進階搜尋


  查詢北醫館藏
系統識別號 U0007-2201201001482700
論文名稱(中文) 化學治療誘發之胰臟間質細胞早發老化對胰臟腺癌復發及抗藥性之異源性影響
論文名稱(英文) The Heterotypic Influences on Chemotherapeutic Agent-induced Prematurely Senescent Stromal Cells on the Malignant Progression of Pancreatic Adenocarcinoma
校院名稱 臺北醫學大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Graduate Institute of Clinical Medicine
學年度 98
學期 1
出版年 99
研究生(中文) 張智翔
研究生(英文) Tze Sian Chan
電子信箱 tzesian@wanfang.gov.tw
學號 M118096003
學位類別 碩士
語文別 英文
口試日期 2009-12-30
論文頁數 78頁
口試委員 委員-王育民
委員-李宗儒
委員-賴文福
共同指導教授-蔡坤志
指導教授-連吉時
中文關鍵字 胰臟癌  基質  微環境  星狀細胞  化學治療  細胞老化 
英文關鍵字 pancreatic cancer  stroma  microenvironments  stellate cells  chemotherapy  senescence. 
學科別分類
中文摘要 背景:腫瘤基質的微環境 (Microenvironment) 會極度影響上皮腫瘤發生的許多步驟。胰臟星狀細胞 (Pancreatic stellate cells) 是造成胰臟腺癌腫瘤纖維化基質 (Desmoplastic stroma) 微環境的主要原因。胰臟星狀細胞和腫瘤細胞間的異源交互作用 (Heterotypic interaction) 在腫瘤的惡性進展 (Malignant progression) 過程也扮演著重要的角色。最近的研究發現,胰臟星狀細胞會被因暴露於低於致死的傷源(如游離輻射及細胞毒性之化學治療藥物)後被誘發進行類似於細胞老化 (Cell senescence) 的變化。更有趣的是,表現這種壓力誘發性早發細胞老化 (Stress-induced premature senescence) 的細胞也會藉由分泌蛋白及細胞外蛋白來對鄰近細胞產生旁分泌作用。延續這種說法,壓力誘發性早發細胞老化之基質纖維細胞也被證實能夠促進多種人類腺體腫瘤的成長及侵犯。

目的:我們假設壓力誘發性早發老化之胰臟星狀細胞在接受臨床使用之化學治療藥物劑量後會累積於胰臟的基質組織,進而逐漸形成一個允許胰臟癌產生抗藥及覆發之惡性腫瘤進展的允許微環境 (Permissive microenvironments)。

方法和結果:在臨床使用劑量下,胰臟星狀細胞確實可以藉由不同種類的細胞毒性化學治療藥物導致壓力誘發之早發老化之特質。在所有的藥物中,Gemcitabine在其臨床使用劑量(10μM x 30分鐘)最能有效地促成早發老化之表現。利用基因體的分析方式,我們發現壓力誘發性早發老化之胰臟星狀細胞能夠調增和壓力、傷口癒合及細胞凋零相關基因的表現。更重要的是,壓力誘發性早發老化之胰臟星狀細胞更會製造多種和細胞素卅趨化素之訊息傳遞及細胞間質重塑相關之蛋白。我們也進一步的利用三次元細胞共同培養之模式證明了早發老化之胰臟星狀細胞對腫瘤惡性進展的促成。為了進一步證實活體外之發現,當被和胰臟癌細胞同時被植入有免疫缺陷的老鼠時,早發老化之胰臟星狀細胞確實能促進腫瘤的發展。
結論:我們的觀察發現,當胰臟星狀細胞受到細胞毒性化學藥物的反覆暴露後,特別是gemcitabine,星狀細胞可以被誘發類似老化之顯性特徵。壓力誘發性早發老化之胰臟星狀細胞不管在活體外或體內的條件之下均可產生一個類似於傷口癒合過程且有利於腫瘤發展的微允許環境。胰臟星狀細胞和胰癌細胞之間的異源交互作用或許是胰臟癌在治療抗性之機轉,同時也可能成為未來潛在的治療靶標。
英文摘要 Background: The stromal microenvironments in which tumors develop profoundly influence many steps of epithelial tumorigenesis. Pancreatic stellate cells (PaSCs) are the major contributors of the desmoplastic stromal microenvironment of pancreatic adenocarcinoma and play a crucial role in malignant progression through their heterotypic interactions with tumor cells. Recent evidence suggests that cells may develop a senescent-like growth arrest program when they are exposed to sub-lethal injuries such as ionizing radiation and/or cytotoxic agents. Intriguingly, cells displaying this stress-induced premature senescence (SIPS) phenotype can elicit paracrine signaling through their induced production of a variety of secretory factors and extracellular proteins. Along this line, SIPS stromal fibroblasts have been shown to promote tumor growth and invasion in several types of human glandular malignancies,

Aim: We hypothesize that SIPS PaSCs may accumulate in the pancreatic stroma over time following cytotoxic chemotherapies at a clinically relevant manner and which may gradually create more permissive microenvironments for the ensuing malignant progression of treatment-resistant or relapsing pancreatic cancers.

Result: A SIPS phenotype was induced in PaSCs by different cytotoxic chemotherapeutic agents that have been used clinically for the treatment of pancreatic cancer. Among them, gemcitabine was most effective in the induction of the SIPS phenotype, which occurred at clinically relevant concentrations (10 μM for 30 minutes). Using genomic profiling approach, we show that SIPS PaSCs upregulated the expressions of several groups of genes involved in stress and wound response, and apoptosis. Most importantly, SIPS PaSCs secreted proteins involved in cytokine/chemokine signaling and extracellular matrix remodeling. Using an in vivo-like three dimensional culture system, we further demonstrated that SIPS PaSCs promoted the invasive growth of co-cultivated pancreatic cancer cells. Corroborating the in vitro findings, SIPS PaSCs, when co-implanted with pancreatic cancer cells subcutaneously into immunocompromised mice, can significantly promoted the growth of xenografted pancreatic tumors.

Conclusion: Our observations suggest that repeatitive exposure of PaSCs to cytotoxic chemotherapeutic agents, especially gemcitabine, induces phenotypical changes in PaSCs resembling senescence. SIPS PaSCs can create a permissive microenvironment similar to that created during the wound healing process and promote tumor progression both in vitro and in vivo. The heterotypic interactions between SIPS PaSCs and pancreatic carcinoma cells may shed a new light on the mechanistic basis of treatment refractoriness in pancreatic adenocarcinoma and may serve as potential therapeutic targets thereof.
論文目次 Abstract in Chinese..........i
Abstract in English.........iv
Introduction.................1
Hypothesis..................17
Materials and Methods.......19
Results.....................27
Discussion..................35
Future Work.................46
Reference ...................53
Figure......................64
參考文獻 1. Jemal, A., et al., Cancer statistics, 2008. CA Cancer J Clin, 2008. 58(2): p. 71-96.
2. Lillemoe, K.D., C.J. Yeo, and J.L. Cameron, Pancreatic cancer: state-of-the-art care. CA Cancer J Clin, 2000. 50(4): p. 241-68.
3. Gemmel, C., et al., Pancreatic cancer screening: state of the art. Expert Rev Gastroenterol Hepatol, 2009. 3(1): p. 89-96.
4. Yeo, T.P., et al., Pancreatic cancer. Curr Probl Cancer, 2002. 26(4): p. 176-275.
5. Cullinan, S., et al., A phase III trial on the therapy of advanced pancreatic carcinoma. Evaluations of the Mallinson regimen and combined 5-fluorouracil, doxorubicin, and cisplatin. Cancer, 1990. 65(10): p. 2207-12.
6. Burris, H.A., 3rd, et al., Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol, 1997. 15(6): p. 2403-13.
7. Shepherd, F.A., et al., Gemcitabine in the treatment of elderly patients with advanced non-small cell lung cancer. Semin Oncol, 1997. 24(2 Suppl 7): p. S7-50-S7-55.
8. Heinemann, V., Gemcitabine plus cisplatin for the treatment of metastatic breast cancer. Clin Breast Cancer, 2002. 3 Suppl 1: p. 24-9.
9. Heinemann, V., Gemcitabine-based combination treatment of pancreatic cancer. Semin Oncol, 2002. 29(1 Suppl 3): p. 25-35.
10. Calvero., Chemical structure of gemcitabine (trade name gemzar). January 2007.
11. Sivalakshmidevi, A., et al., 2'-Deoxy-2',2'-difluorocytidine monohydrochloride (Gemcitabine hydrochloride) DRL publication No. 256. Acta Crystallographica Section E, 2003. 59(10): p. o1435-o1437.
12. Mackey, J.R., et al., Nucleoside transport and its significance for anticancer drug resistance. Drug Resist Updat, 1998. 1(5): p. 310-24.
13. Grunewald, R., et al., Saturation of 2',2'-difluorodeoxycytidine 5'-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine. Cancer Chemother Pharmacol, 1991. 27(4): p. 258-62.
14. Abbruzzese, J.L., et al., A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol, 1991. 9(3): p. 491-8.
15. Grunewald, R., et al., Gemcitabine in leukemia: a phase I clinical, plasma, and cellular pharmacology study. J Clin Oncol, 1992. 10(3): p. 406-13.
16. Chabner, B.A., et al., Chapter 51. Antineoplastic Agents" . Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11e.
17. Miura, T., et al., [A case of interstitial pneumonia induced by gemcitabine hydrochloride for unresectable bile duct cancer]. Gan To Kagaku Ryoho, 2009. 36(10): p. 1757-60.
18. Galvao, F.H., J.O. Pestana, and V.L. Capelozzi, Fatal gemcitabine-induced pulmonary toxicity in metastatic gallbladder adenocarcinoma. Cancer Chemother Pharmacol, 2010. 65(3): p. 607-10.
19. Glezerman, I., et al., Gemcitabine nephrotoxicity and hemolytic uremic syndrome: report of 29 cases from a single institution. Clin Nephrol, 2009. 71(2): p. 130-9.
20. Storniolo, A.M., et al., An investigational new drug treatment program for patients with gemcitabine: results for over 3000 patients with pancreatic carcinoma. Cancer, 1999. 85(6): p. 1261-8.
21. W. F. Regine, K.W.W., R. Abrams, H. Safran, J. P. Hoffman, A. Konski, A. B. Benson, J. S. MacDonald, C. G. Willett, T. A. Rich, RTOG 9704 a phase III study of adjuvant pre and post chemoradiation (CRT) 5-FU vs. gemcitabine (G) for resected pancreatic adenocarcinoma. Journal of Clinical Oncology, 2006. 24(18S): p. 4007.
22. Oettle, H., et al., Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA, 2007. 297(3): p. 267-77.
23. Berlin, J.D., et al., Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol, 2002. 20(15): p. 3270-5.
24. Heinemann, V., et al., Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol, 2006. 24(24): p. 3946-52.
25. Rocha Lima, C.M., et al., Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol, 2004. 22(18): p. 3776-83.
26. Louvet, C., et al., Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol, 2005. 23(15): p. 3509-16.
27. Oettle, H., et al., A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol, 2005. 16(10): p. 1639-45.
28. Cunningham, D., I. Chau, and D. Stocken, Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. Eur J Cancer. 2005(3): p. 4.
29. Moore, M.J., et al., Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol, 2007. 25(15): p. 1960-6.
30. Kim, M.P. and G.E. Gallick, Gemcitabine resistance in pancreatic cancer: picking the key players. Clin Cancer Res, 2008. 14(5): p. 1284-5.
31. Xu, Z.W., et al., Overexpression of Bax sensitizes human pancreatic cancer cells to apoptosis induced by chemotherapeutic agents. Cancer Chemother Pharmacol, 2002. 49(6): p. 504-10.
32. Yin, T., et al., Expression of snail in pancreatic cancer promotes metastasis and chemoresistance. J Surg Res, 2007. 141(2): p. 196-203.
33. Miyamoto, H., et al., Tumor-stroma interaction of human pancreatic cancer: acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas, 2004. 28(1): p. 38-44.
34. Chang, H.Y., et al., Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci U S A, 2002. 99(20): p. 12877-82.
35. Hanahan, D. and R.A. Weinberg, The hallmarks of cancer. Cell, 2000. 100(1): p. 57-70.
36. Mollenhauer, J., I. Roether, and H.F. Kern, Distribution of extracellular matrix proteins in pancreatic ductal adenocarcinoma and its influence on tumor cell proliferation in vitro. Pancreas, 1987. 2(1): p. 14-24.
37. Apte, M.V., et al., Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas, 2004. 29(3): p. 179-87.
38. Folkman, J., Tumor angiogenesis: therapeutic implications. N Engl J Med, 1971. 285(21): p. 1182-6.
39. O'Reilly, M.S., et al., Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell, 1997. 88(2): p. 277-85.
40. Folkman, J., et al., Isolation of a tumor factor responsible for angiogenesis. J Exp Med, 1971. 133(2): p. 275-88.
41. Ishii, G., et al., Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem Biophys Res Commun, 2003. 309(1): p. 232-40.
42. Kim, K.J., et al., Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature, 1993. 362(6423): p. 841-4.
43. Coussens, L.M. and Z. Werb, Inflammation and cancer. Nature, 2002. 420(6917): p. 860-7.
44. de Visser, K.E., L.V. Korets, and L.M. Coussens, De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell, 2005. 7(5): p. 411-23.
45. Kalluri, R. and M. Zeisberg, Fibroblasts in cancer. Nat Rev Cancer, 2006. 6(5): p. 392-401.
46. Mueller, M.M. and N.E. Fusenig, Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer, 2004. 4(11): p. 839-49.
47. Ronnov-Jessen, L., O.W. Petersen, and M.J. Bissell, Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev, 1996. 76(1): p. 69-125.
48. Lazard, D., et al., Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc Natl Acad Sci U S A, 1993. 90(3): p. 999-1003.
49. Schurch, W., T.A. Seemayer, and G. Gabbiani, The myofibroblast: a quarter century after its discovery. Am J Surg Pathol, 1998. 22(2): p. 141-7.
50. Camps, J.L., et al., Fibroblast-mediated acceleration of human epithelial tumor growth in vivo. Proc Natl Acad Sci U S A, 1990. 87(1): p. 75-9.
51. Gleave, M., et al., Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts. Cancer Res, 1991. 51(14): p. 3753-61.
52. Olumi, A.F., et al., Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res, 1999. 59(19): p. 5002-11.
53. Tlsty, T.D. and P.W. Hein, Know thy neighbor: stromal cells can contribute oncogenic signals. Curr Opin Genet Dev, 2001. 11(1): p. 54-9.
54. Dong-Le Bourhis, X., et al., Effect of stromal and epithelial cells derived from normal and tumorous breast tissue on the proliferation of human breast cancer cell lines in co-culture. Int J Cancer, 1997. 71(1): p. 42-8.
55. Brouty-Boye, D., et al., Fibroblast-mediated differentiation in human breast carcinoma cells (MCF-7) grown as nodules in vitro. Int J Cancer, 1994. 56(5): p. 731-5.
56. Cheng, J.D., et al., Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model. Cancer Res, 2002. 62(16): p. 4767-72.
57. Loeffler, M., et al., Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest, 2006. 116(7): p. 1955-62.
58. Apte, M.V., et al., Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut, 1998. 43(1): p. 128-33.
59. Geerts, A., History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis, 2001. 21(3): p. 311-35.
60. Bachem, M.G., et al., Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology, 1998. 115(2): p. 421-32.
61. Omary, M.B., et al., The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest, 2007. 117(1): p. 50-9.
62. Haber, P.S., et al., Activation of pancreatic stellate cells in human and experimental pancreatic fibrosis. Am J Pathol, 1999. 155(4): p. 1087-95.
63. Zimmermann, A., et al., Pancreatic stellate cells contribute to regeneration early after acute necrotising pancreatitis in humans. Gut, 2002. 51(4): p. 574-8.
64. Hartel, M., et al., Desmoplastic reaction influences pancreatic cancer growth behavior. World J Surg, 2004. 28(8): p. 818-25.
65. Watanabe, I., et al., Advanced pancreatic ductal cancer: fibrotic focus and beta-catenin expression correlate with outcome. Pancreas, 2003. 26(4): p. 326-33.
66. Vaquero, E.C., et al., Extracellular matrix proteins protect pancreatic cancer cells from death via mitochondrial and nonmitochondrial pathways. Gastroenterology, 2003. 125(4): p. 1188-202.
67. Munshi, H.G. and M.S. Stack, Reciprocal interactions between adhesion receptor signaling and MMP regulation. Cancer Metastasis Rev, 2006. 25(1): p. 45-56.
68. Yamamoto, H., et al., Relation of enhanced secretion of active matrix metalloproteinases with tumor spread in human hepatocellular carcinoma. Gastroenterology, 1997. 112(4): p. 1290-6.
69. Bhatia, S.N., et al., Effect of cell-cell interactions in preservation of cellular phenotype: cocultivation of hepatocytes and nonparenchymal cells. FASEB J, 1999. 13(14): p. 1883-900.
70. Grinnell, A.D., Dynamics of nerve-muscle interaction in developing and mature neuromuscular junctions. Physiol Rev, 1995. 75(4): p. 789-834.
71. Shekhar, M.P., et al., Breast stroma plays a dominant regulatory role in breast epithelial growth and differentiation: implications for tumor development and progression. Cancer Res, 2001. 61(4): p. 1320-6.
72. Streuli, C., Extracellular matrix remodelling and cellular differentiation. Curr Opin Cell Biol, 1999. 11(5): p. 634-40.
73. Aboseif, S., et al., Mesenchymal reprogramming of adult human epithelial differentiation. Differentiation, 1999. 65(2): p. 113-8.
74. Frisch, S.M. and E. Ruoslahti, Integrins and anoikis. Curr Opin Cell Biol, 1997. 9(5): p. 701-6.
75. Zhang, H.Z., et al., Estrogen mediates mammary epithelial cell proliferation in serum-free culture indirectly via mammary stroma-derived hepatocyte growth factor. Endocrinology, 2002. 143(9): p. 3427-34.
76. Chang, H.Y., et al., Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol, 2004. 2(2): p. E7.
77. Kuperwasser, C., et al., Reconstruction of functionally normal and malignant human breast tissues in mice. Proc Natl Acad Sci U S A, 2004. 101(14): p. 4966-71.
78. Vonlaufen, A., et al., Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res, 2008. 68(7): p. 2085-93.
79. Friedman, S.L., Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N Engl J Med, 1993. 328(25): p. 1828-35.
80. Schmitt, C.A., et al., A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell, 2002. 109(3): p. 335-46.
81. Ly, D.H., et al., Mitotic misregulation and human aging. Science, 2000. 287(5462): p. 2486-92.
82. Toussaint, O., et al., From the Hayflick mosaic to the mosaics of ageing. Role of stress-induced premature senescence in human ageing. Int J Biochem Cell Biol, 2002. 34(11): p. 1415-29.
83. Toussaint, O., E.E. Medrano, and T. von Zglinicki, Cellular and molecular mechanisms of stress-induced premature senescence (SIPS) of human diploid fibroblasts and melanocytes. Exp Gerontol, 2000. 35(8): p. 927-45.
84. te Poele, R.H., et al., DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res, 2002. 62(6): p. 1876-83.
85. Chang, B.D., et al., Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent. Proc Natl Acad Sci U S A, 2002. 99(1): p. 389-94.
86. Chang, B.D., et al., A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res, 1999. 59(15): p. 3761-7.
87. Millis, A.J., et al., Differential expression of metalloproteinase and tissue inhibitor of metalloproteinase genes in aged human fibroblasts. Exp Cell Res, 1992. 201(2): p. 373-9.
88. Shelton, D.N., et al., Microarray analysis of replicative senescence. Curr Biol, 1999. 9(17): p. 939-45.
89. West, M.D., O.M. Pereira-Smith, and J.R. Smith, Replicative senescence of human skin fibroblasts correlates with a loss of regulation and overexpression of collagenase activity. Exp Cell Res, 1989. 184(1): p. 138-47.
90. Wick, M., et al., A novel member of human tissue inhibitor of metalloproteinases (TIMP) gene family is regulated during G1 progression, mitogenic stimulation, differentiation, and senescence. J Biol Chem, 1994. 269(29): p. 18953-60.
91. Schwarze, S.R., et al., Novel pathways associated with bypassing cellular senescence in human prostate epithelial cells. J Biol Chem, 2002. 277(17): p. 14877-83.
92. Kirkwood, T.B. and S.N. Austad, Why do we age? Nature, 2000. 408(6809): p. 233-8.
93. Krtolica, A., et al., Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A, 2001. 98(21): p. 12072-7.
94. Chang, B.D., et al., Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases. Proc Natl Acad Sci U S A, 2000. 97(8): p. 4291-6.
95. Tsai, K.K., et al., Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment. Cancer Res, 2005. 65(15): p. 6734-44.
96. Liu, D. and P.J. Hornsby, Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res, 2007. 67(7): p. 3117-26.
97. Jesnowski, R., et al., Immortalization of pancreatic stellate cells as an in vitro model of pancreatic fibrosis: deactivation is induced by matrigel and N-acetylcysteine. Lab Invest, 2005. 85(10): p. 1276-91.
98. Dimri, G.P., et al., A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A, 1995. 92(20): p. 9363-7.
99. Kimball, R.E., et al., Flow cytometric analysis of lymph node metastases in advanced ovarian cancer: clinical and biologic significance. Am J Obstet Gynecol, 1997. 176(6): p. 1319-26; discussion 1326-7.
100. Wang, X. and B. Seed, A PCR primer bank for quantitative gene expression analysis. Nucleic Acids Res, 2003. 31(24): p. e154.
101. Mogal, A. and S.A. Abdulkadir, Effects of Histone Deacetylase Inhibitor (HDACi); Trichostatin-A (TSA) on the expression of housekeeping genes. Mol Cell Probes, 2006. 20(2): p. 81-6.
102. Lee, G.Y., et al., Three-dimensional culture models of normal and malignant breast epithelial cells. Nat Methods, 2007. 4(4): p. 359-65.
103. Hoffman, R.M. and M. Yang, Subcellular imaging in the live mouse. Nat Protoc, 2006. 1(2): p. 775-82.
104. Bouvet, M., et al., In vivo color-coded imaging of the interaction of colon cancer cells and splenocytes in the formation of liver metastases. Cancer Res, 2006. 66(23): p. 11293-7.
105. Niggli, H.J., et al., Mitomycin C-induced postmitotic fibroblasts retain the capacity to repair pyrimidine photodimers formed after UV-irradiation. Mutat Res, 1989. 219(4): p. 231-40.
106. Rodemann, H.P., et al., Selective enrichment and biochemical characterization of seven human skin fibroblasts cell types in vitro. Exp Cell Res, 1989. 180(1): p. 84-93.
107. van Moorsel, C.J., G.J. Peters, and H.M. Pinedo, Gemcitabine: Future Prospects of Single-Agent and Combination Studies. Oncologist, 1997. 2(3): p. 127-134.
108. Veltkamp, S.A., J.H. Beijnen, and J.H. Schellens, Prolonged versus standard gemcitabine infusion: translation of molecular pharmacology to new treatment strategy. Oncologist, 2008. 13(3): p. 261-76.
109. Horan, P.K. and S.E. Slezak, Stable cell membrane labelling. Nature, 1989. 340(6229): p. 167-8.
110. Majeti, R., et al., Dysregulated gene expression networks in human acute myelogenous leukemia stem cells. Proc Natl Acad Sci U S A, 2009. 106(9): p. 3396-401.
111. Jemal, A., et al., Cancer statistics, 2009. CA Cancer J Clin, 2009. 59(4): p. 225-49.
112. Bachem, M.G., et al., Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology, 2005. 128(4): p. 907-21.
113. Thiery, J.P., Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer, 2002. 2(6): p. 442-54.
114. Yang, A.D., et al., Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res, 2006. 12(14 Pt 1): p. 4147-53.
115. Hiscox, S., et al., Tamoxifen resistance in breast cancer cells is accompanied by an enhanced motile and invasive phenotype: inhibition by gefitinib ('Iressa', ZD1839). Clin Exp Metastasis, 2004. 21(3): p. 201-12.
116. Hiscox, S., et al., Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of beta-catenin phosphorylation. Int J Cancer, 2006. 118(2): p. 290-301.
117. Li, H., X. Fan, and J. Houghton, Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem, 2007. 101(4): p. 805-15.
118. Kurz, D.J., et al., Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci, 2000. 113 ( Pt 20): p. 3613-22.
119. Hayflick, L. and P.S. Moorhead, The serial cultivation of human diploid cell strains. Exp Cell Res, 1961. 25: p. 585-621.
120. Roninson, I.B., Tumor cell senescence in cancer treatment. Cancer Res, 2003. 63(11): p. 2705-15.
121. Lanz, C., et al., Rapid determination of gemcitabine in plasma and serum using reversed-phase HPLC. J Sep Sci, 2007. 30(12): p. 1811-20.
122. Fakih, M.G., et al., Phase I and pharmacokinetic study of weekly docetaxel, cisplatin, and daily capecitabine in patients with advanced solid tumors. Clin Cancer Res, 2005. 11(16): p. 5942-9.
123. Massova, I., et al., Matrix metalloproteinases: structures, evolution, and diversification. FASEB J, 1998. 12(12): p. 1075-95.
124. Stamenkovic, I., Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol, 2000. 10(6): p. 415-33.
125. Walker, R.A., The complexities of breast cancer desmoplasia. Breast Cancer Res, 2001. 3(3): p. 143-5.
126. Burris, H., 3rd and C. Rocha-Lima, New therapeutic directions for advanced pancreatic cancer: targeting the epidermal growth factor and vascular endothelial growth factor pathways. Oncologist, 2008. 13(3): p. 289-98.
127. Wilson, J. and F. Balkwill, The role of cytokines in the epithelial cancer microenvironment. Semin Cancer Biol, 2002. 12(2): p. 113-20.
128. Arenberg, D.A., et al., Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. J Clin Invest, 1998. 102(3): p. 465-72.
129. Yoneda, J., et al., Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice. J Natl Cancer Inst, 1998. 90(6): p. 447-54.
130. Luan, J., et al., Mechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression. J Leukoc Biol, 1997. 62(5): p. 588-97.
131. Takamori, H., et al., Autocrine growth effect of IL-8 and GROalpha on a human pancreatic cancer cell line, Capan-1. Pancreas, 2000. 21(1): p. 52-6.
132. Koshiba, T., et al., Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression. Clin Cancer Res, 2000. 6(9): p. 3530-5.
133. Orimo, A., et al., Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 2005. 121(3): p. 335-48.
134. Lev, D.C., et al., Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol, 2004. 22(11): p. 2092-100.
135. Olnes, M.J. and R. Erlich, A review and update on cholangiocarcinoma. Oncology, 2004. 66(3): p. 167-79.
136. Shaib, Y. and H.B. El-Serag, The epidemiology of cholangiocarcinoma. Semin Liver Dis, 2004. 24(2): p. 115-25.
137. Klempnauer, J., et al., What constitutes long-term survival after surgery for hilar cholangiocarcinoma? Cancer, 1997. 79(1): p. 26-34.
138. Burke, E.C., et al., Hilar Cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. Ann Surg, 1998. 228(3): p. 385-94.
139. Alberts, S.R., et al., Treatment options for hepatobiliary and pancreatic cancer. Mayo Clin Proc, 2007. 82(5): p. 628-37.
140. Maruyama, M., et al., Establishment of a highly differentiated immortalized human cholangiocyte cell line with SV40T and hTERT. Transplantation, 2004. 77(3): p. 446-51.
論文全文使用權限
  • 同意授權瀏覽/列印電子全文服務,於2012-02-23起公開。


  • 若您有任何疑問,請與我們聯絡!
    臺北醫學大學 圖書館 簡莉婷
    E-mail:etds@tmu.edu.tw
    Tel:(02) 2736-1661 ext.2519
    Fax:(02) 2737-5446