Sorafenib对胆管癌裸鼠移植瘤淋巴管生成与淋巴结转移的影响
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摘要
目的探讨多靶点靶向新药Sorafenib对胆管癌移植瘤淋巴管生成和淋巴结转移的影响。
方法皮下接种胆管癌细胞株QBC939构建裸鼠(BALB/c-nu)移植瘤模型;成瘤后随机分为对照组、sorafenib 30mg/kg.day剂量组和60mg/kg.day剂量组,灌胃法连续给药6周,游标卡尺观察用药组与对照组移植瘤的生长情况;免疫组织化学染色LYVE-1标记胆管癌边缘淋巴管,观察比较6周后各组微淋巴管密度的差异;逆转录-聚合酶链反应(RT-PCR法)检测各组胆管癌周边VEGFR-3 mRNA的表达差异;HE染色裸鼠腋下淋巴结,观察比较胆管癌淋巴结转移发生率。
结果
1.对照组胆管癌生长速度显著快于用药组;
2.sorafenib给药6周后,用药组微淋巴管密度LMVD小于对照组,有统计学意义(P<0.05);30mg/kg.day剂量组与60mg/kg.day剂量组之间差异无统计学意义(P>0.05);
3.Sorafenib可显著抑制裸鼠胆管癌皮下移植模型肿瘤边缘VEGFR-3 mRNA表达,各组之间的差异具有统计学意义(P<0.05);
4.各组均未能观察到镜下胆管癌淋巴结转移。
结论
1.Sorafenib显著抑制胆管癌裸鼠移植瘤的生长;
2.Sorafenib可能通过抑制胆管癌周边VEGF-C/D、VEGFR-3轴表达,降低微淋巴管密度。
Objective: To study the effect of sorafenib on Lymphangiogenesis and lymph node metastasis of transplanted tumor of human cholangiocarcinoma in nude mice.
Methods: Transplanted tumor of human cholangiocarcinoma in nude mice was estabished by subcutaneous vaccination of Cholangiocarcinoma cell lines QBC 939 .We randomly divided the mice into control group, sorafenib 30mg/kg.day group and 60mg/kg.day group after tumorigenicity, and then treated the groups with gavage method for 6 weeks. The growth of dose groups and control groups was observed with caliper. Using Immunohistochemistry method, lymphatic microvessles of the edge of the tumor was marked by LYVE-1. The differences of LMVD and VEGFR-3 mRNA expression was evaluated by using RT-PCR in different groups. HE staining the tumor’s ipsilateral axillary lymph node , the occurrence rate of different groups of lymph node metastasis of Cholangiocarcinoma was investigated. Results:
1. sorafenib significantly depress the growth of cholangiocarcinoma.
2. Dose groups’LMVD was significantly less than control group with P<0.05.
3. After 6 weeks’treatment of sorafenib, the expression of VEGFR-3 mRNA in dose groups was less than that in control group with a statistical significance(P<0.05).
4. No occurrence of lymph node metastasis was found in the transplanted cholangiocarcinoma model.
Conclusion: Sorafenib could significantly inhibit the growth of xenograft Cholangiocarcinoma in nude mice. Sorafenib might reduce LMVD by down-regulating the expression of VEGF-C/D and VEGFR-3 signaling axis in Tumor edge.
Conclusion:
1.Sorafenib could significantly inhibit the growth of xenograft Cholangiocarcinoma in nude mice
2.Sorafenib might reduce LMVD by down-regulating the expression of VEGF-C/D and VEGFR-3 signaling axis in Tumor edge.
方法皮下接种胆管癌细胞株QBC939构建裸鼠(BALB/c-nu)移植瘤模型;成瘤后随机分为对照组、sorafenib 30mg/kg.day剂量组和60mg/kg.day剂量组,灌胃法连续给药6周,游标卡尺观察用药组与对照组移植瘤的生长情况;免疫组织化学染色LYVE-1标记胆管癌边缘淋巴管,观察比较6周后各组微淋巴管密度的差异;逆转录-聚合酶链反应(RT-PCR法)检测各组胆管癌周边VEGFR-3 mRNA的表达差异;HE染色裸鼠腋下淋巴结,观察比较胆管癌淋巴结转移发生率。
结果
1.对照组胆管癌生长速度显著快于用药组;
2.sorafenib给药6周后,用药组微淋巴管密度LMVD小于对照组,有统计学意义(P<0.05);30mg/kg.day剂量组与60mg/kg.day剂量组之间差异无统计学意义(P>0.05);
3.Sorafenib可显著抑制裸鼠胆管癌皮下移植模型肿瘤边缘VEGFR-3 mRNA表达,各组之间的差异具有统计学意义(P<0.05);
4.各组均未能观察到镜下胆管癌淋巴结转移。
结论
1.Sorafenib显著抑制胆管癌裸鼠移植瘤的生长;
2.Sorafenib可能通过抑制胆管癌周边VEGF-C/D、VEGFR-3轴表达,降低微淋巴管密度。
Objective: To study the effect of sorafenib on Lymphangiogenesis and lymph node metastasis of transplanted tumor of human cholangiocarcinoma in nude mice.
Methods: Transplanted tumor of human cholangiocarcinoma in nude mice was estabished by subcutaneous vaccination of Cholangiocarcinoma cell lines QBC 939 .We randomly divided the mice into control group, sorafenib 30mg/kg.day group and 60mg/kg.day group after tumorigenicity, and then treated the groups with gavage method for 6 weeks. The growth of dose groups and control groups was observed with caliper. Using Immunohistochemistry method, lymphatic microvessles of the edge of the tumor was marked by LYVE-1. The differences of LMVD and VEGFR-3 mRNA expression was evaluated by using RT-PCR in different groups. HE staining the tumor’s ipsilateral axillary lymph node , the occurrence rate of different groups of lymph node metastasis of Cholangiocarcinoma was investigated. Results:
1. sorafenib significantly depress the growth of cholangiocarcinoma.
2. Dose groups’LMVD was significantly less than control group with P<0.05.
3. After 6 weeks’treatment of sorafenib, the expression of VEGFR-3 mRNA in dose groups was less than that in control group with a statistical significance(P<0.05).
4. No occurrence of lymph node metastasis was found in the transplanted cholangiocarcinoma model.
Conclusion: Sorafenib could significantly inhibit the growth of xenograft Cholangiocarcinoma in nude mice. Sorafenib might reduce LMVD by down-regulating the expression of VEGF-C/D and VEGFR-3 signaling axis in Tumor edge.
Conclusion:
1.Sorafenib could significantly inhibit the growth of xenograft Cholangiocarcinoma in nude mice
2.Sorafenib might reduce LMVD by down-regulating the expression of VEGF-C/D and VEGFR-3 signaling axis in Tumor edge.
引文
[1]陈孝平,石应康,段德生.外科学.人民卫生出版社.2002:692
[2]Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet 2005;366:1303–14.
[3]Shaib Y, El Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115–25.
[4]TUTTLE, T.M. 2004. Technical advances in sentinel lymph node biopsy for breast cancer. Am. Surg. 70: 407–413.
[5]LEAK, L.V. 1970. Electron microscopic observations on lymphatic capillaries and the structural components of the connective tissue-lymph interface. Microvasc. Res.2: 361–391.
[6]CASLEY-SMITH, J.R. & H.W. FLOREY. 1961. The structure of normal small lymphatics. Quart. J. Expt. Physiol. 46:101–116.
[7]SWARTZ, M.A. & M. SKOBE. 2001. Lymphatic function, lymphangiogenesis, and cancer metastasis.Microsc. Res.Tech. 55: 92–99.
[8]SAHARINEN, P. et al. 2004. Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol. 25: 387–395.
[9]STACKER, S.A. et al. 2002. Lymphangiogenesis and cancer metastasis. Nat. Rev. Cancer 2: 573–583.
[10]VAN DERAUWERA, L. et al. 2005.Tumor lymphangiogenesis in inflammatory breast carcinoma: a histomorphometric study. Clin Cancer Res. 11: 7637–7642.
[11]RENYI-VAMOS, F. et al. 2005. Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer. Clin. Cancer Res. 11: 7344–7353.
[12]FERNANDEZ, M.I. et al. 2007. Prognostic implications of lymphangiogenesis in muscle-invasive transitional cell carcinoma of the bladder. Eur. Urol. 53:571–580.
[13]BEASLEY, N.J. P. et al. 2002. Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. Cancer Res. 62: 1315–1320.
[14]HIRAKAWA, S. et al. 2005. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J. Exp. Med. 201: 1089–1099.
[15]ROBERTS, N. et al. 2006. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res. 66: 2650–2657.
[16]HARRELL, M.I., B.M. IRITANI & A. RUDDELL. 2007. Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis.Am. J. Pathol. 170: 774–786.
[17]SHIELDS, J.D. et al. 2007. Chemokine-mediated migration of melanoma cells towards lymphatics—a mechanism contributing to metastasis. Oncogene 26: 2997–3005.
[18]Takanami I. Lymphatic microvessel density using D2-40 is associated with nodal metastasis in non-small cell lung cancer.Oncol Rep. 2006 Feb;15(2):437-42.
[19]Padera TP, Kadambi A, di Tomaso E, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics [ J ]. Science, 2002, 296 (5574) : 1883 - 1886.
[20]VALLET, S. et al. 2007. MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiplemyeloma cells and osteoclasts. Blood 110:3744–3752.
[21]SMITH, M.C. et al. 2004. CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res. 64:8604–8612.
[22]Strumberg D. Preclinical and clinical development of the oralmultikinase inhibitor sorafenib in cancer treatment [ J ] .Drugs Today(Barc) , 2005 ,41 (12) :773 - 784.
[23]Wilhelm SM , Carter C , Tang L , et al. BAY 43 - 9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ ERK pathway and receptor tyrosinekinases involved in tumor progression and angiogenesis [J] . Cancer Res ,2004 , 64 (19) :7099 - 7109.
[24]Weidner N,Semple JP,Welch WR,et al. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med,1991,324:1-8
[25]Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 2003;52:706–12.
[26]Chunxia Wang,ThorstenMaass,Markus Krupp, Florian Thieringer,Susanne Strand,MarcusA.Worns,Ana-PaulaBarreiros, PeterR. Galle,Andreas Teufel.A systems biology perspective on cholangiocellular carcinoma development: Focus on MAPK-signaling and the extracellular environment.Journal of Hepatology 50 (2009) 1122–1131
[27]Schneider M, Büchler P, Giese N , et a1. lymphangiogenesis and lymphangiogenic factors during pancreatic cancer progression and lymphatic spread[J]. Int J Oncol, 2006,28(4):883-890.
[28]Yamada N,Chung YS,Arimoto Y,et al. Establishment of a new human extrahepatic bile duct carcinoma cell line( OCUCh-LM1) and experimental liver metastatic model [J].Br J Cancer,1995,71(3):543-548.
[29]周晋生,吴小鹏.人肝门部胆管癌转移动物模型的建立及生物学特性研究[J]中华肝胆外科杂志,2006,(08).
[30]李志伟,王占民,吴小鹏,常新忠,马道新,丛超.利用裸鼠建立人肝门部胆管癌肝门移植模型[J].中国现代普通外科进展, 2004, (04) .
[31]丛超,吴小鹏,孙文娟.人类肝门部胆管癌裸鼠瘤株的建立及其生物学特性研究[J]中华肝胆外科杂志, 2005,(06) .
[32]范毓东,李开宗,孙岚等.人胆管细胞癌荷瘤裸鼠模型的建立[J].中华肝胆外科杂志,2000,6(6):420.
[33]唐文皓,袁胜涛,王炳生,陆丽娟,丁健.人胆管癌裸鼠移植瘤2号模型的建立[J]中华肝胆外科杂志, 2003,(12) .
[34]Emura F, Kamma H, Ghosh M, Koike N, Kawamoto T, Saijo K, Ohno T, Ohkohchi N, Todoroki T. Establishment and characterization of novel xenograft models of human biliary tract carcinomas.Int J Oncol. 2003 Nov;23(5):1293-300.
[35]IOACHIM, H. 2002. Tumor-Reactive Lymphadenopathy. Lippincott, Williams and Wilkins. Philadelphia, PA.
[36]JAIN, R.K. & T.P. PADERA. 2002. Prevention and treatment of lymphatic metastasis by antilymphangiogenic therapy. J. Natl. Cancer Inst. 94: 785–787.
[37]BJORNDAHL, M.A. et al. 2005. Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. Cancer Res. 65: 9261–9268.
[38]WHITEHURST, B. et al. 2007. Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. Int. J. Cancer 121:2181–2191.
[39]CAO, R. et al. 2004. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis.Cancer Cell 6: 333–345.
[40]DANILKOVITCH-MIAGKOVA, A. & B. ZBAR. 2002. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J. Clin. Invest. 109: 863–867.
[41]Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellμlar carcinoma. Gut 2003;52:706–12.
[42]Chunxia Wang,ThorstenMaass,Markus Krupp, Florian Thieringer,Susanne Strand,MarcusA.Wo¨rns,Ana-PaulaBarreiros, PeterR. Galle,Andreas Teufel.A systems biology perspective on cholangiocellular carcinoma development: Focus on MAPK-signaling and the extracellular environment.Journal of Hepatology 50 (2009) 1122–1131
[43]El-Khoureiry AB, Rankin C, Lenz HJ, Philip P, Rivkin SE, Blanke CD (2007)SWOG 0514: a phase II study of sorafenib (BAY43-9006) as single agent in patients with unresectable or metastatic gallbladder cancer or cholangiocarcinomas. J Clin Oncol 25: 18s: 4639
[44]C Bengala, Bertolini F, Malavasi N, Zironi S, Boni C, Banzi M, Aitini E, Cavazzini G, Luppi G, Conte PF. Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial. British Journal of Cancer 2010;102:68–72
[45]Baradari V, Hopfner M, Huether A, Schuppan D, Scherubl H. Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells. World J Gastroenterol 2007; 13: 4458-4466
[46] Huether A, Hopfner M, Baradari V, Schuppan D, Scherubl H.Sorafenib alone or as combination therapy for growth control ofcholangiocarcinoma. Biochem Pharmacol 2007; 73: 1308-1317
[47] Beeram M, Patnaik A, Rowinsky EK. Regulation of c-Raf-1: therapeutic implications [J]. Clin Adv Hematol Oncol,2003,1(8):476-481.
[1]Vauthey JN, Blumgart LH. Recent advances in the management of cholangiocarcinomas[J]. Semin Liver Dis,1994,14(2):109–114.
[2]Khan SA,Thomas HC,Davidson BR,Taylor-Robinson SD. Cholangiocarcinoma[J]. Lancet,2005,366(9493):1303–1314.
[3]Shaib Y, El Serag HB. The epidemiology of cholangiocarcinoma[J]. Semin Liver Dis,2004,24(2):115–125.
[4]Wilhelm SM, Carter C, Tang L,et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ ERK pathway and receptor tyrosinekinases involved in tumor progression and angiogenesis[J]. Cancer Res,2004,64(19):7099-7109.
[5]Tannapfel A, Sommerer F, Benicke M,et al.Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma[J]. Gut,2003,52(5):706–712.
[6]Chunxia Wang,ThorstenMaass,Markus Krupp,et al.A systems biology perspective on cholangiocellular carcinoma development: Focus on MAPK-signaling and the extracellular environment[J].Journal of Hepatology,2009,50(6):1122–1131
[7]Strumberg D.Preclinical and clinical development of the oralmultikinase inhibitor sorafenib in cancer treatment[J].Drugs Today(Barc),2005,41(12):773-784.
[8]Blechacz, Smoot, Bronk. Sorafenib Inhibits Signal Transducer and Activator of Transcription-3 Signaling in Cholangiocarcinoma Cells by Activating the Phosphatase Shatterproof 2[J].Hepatology,2009,50(6):1861-1870
[9]Baradari V,Hopfner M,Huether A,et al. Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells[J].World J Gastroenterol,2007,13(33):4458-4466
[10]Huether A, Hopfner M, Baradari V,et al. Sorafenib alone or as combination therapy for growth control of cholangiocarcinoma[J]. Biochem Pharmacol,2007,73(9):1308-1317
[11]El-Khoureiry AB, Rankin C, Lenz HJ,et al. a phase II study of sorafenib (BAY43-9006) as single agent in patients with unresectable or metastatic gallbladder cancer or cholangiocarcinomas[J].J Clin Oncol,2007,25(18s):4639
[12]C Bengala, Bertolini F, Malavasi N,et al. Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial[J]. British Journal of Cancer 2010,102(1):68–72
[13]LaRocca RV, Hicks MD, Foreman B. Effective palliation of advanced cholangiocarcinoma with sorafenib: a two patient case report[J]. J Gastrointest Cancer,2007,38(12): 154–156
[2]Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet 2005;366:1303–14.
[3]Shaib Y, El Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115–25.
[4]TUTTLE, T.M. 2004. Technical advances in sentinel lymph node biopsy for breast cancer. Am. Surg. 70: 407–413.
[5]LEAK, L.V. 1970. Electron microscopic observations on lymphatic capillaries and the structural components of the connective tissue-lymph interface. Microvasc. Res.2: 361–391.
[6]CASLEY-SMITH, J.R. & H.W. FLOREY. 1961. The structure of normal small lymphatics. Quart. J. Expt. Physiol. 46:101–116.
[7]SWARTZ, M.A. & M. SKOBE. 2001. Lymphatic function, lymphangiogenesis, and cancer metastasis.Microsc. Res.Tech. 55: 92–99.
[8]SAHARINEN, P. et al. 2004. Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol. 25: 387–395.
[9]STACKER, S.A. et al. 2002. Lymphangiogenesis and cancer metastasis. Nat. Rev. Cancer 2: 573–583.
[10]VAN DERAUWERA, L. et al. 2005.Tumor lymphangiogenesis in inflammatory breast carcinoma: a histomorphometric study. Clin Cancer Res. 11: 7637–7642.
[11]RENYI-VAMOS, F. et al. 2005. Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer. Clin. Cancer Res. 11: 7344–7353.
[12]FERNANDEZ, M.I. et al. 2007. Prognostic implications of lymphangiogenesis in muscle-invasive transitional cell carcinoma of the bladder. Eur. Urol. 53:571–580.
[13]BEASLEY, N.J. P. et al. 2002. Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. Cancer Res. 62: 1315–1320.
[14]HIRAKAWA, S. et al. 2005. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J. Exp. Med. 201: 1089–1099.
[15]ROBERTS, N. et al. 2006. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res. 66: 2650–2657.
[16]HARRELL, M.I., B.M. IRITANI & A. RUDDELL. 2007. Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis.Am. J. Pathol. 170: 774–786.
[17]SHIELDS, J.D. et al. 2007. Chemokine-mediated migration of melanoma cells towards lymphatics—a mechanism contributing to metastasis. Oncogene 26: 2997–3005.
[18]Takanami I. Lymphatic microvessel density using D2-40 is associated with nodal metastasis in non-small cell lung cancer.Oncol Rep. 2006 Feb;15(2):437-42.
[19]Padera TP, Kadambi A, di Tomaso E, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics [ J ]. Science, 2002, 296 (5574) : 1883 - 1886.
[20]VALLET, S. et al. 2007. MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiplemyeloma cells and osteoclasts. Blood 110:3744–3752.
[21]SMITH, M.C. et al. 2004. CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res. 64:8604–8612.
[22]Strumberg D. Preclinical and clinical development of the oralmultikinase inhibitor sorafenib in cancer treatment [ J ] .Drugs Today(Barc) , 2005 ,41 (12) :773 - 784.
[23]Wilhelm SM , Carter C , Tang L , et al. BAY 43 - 9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ ERK pathway and receptor tyrosinekinases involved in tumor progression and angiogenesis [J] . Cancer Res ,2004 , 64 (19) :7099 - 7109.
[24]Weidner N,Semple JP,Welch WR,et al. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med,1991,324:1-8
[25]Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 2003;52:706–12.
[26]Chunxia Wang,ThorstenMaass,Markus Krupp, Florian Thieringer,Susanne Strand,MarcusA.Worns,Ana-PaulaBarreiros, PeterR. Galle,Andreas Teufel.A systems biology perspective on cholangiocellular carcinoma development: Focus on MAPK-signaling and the extracellular environment.Journal of Hepatology 50 (2009) 1122–1131
[27]Schneider M, Büchler P, Giese N , et a1. lymphangiogenesis and lymphangiogenic factors during pancreatic cancer progression and lymphatic spread[J]. Int J Oncol, 2006,28(4):883-890.
[28]Yamada N,Chung YS,Arimoto Y,et al. Establishment of a new human extrahepatic bile duct carcinoma cell line( OCUCh-LM1) and experimental liver metastatic model [J].Br J Cancer,1995,71(3):543-548.
[29]周晋生,吴小鹏.人肝门部胆管癌转移动物模型的建立及生物学特性研究[J]中华肝胆外科杂志,2006,(08).
[30]李志伟,王占民,吴小鹏,常新忠,马道新,丛超.利用裸鼠建立人肝门部胆管癌肝门移植模型[J].中国现代普通外科进展, 2004, (04) .
[31]丛超,吴小鹏,孙文娟.人类肝门部胆管癌裸鼠瘤株的建立及其生物学特性研究[J]中华肝胆外科杂志, 2005,(06) .
[32]范毓东,李开宗,孙岚等.人胆管细胞癌荷瘤裸鼠模型的建立[J].中华肝胆外科杂志,2000,6(6):420.
[33]唐文皓,袁胜涛,王炳生,陆丽娟,丁健.人胆管癌裸鼠移植瘤2号模型的建立[J]中华肝胆外科杂志, 2003,(12) .
[34]Emura F, Kamma H, Ghosh M, Koike N, Kawamoto T, Saijo K, Ohno T, Ohkohchi N, Todoroki T. Establishment and characterization of novel xenograft models of human biliary tract carcinomas.Int J Oncol. 2003 Nov;23(5):1293-300.
[35]IOACHIM, H. 2002. Tumor-Reactive Lymphadenopathy. Lippincott, Williams and Wilkins. Philadelphia, PA.
[36]JAIN, R.K. & T.P. PADERA. 2002. Prevention and treatment of lymphatic metastasis by antilymphangiogenic therapy. J. Natl. Cancer Inst. 94: 785–787.
[37]BJORNDAHL, M.A. et al. 2005. Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. Cancer Res. 65: 9261–9268.
[38]WHITEHURST, B. et al. 2007. Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. Int. J. Cancer 121:2181–2191.
[39]CAO, R. et al. 2004. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis.Cancer Cell 6: 333–345.
[40]DANILKOVITCH-MIAGKOVA, A. & B. ZBAR. 2002. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J. Clin. Invest. 109: 863–867.
[41]Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellμlar carcinoma. Gut 2003;52:706–12.
[42]Chunxia Wang,ThorstenMaass,Markus Krupp, Florian Thieringer,Susanne Strand,MarcusA.Wo¨rns,Ana-PaulaBarreiros, PeterR. Galle,Andreas Teufel.A systems biology perspective on cholangiocellular carcinoma development: Focus on MAPK-signaling and the extracellular environment.Journal of Hepatology 50 (2009) 1122–1131
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