, Rosenbaum J. Myofibroblasts are responsible for collagen synthesis in the stroma of human hepatocellular carcinoma: an in vivo and in vitro study. J Hepatol; 30:275-84. 1999
34. Ju MJ, Qiu SJ, Fan J, Xiao YS, Gao Q, Zhou J, Li YW, Tang ZY. Peritumoral activated hepatic stellate cells predict poor clinical outcome in hepatocellular carcinoma after curative resection. Am J Clin Pathol; 131:498-510. 2009
35. Sancho-Bru P, Juez E, Moreno M, Khurdayan V, Morales-Ruiz M, Colmenero J, Arroyo V, Brenner DA, Gines P, Bataller R. Hepatocarcinoma cells stimulate the growth, migration and expression of pro-angiogenic genes in human hepatic stellate cells. Liver Int; 30:31-41. 2010
36. Taura K, De Minicis S, Seki E, Hatano E, Iwaisako K, Osterreicher CH, Kodama Y, Miura K, Ikai I, Uemoto S, Brenner DA. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology; 135:1729-38. 2008
37. Amann T, Bataille F, Spruss T, Muhlbauer M, Gabele E, Scholmerich J, Kiefer P, Bosserhoff AK, Hellerbrand C. Activated hepatic stellate cells promote tumorigenicity of hepatocellular carcinoma. Cancer Sci; 100:646-53. 2009
38. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest; 119:1429-37. 2009
39. Kolsch V, Seher T, Fernandez-Ballester GJ, Serrano L, Leptin M. Control of Drosophila gastrulation by apical localization of adherens junctions and RhoGEF2. Science; 315:384-6. 2007
40. Nitta T, Kim JS, Mohuczy D, Behrns KE. Murine cirrhosis induces hepatocyte epithelial mesenchymal transition and alterations in survival signaling pathways. Hepatology; 48:909-19. 2008
41. Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A; 103:13180-5. 2006
42. Prall F, Weirich V, Ostwald C. Phenotypes of invasion in sporadic colorectal carcinomas related to aberrations of the adenomatous polyposis coli (APC ) gene. Histopathology; 50:318-30. 2007
43. Ahmed N, Abubaker K, Findlay J, Quinn M. Epithelial mesenchymal transition and cancer stem cell-like phenotypes facilitate chemoresistance in recurrent ovarian cancer. Curr Cancer Drug Targets; 10:268-78. 2010
44. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest; 119:1420-8. 2009
45. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell; 139:871-90. 2009
46. Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E. TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev; 10:2462-77. 1996
47. Lu Z, Ghosh S, Wang Z, Hunter T. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell; 4:499-515. 2003
48. Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P, Donovan M, Cordon-Cardo C, Beug H, Grunert S. Autocrine PDGFR signaling promotes mammary cancer metastasis. J Clin Invest; 116:1561-70. 2006
49. Shintani Y, Maeda M, Chaika N, Johnson KR, Wheelock MJ. Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-beta signaling. Am J Respir Cell Mol Biol; 38:95-104. 2008
50. Medici D, Nawshad A. Type I collagen promotes epithelial-mesenchymal transition through ILK-dependent activation of NF-kappaB and LEF-1. Matrix Biol; 29:161-5. 2010
51. Chang CP, Yang MC, Liu HS, Lin YS, Lei HY. Concanavalin A induces autophagy in hepatoma cells and has a therapeutic effect in a murine in situ hepatoma model. Hepatology; 45:286-96. 2007
52. El-Karef A, Yoshida T, Gabazza EC, Nishioka T, Inada H, Sakakura T, Imanaka-Yoshida K. Deficiency of tenascin-C attenuates liver fibrosis in immune-mediated chronic hepatitis in mice. J Pathol; 211:86-94. 2007
53. Miyagi T, Takehara T, Tatsumi T, Suzuki T, Jinushi M, Kanazawa Y, Hiramatsu N, Kanto T, Tsuji S, Hori M, Hayashi N. Concanavalin a injection activates intrahepatic innate immune cells to provoke an antitumor effect in murine liver. Hepatology; 40:1190-6. 2004
54. Jeong WI, Park O, Radaeva S, Gao B. STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell proliferation and stimulating NK cell cytotoxicity. Hepatology; 44:1441-51. 2006
55. Ledda-Columbano GM, Coni P, Curto M, Giacomini L, Faa G, Oliverio S, Piacentini M, Columbano A. Induction of two different modes of cell death, apoptosis and necrosis, in rat liver after a single dose of thioacetamide. Am J Pathol; 139:1099-109. 1991
56. Winau F, Quack C, Darmoise A, Kaufmann SH. Starring stellate cells in liver immunology. Curr Opin Immunol; 20:68-74. 2008
57. Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin CH, Moustakas A. Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition. J Cell Biol; 174:175-83. 2006
58. He J, Baum LG. Presentation of galectin-1 by extracellular matrix triggers T cell death. J Biol Chem; 279:4705-12. 2004
59. Ruffell B, Johnson P. Hyaluronan induces cell death in activated T cells through CD44. J Immunol; 181:7044-54. 2008
60. Meyaard L. The inhibitory collagen receptor LAIR-1 (CD305). J Leukoc Biol; 83:799-803. 2008
61. Buttner C, Skupin A, Reimann T, Rieber EP, Unteregger G, Geyer P, Frank KH. Local production of interleukin-4 during radiation-induced pneumonitis and pulmonary fibrosis in rats: macrophages as a prominent source of interleukin-4. Am J Respir Cell Mol Biol; 17:315-25. 1997
62. Fertin C, Nicolas JF, Gillery P, Kalis B, Banchereau J, Maquart FX. Interleukin-4 stimulates collagen synthesis by normal and scleroderma fibroblasts in dermal equivalents. Cell Mol Biol; 37:823-9. 1991
63. Yang L, Pang Y, Moses HL. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol; 31:220-7. 2010
64. Zhang HH, Mei MH, Fei R, Liao WJ, Wang XY, Qin LL, Wang JH, Wei L, Chen HS. Regulatory T cell depletion enhances tumor specific CD8 T-cell responses, elicited by tumor antigen NY-ESO-1b in hepatocellular carcinoma patients, in vitro. Int J Oncol; 36:841-8. 2010
65. Cao M, Cabrera R, Xu Y, Firpi R, Zhu H, Liu C, Nelson DR. Hepatocellular carcinoma cell supernatants increase expansion and function of CD4(+)CD25(+) regulatory T cells. Lab Invest; 87:582-90. 2007
66. Chen CH, Kuo LM, Chang Y, Wu W, Goldbach C, Ross MA, Stolz DB, Chen L, Fung JJ, Lu L, Qian S. In vivo immune modulatory activity of hepatic stellate cells in mice. Hepatology; 44:1171-81. 2006
67. Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, Kalluri R. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem; 282:23337-47. 2007
68. Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS, Witek RP, Alpini G, Venter J, Vandongen HM, Syn WK, Baroni GS, Benedetti A, Schuppan D, Diehl AM. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest; 118:3331-42. 2008
69. Cai Z, Wang Q, Zhou Y, Zheng L, Chiu JF, He QY. Epidermal growth factor-induced epithelial-mesenchymal transition in human esophageal carcinoma cells--a model for the study of metastasis. Cancer Lett; 296:88-95. 2010
70. Nagai T, Arao T, Furuta K, Sakai K, Kudo K, Kaneda H, Tamura D, Aomatsu K, Kimura H, Fujita Y, Matsumoto K, Saijo N, Kudo M, Nishio K. Sorafenib inhibits the hepatocyte growth factor-mediated epithelial mesenchymal transition in hepatocellular carcinoma. Mol Cancer Ther; 10:169-77. 2011
71. Chow G, Tauler J, Mulshine JL. Cytokines and growth factors stimulate hyaluronan production: role of hyaluronan in epithelial to mesenchymal-like transition in non-small cell lung cancer. J Biomed Biotechnol; 2010:485468. 2010
72. Leroy P, Mostov KE. Slug is required for cell survival during partial epithelial-mesenchymal transition of HGF-induced tubulogenesis. Mol Biol Cell; 18:1943-52. 2007
73. Rasanen K, Vaheri A. TGF-beta1 causes epithelial-mesenchymal transition in HaCaT derivatives, but induces expression of COX-2 and migration only in benign, not in malignant keratinocytes. J Dermatol Sci; 58:97-104. 2010
74. Zhang K, Chen D, Jiao X, Zhang S, Liu X, Cao J, Wu L, Wang D. Slug enhances invasion ability of pancreatic cancer cells through upregulation of matrix metalloproteinase-9 and actin cytoskeleton remodeling. Lab Invest 2011.
75. Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol; 172:973-81. 2006
76. Kikuta K, Masamune A, Watanabe T, Ariga H, Itoh H, Hamada S, Satoh K, Egawa S, Unno M, Shimosegawa T. Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells. Biochem Biophys Res Commun; 403:380-4. 2010
77. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell; 133:704-15. 2008
78. Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One; 3:e2888. 2008
79. Wei J, Barr J, Kong LY, Wang Y, Wu A, Sharma AK, Gumin J, Henry V, Colman H, Sawaya R, Lang FF, Heimberger AB. Glioma-associated cancer-initiating cells induce immunosuppression. Clin Cancer Res; 16:461-73. 2010
80. Wu A, Wei J, Kong LY, Wang Y, Priebe W, Qiao W, Sawaya R, Heimberger AB. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro Oncol; 12:1113-25. 2010
81. Rasanen K, Vaheri A. Activation of fibroblasts in cancer stroma. Exp Cell Res; 316:2713-22. 2010
82. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer; 6:392-401. 2006
83. Giannoni E, Bianchini F, Masieri L, Serni S, Torre E, Calorini L, Chiarugi P. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res; 70:6945-56. 2010
84. Direkze NC, Hodivala-Dilke K, Jeffery R, Hunt T, Poulsom R, Oukrif D, Alison MR, Wright NA. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res; 64:8492-5. 2004
85. Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res; 67:10123-8. 2007
86. Ulrich TA, de Juan Pardo EM, Kumar S. The mechanical rigidity of the extracellular matrix regulates the structure, motility, and proliferation of glioma cells. Cancer Res; 69:4167-74. 2009
87. Kimura K, Ando K, Ohnishi H, Ishikawa T, Kakumu S, Takemura M, Muto Y, Moriwaki H. Immunopathogenesis of hepatic fibrosis in chronic liver injury induced by repeatedly administered concanavalin A. Int Immunol; 11:1491-500. 1999
88. Galbraith SM, Chaplin DJ, Lee F, Stratford MR, Locke RJ, Vojnovic B, Tozer GM. Effects of combretastatin A4 phosphate on endothelial cell morphology in vitro and relationship to tumour vascular targeting activity in vivo. Anticancer Res; 21:93-102. 2001
89. Zhao L, Ching LM, Kestell P, Kelland LR, Baguley BC. Mechanisms of tumor vascular shutdown induced by 5,6-dimethylxanthenone-4-acetic acid (DMXAA): Increased tumor vascular permeability. Int J Cancer; 116:322-6. 2005
90. Xiong YQ, Sun HC, Zhang W, Zhu XD, Zhuang PY, Zhang JB, Wang L, Wu WZ, Qin LX, Tang ZY. Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells. Clin Cancer Res; 15:4838-46. 2009
91. Jain RK. Molecular regulation of vessel maturation. Nat Med; 9:685-93. 2003
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2012-04-25起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw