Advances of Study on Angiogenesis and Antiangiogenic Therapy in Hepatocellular Carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YE Yibiao , CHEN Tao

Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital (The Second Affiliated Hospital) of Sun Yat-sen University, Guangzhou 510120, ChinaCorresponding Author: CHEN Tao, E-mail: chentao@mail.sysu.edu.cn;

Corresponding author：

Keywords：

Hepatocellular carcinoma; Angiogenesis; Antiangiogenic therapy; Metastasis

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Objective　To introduce the possible effects and significances of angiogenesis and antiangiogenic in the development and treatment of hepatocellular carcinoma (HCC).
Methods　Recently relevant literatures were reviewed.
Results　Angiogenesis played a significant role in the development and therapy of HCC, and the development and metastasis of HCC could be effectively suppressed by antiangiogenic therapy. This might provide a new approach for the treatment of HCC.
Conclusion　Comprehending the molecular mechanism of angiogenesis and applying antiangiogenic therapy will contribute a lot for the prevention and treatment of HCC.

Citation： YE Yibiao,CHEN Tao. Advances of Study on Angiogenesis and Antiangiogenic Therapy in Hepatocellular Carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2009, 16(10): 861-865. doi: Copy

1.	Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells [Ｊ]. Biochem Biophys Res Commun, 1989; 161(2): 851-858.
2.	Teramoto S, Arihiro K, Koseki M, et al. Role of vascular endothelial growth factor-C and -D mRNA in breast cancer [Ｊ]. Hiroshima J Med Sci, 2008; 57(2): 73-88.
3.	Thelen A, Scholz A, Benckert C, et al. VEGF-D promotes tumor growth and lymphatic spread in a mouse model of hepatocellular carcinoma [Ｊ]. Int J Cancer, 2008; 122(11): 2471-2481.
4.	Brekken RA, Overholser JP, Stastny VA, et al. Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice [Ｊ]. Cancer Res, 2000; 60(18): 5117-5124.
5.	Brodsky SV, Mendelev N, Melamed M, et al. Vascular density and VEGF expression in hepatic lesions [Ｊ]. J Gastrointestin Liver Dis, 2007; 16(4): 373-377.
6.	Li Q, Xu B, Fu L, et al. Correlation of four vascular specific growth factors with carcinogenesis and portal vein tumor thrombus formation in human hepatocellular carcinoma [Ｊ]. J Exp Clin Cancer Res, 2006; 25(3): 403-409.
7.	Raskopf E, Vogt A, Sauerbruch T, et al. siRNA targeting VEGF inhibits hepatocellular carcinoma growth and tumor angiogenesis in vivo [Ｊ]. J Hepatol, 2008; 49(6): 977-984.
8.	Amaoka N, Saio M, Nonaka K, et al. Expression of vascular endothelial growth factor receptors is closely related to the histological grade of hepatocellular carcinoma [Ｊ]. Oncol Rep, 2006; 16(1): 3-10.
9.	Yasuda S, Arii S, Mori A, et al. Hexokinase Ⅱ and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1 alpha and its significance [Ｊ]. J Hepatol, 2004; 40(1): 117-123.
10.	Tang TC, Poon RT, Lau CP, et al. Tumor cyclooxygenase-2 levels correlate with tumor invasiveness in human hepatocellular carcinoma [Ｊ]. World J Gastroenterol, 2005; 11(13): 1896-1902.
11.	Tseng PL, Tai MH, Huang CC, et al. Overexpression of VEGF is associated with positive p53 immunostaining in hepatocellular carcinoma (HCC) and adverse outcome of HCC patients [Ｊ]. J Surg Oncol, 2008; 98(5): 349-357.
12.	Bhagwat SV, Petrovic N, Okamoto Y, et al. The angiogenic regulator CD13/APN is a transcriptional target of Ras signaling pathways in endothelial morphogenesis [Ｊ]. Blood, 2003; 101(5): 1818-1826.
13.	Poon RT, Ng IO, Lau C, et al. Correlation of serum basic fibroblast growth factor levels with clinicopathologic features and postoperative recurrence in hepatocellular carcinoma [Ｊ]. Am J Surg, 2001; 182(3): 298-304.
14.	Kin M, Sata M, Ueno T, et al. Basic fibroblast growth factor regulates proliferation and motility of human hepatoma cells by an autocrine mechanism [Ｊ]. J Hepatol, 1997; 27(4): 677-687.
15.	Yoshiji H, Kuriyama S, Yoshii J, et al. Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma [Ｊ]. Hepatology, 2002; 35(4): 834-842.
16.	Kuboki S, Shimizu H, Mitsuhashi N, et al. Angiopoietin-2 levels in the hepatic vein as a useful predictor of tumor invasiveness and prognosis in human hepatocellular carcinoma [Ｊ]. J Gastroenterol Hepatol, 2008; 23(7 Pt 2): e157-e164.
17.	Wada H, Nagano H, Yamamoto H, et al. Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma: importance of angiopoietin-2 and hypoxia-induced factor-1 alpha [Ｊ]. Liver Int, 2006; 26(4): 414-423.
18.	Tanaka S, Wands JR, Arii S. Induction of angiopoietin-2 ge-ne expression by COX-2: a novel role for COX-2 inhibitors during hepatocarcinogenesis [Ｊ]. J Hepatol, 2006; 44(1): 233-235.
19.	Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? [Ｊ]. Lancet, 2001; 357(9255): 539-545.
20.	Pérez-Ruiz M, Ros J, Morales-Ruiz M, et al. Vascular endothelial growth factor production in peritoneal macrophages of cirrhotic patients: regulation by cytokines and bacterial lipopolysaccharide [Ｊ]. Hepatology, 1999; 29(4): 1057-1063.
21.	Menon C, Iyer M, Prabakaran I, et al. TNF-alpha downregulates vascular endothelial Flk-1 expression in human melanoma xenograft model [Ｊ]. Am J Physiol Heart Circ Physiol, 2003; 284(1): H317-H329.
22.	Bai L, Mao GP, Cao CP. Effects of inflammatory cytokines on the recurrence of liver cancer after an apparently curative operation [Ｊ]. J Dig Dis, 2007; 8(3): 154-159.
23.	Qiu LW, Yao DF, Zong L, et al. Abnormal expression of insulin-like growth factor-Ⅱ and its dynamic quantitative analysis at different stages of hepatocellular carcinoma development [Ｊ]. Hepatobiliary Pancreat Dis Int, 2008; 7(4): 406-411.
24.	Nussbaum T, Samarin J, Ehemann V, et al. Autocrine insulin-like growth factor-Ⅱ stimulation of tumor cell migration is a progression step in human hepatocarcinogenesis [Ｊ]. Hepatology, 2008; 48(1): 146-156.
25.	Ishikawa H, Nakao K, Matsumoto K, et al. Antiangiogenic gene therapy for hepatocellular carcinoma using angiostatin gene [Ｊ]. Hepatology, 2003; 37(3): 696-704.
26.	Yuan S, Fu Y, Wang X, et al. Voltage-dependent anion channel 1 is involved in endostatin-induced endothelial cell apoptosis [Ｊ]. FASEB J, 2008; 22(8): 2809-2820.
27.	Poon RT, Ho JW, Tong CS, et al. Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma [Ｊ]. Br J Surg, 2004; 91(10): 1354-1360.
28.	Dhar DK, Ono T, Yamanoi A, et al. Serum endostatin predicts tumor vascularity in hepatocellular carcinoma [Ｊ]. Cancer, 2002; 95(10): 2188-2195.
29.	Poon RT, Chung KK, Cheung ST, et al. Clinical significance of thrombospondin 1 expression in hepatocellular carcinoma [Ｊ]. Clin Cancer Res, 2004; 10(12 Pt 1): 4150-4157.
30.	Altadill A, Rodríguez M, González LO, et al. Liver expression of matrix metalloproteases and their inhibitors in hepatocellular carcinoma [Ｊ]. Dig Liver Dis, 2009 Apr 14[Epub ahead of print].
31.	Xia D, Yan LN, Xie JG, et al. Overexpression of TIMP-1 mediated by recombinant adenovirus in hepatocellular carcinoma cells inhibits proliferation and invasion in vitro [Ｊ]. Hepatobiliary Pancreat Dis Int, 2006; 5(3): 409-415.
32.	Morinaga S, Yamamoto Y, Noguchi Y, et al. Platelet-derived endothelial cell growth factor (PD-ECGF) is up-regulated in human hepatocellular carcinoma (HCC) and the corresponding hepatitis liver [Ｊ]. Hepatogastroenterology, 2003; 50(53): 1521-1526.
33.	Cervello M, Montalto G. Cyclooxygenases in hepatocellular carcinoma [Ｊ]. World J Gastroenterol, 2006; 12(32): 5113-5121.
34.	Horiguchi N, Takayama H, Toyoda M, et al. Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine [Ｊ]. Oncogene, 2002; 21(12): 1791-1799.
35.	Chau GY, Lui WY, Chi CW, et al. Significance of serum hepatocyte growth factor levels in patients with hepatocellular carcinoma undergoing hepatic resection [Ｊ]. Eur J Surg Oncol, 2008; 34(3): 333-338.
36.	Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase Ⅱ study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma [Ｊ]. J Clin Oncol, 2006; 24(12): 1898-1903.
37.	Siegel AB, Cohen EI, Ocean A, et al. Phase Ⅱ trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma [Ｊ]. J Clin Oncol, 2008; 26(18): 2992-2998.
38.	Ueda S, Basaki Y, Yoshie M, et al. PTEN/Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib [Ｊ]. Cancer Res, 2006; 66(10): 5346-5353.
39.	Hpfner M, Sutter AP, Huether A, et al. Targeting the epidermal growth factor receptor by gefitinib for treatment of hepatocellular carcinoma [Ｊ]. J Hepatol, 2004; 41(6): 1008-1016.
40.	Herrmann E, Bierer S, Gerss J, et al. Prospective comparison of sorafenib and sunitinib for second-line treatment of cytokine-refractory kidney cancer patients [Ｊ]. Oncology, 2008; 74(3-4): 216-222.
41.	Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase Ⅲ randomised, double-blind, placebo-controlled trial [Ｊ]. Lancet Oncol, 2009; 10(1): 25-34.
42.	Hsieh CH, Jeng KS, Lin CC, et al. Combination of sorafenib and intensity modulated radiotherapy for unresectable hepatocellular carcinoma [Ｊ]. Clin Drug Investig, 2009; 29(1): 65-71.
43.	李勇，张湘茹，孙燕. 多靶点抗肿瘤药物： ZD6474 [Ｊ]. 癌症进展， 2006; 4(3): 206-210.
44.	Zhu AX, Raymond E. Early development of sunitinib in hepatocellular carcinoma [Ｊ]. Expert Rev Anticancer Ther, 2009; 9(1): 143-150.
45.	Zhu AX, Sahani DV, di Tomaso E, et al. A Phase Ⅱstudy of sunitinib in patients with ad advanced hepatocellular carcinoma (poster) [C]. The 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO). Chicago, June 1-5, 2007.
46.	Faivre SJ, Raymond E, Douillard J, et al. Phase Ⅱtrial investigating the efficacy and and safety of sunitinib in patients with unresectable hepatocellular carcinoma (poster) [C]. The 14th European Cancer Conference (ECCO). Barcelona, Spain. September 23-27, 2007.
47.	Yang ZF, Poon RT, Liu Y, et al. High doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: dual effects on cancer cell and angiogenesis [Ｊ]. Mol Cancer Ther, 2006; 5(9): 2261-2270.
48.	Ribatti D, Vacca A. Therapeutic renaissance of thalidomide in the treatment of haematological malignancies [Ｊ]. Leukemia, 2005; 19(9): 1525-1531.
49.	Chiou HE, Wang TE, Wang YY, et al. Efficacy and safety of thalidomide in patients with hepatocellular carcinoma. World J Gastroenterol, 2006; 12(43): 6955-6960.
50.	Chuah B, Lim R, Boyer M, et al. Multi-centre phase Ⅱ trial of Thalidomide in the treatment of unresectable hepatocellular carcinoma [Ｊ]. Acta Oncol, 2007; 46(2): 234-238.
51.	Celik I, Sürücü O, Dietz C, et al. Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve [Ｊ]. Cancer Res, 2005; 65(23): 11044-11050.
52.	Mauriz JL, Gonzalez P, Duran MC, et al. Cell-cycle inhibition by TNP-470 in an in vivo model of hepatocarcinoma is mediated by a p53 and p21WAF1/CIP1 mechanism [Ｊ]. Transl Res, 2007; 149(1): 46-53.
53.	Bu W, Tang ZY, Sun FX, et al. Effects of matrix metalloproteinase inhibitor BB-94 on liver cancer growth and metastasis in a patient-like orthotopic model LCI-D20 [Ｊ]. Hepatogastroenterology, 1998; 45(22): 1056-1061.
54.	Zhao QT, Yue SQ, Cui Z, et al. Potential involvement of the cyclooxygenase-2 pathway in hepatocellular carcinoma-associated angiogenesis [Ｊ]. Life Sci, 2007; 80(5): 484-492.
55.	Baek JY, Hur W, Wang JS, et al. Selective COX-2 inhibitor, NS-398, suppresses cellular proliferation in human hepatocellular carcinoma cell lines via cell cycle arrest [Ｊ]. World J Gastroenterol, 2007; 13(8): 1175-1181.
56.	Lin SM, Yu ML, Lee CM, et al. Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma [Ｊ]. J Hepatol, 2007; 46(1): 45-52.
57.	Wada H, Nagano H, Yamamoto H, et al. Combination therapy of interferon-alpha and 5-fluorouracil inhibits tumor angiogenesis in human hepatocellular carcinoma cells by regulating vascular endothelial growth factor and angiopoietins [Ｊ]. Oncol Rep, 2007; 18(4): 801-809.
58.	Treiber G, Wex T, Rcken C, et al. Impact of biomarkers on disease survival and progression in patients treated with octreotide for advanced hepatocellular carcinoma [Ｊ]. J Cancer Res Clin Oncol, 2006; 132(11): 699-708.
59.	Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy [Ｊ]. Nat Rev Cancer, 2004; 4(6): 423-436.

1. Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells [Ｊ]. Biochem Biophys Res Commun, 1989; 161(2): 851-858.
2. Teramoto S, Arihiro K, Koseki M, et al. Role of vascular endothelial growth factor-C and -D mRNA in breast cancer [Ｊ]. Hiroshima J Med Sci, 2008; 57(2): 73-88.
3. Thelen A, Scholz A, Benckert C, et al. VEGF-D promotes tumor growth and lymphatic spread in a mouse model of hepatocellular carcinoma [Ｊ]. Int J Cancer, 2008; 122(11): 2471-2481.
4. Brekken RA, Overholser JP, Stastny VA, et al. Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice [Ｊ]. Cancer Res, 2000; 60(18): 5117-5124.
5. Brodsky SV, Mendelev N, Melamed M, et al. Vascular density and VEGF expression in hepatic lesions [Ｊ]. J Gastrointestin Liver Dis, 2007; 16(4): 373-377.
6. Li Q, Xu B, Fu L, et al. Correlation of four vascular specific growth factors with carcinogenesis and portal vein tumor thrombus formation in human hepatocellular carcinoma [Ｊ]. J Exp Clin Cancer Res, 2006; 25(3): 403-409.
7. Raskopf E, Vogt A, Sauerbruch T, et al. siRNA targeting VEGF inhibits hepatocellular carcinoma growth and tumor angiogenesis in vivo [Ｊ]. J Hepatol, 2008; 49(6): 977-984.
8. Amaoka N, Saio M, Nonaka K, et al. Expression of vascular endothelial growth factor receptors is closely related to the histological grade of hepatocellular carcinoma [Ｊ]. Oncol Rep, 2006; 16(1): 3-10.
9. Yasuda S, Arii S, Mori A, et al. Hexokinase Ⅱ and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1 alpha and its significance [Ｊ]. J Hepatol, 2004; 40(1): 117-123.
10. Tang TC, Poon RT, Lau CP, et al. Tumor cyclooxygenase-2 levels correlate with tumor invasiveness in human hepatocellular carcinoma [Ｊ]. World J Gastroenterol, 2005; 11(13): 1896-1902.
11. Tseng PL, Tai MH, Huang CC, et al. Overexpression of VEGF is associated with positive p53 immunostaining in hepatocellular carcinoma (HCC) and adverse outcome of HCC patients [Ｊ]. J Surg Oncol, 2008; 98(5): 349-357.
12. Bhagwat SV, Petrovic N, Okamoto Y, et al. The angiogenic regulator CD13/APN is a transcriptional target of Ras signaling pathways in endothelial morphogenesis [Ｊ]. Blood, 2003; 101(5): 1818-1826.
13. Poon RT, Ng IO, Lau C, et al. Correlation of serum basic fibroblast growth factor levels with clinicopathologic features and postoperative recurrence in hepatocellular carcinoma [Ｊ]. Am J Surg, 2001; 182(3): 298-304.
14. Kin M, Sata M, Ueno T, et al. Basic fibroblast growth factor regulates proliferation and motility of human hepatoma cells by an autocrine mechanism [Ｊ]. J Hepatol, 1997; 27(4): 677-687.
15. Yoshiji H, Kuriyama S, Yoshii J, et al. Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma [Ｊ]. Hepatology, 2002; 35(4): 834-842.
16. Kuboki S, Shimizu H, Mitsuhashi N, et al. Angiopoietin-2 levels in the hepatic vein as a useful predictor of tumor invasiveness and prognosis in human hepatocellular carcinoma [Ｊ]. J Gastroenterol Hepatol, 2008; 23(7 Pt 2): e157-e164.
17. Wada H, Nagano H, Yamamoto H, et al. Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma: importance of angiopoietin-2 and hypoxia-induced factor-1 alpha [Ｊ]. Liver Int, 2006; 26(4): 414-423.
18. Tanaka S, Wands JR, Arii S. Induction of angiopoietin-2 ge-ne expression by COX-2: a novel role for COX-2 inhibitors during hepatocarcinogenesis [Ｊ]. J Hepatol, 2006; 44(1): 233-235.
19. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? [Ｊ]. Lancet, 2001; 357(9255): 539-545.
20. Pérez-Ruiz M, Ros J, Morales-Ruiz M, et al. Vascular endothelial growth factor production in peritoneal macrophages of cirrhotic patients: regulation by cytokines and bacterial lipopolysaccharide [Ｊ]. Hepatology, 1999; 29(4): 1057-1063.
21. Menon C, Iyer M, Prabakaran I, et al. TNF-alpha downregulates vascular endothelial Flk-1 expression in human melanoma xenograft model [Ｊ]. Am J Physiol Heart Circ Physiol, 2003; 284(1): H317-H329.
22. Bai L, Mao GP, Cao CP. Effects of inflammatory cytokines on the recurrence of liver cancer after an apparently curative operation [Ｊ]. J Dig Dis, 2007; 8(3): 154-159.
23. Qiu LW, Yao DF, Zong L, et al. Abnormal expression of insulin-like growth factor-Ⅱ and its dynamic quantitative analysis at different stages of hepatocellular carcinoma development [Ｊ]. Hepatobiliary Pancreat Dis Int, 2008; 7(4): 406-411.
24. Nussbaum T, Samarin J, Ehemann V, et al. Autocrine insulin-like growth factor-Ⅱ stimulation of tumor cell migration is a progression step in human hepatocarcinogenesis [Ｊ]. Hepatology, 2008; 48(1): 146-156.
25. Ishikawa H, Nakao K, Matsumoto K, et al. Antiangiogenic gene therapy for hepatocellular carcinoma using angiostatin gene [Ｊ]. Hepatology, 2003; 37(3): 696-704.
26. Yuan S, Fu Y, Wang X, et al. Voltage-dependent anion channel 1 is involved in endostatin-induced endothelial cell apoptosis [Ｊ]. FASEB J, 2008; 22(8): 2809-2820.
27. Poon RT, Ho JW, Tong CS, et al. Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma [Ｊ]. Br J Surg, 2004; 91(10): 1354-1360.
28. Dhar DK, Ono T, Yamanoi A, et al. Serum endostatin predicts tumor vascularity in hepatocellular carcinoma [Ｊ]. Cancer, 2002; 95(10): 2188-2195.
29. Poon RT, Chung KK, Cheung ST, et al. Clinical significance of thrombospondin 1 expression in hepatocellular carcinoma [Ｊ]. Clin Cancer Res, 2004; 10(12 Pt 1): 4150-4157.
30. Altadill A, Rodríguez M, González LO, et al. Liver expression of matrix metalloproteases and their inhibitors in hepatocellular carcinoma [Ｊ]. Dig Liver Dis, 2009 Apr 14[Epub ahead of print].
31. Xia D, Yan LN, Xie JG, et al. Overexpression of TIMP-1 mediated by recombinant adenovirus in hepatocellular carcinoma cells inhibits proliferation and invasion in vitro [Ｊ]. Hepatobiliary Pancreat Dis Int, 2006; 5(3): 409-415.
32. Morinaga S, Yamamoto Y, Noguchi Y, et al. Platelet-derived endothelial cell growth factor (PD-ECGF) is up-regulated in human hepatocellular carcinoma (HCC) and the corresponding hepatitis liver [Ｊ]. Hepatogastroenterology, 2003; 50(53): 1521-1526.
33. Cervello M, Montalto G. Cyclooxygenases in hepatocellular carcinoma [Ｊ]. World J Gastroenterol, 2006; 12(32): 5113-5121.
34. Horiguchi N, Takayama H, Toyoda M, et al. Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine [Ｊ]. Oncogene, 2002; 21(12): 1791-1799.
35. Chau GY, Lui WY, Chi CW, et al. Significance of serum hepatocyte growth factor levels in patients with hepatocellular carcinoma undergoing hepatic resection [Ｊ]. Eur J Surg Oncol, 2008; 34(3): 333-338.
36. Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase Ⅱ study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma [Ｊ]. J Clin Oncol, 2006; 24(12): 1898-1903.
37. Siegel AB, Cohen EI, Ocean A, et al. Phase Ⅱ trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma [Ｊ]. J Clin Oncol, 2008; 26(18): 2992-2998.
38. Ueda S, Basaki Y, Yoshie M, et al. PTEN/Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib [Ｊ]. Cancer Res, 2006; 66(10): 5346-5353.
39. Hpfner M, Sutter AP, Huether A, et al. Targeting the epidermal growth factor receptor by gefitinib for treatment of hepatocellular carcinoma [Ｊ]. J Hepatol, 2004; 41(6): 1008-1016.
40. Herrmann E, Bierer S, Gerss J, et al. Prospective comparison of sorafenib and sunitinib for second-line treatment of cytokine-refractory kidney cancer patients [Ｊ]. Oncology, 2008; 74(3-4): 216-222.
41. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase Ⅲ randomised, double-blind, placebo-controlled trial [Ｊ]. Lancet Oncol, 2009; 10(1): 25-34.
42. Hsieh CH, Jeng KS, Lin CC, et al. Combination of sorafenib and intensity modulated radiotherapy for unresectable hepatocellular carcinoma [Ｊ]. Clin Drug Investig, 2009; 29(1): 65-71.
43. 李勇，张湘茹，孙燕. 多靶点抗肿瘤药物： ZD6474 [Ｊ]. 癌症进展， 2006; 4(3): 206-210.
44. Zhu AX, Raymond E. Early development of sunitinib in hepatocellular carcinoma [Ｊ]. Expert Rev Anticancer Ther, 2009; 9(1): 143-150.
45. Zhu AX, Sahani DV, di Tomaso E, et al. A Phase Ⅱstudy of sunitinib in patients with ad advanced hepatocellular carcinoma (poster) [C]. The 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO). Chicago, June 1-5, 2007.
46. Faivre SJ, Raymond E, Douillard J, et al. Phase Ⅱtrial investigating the efficacy and and safety of sunitinib in patients with unresectable hepatocellular carcinoma (poster) [C]. The 14th European Cancer Conference (ECCO). Barcelona, Spain. September 23-27, 2007.
47. Yang ZF, Poon RT, Liu Y, et al. High doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: dual effects on cancer cell and angiogenesis [Ｊ]. Mol Cancer Ther, 2006; 5(9): 2261-2270.
48. Ribatti D, Vacca A. Therapeutic renaissance of thalidomide in the treatment of haematological malignancies [Ｊ]. Leukemia, 2005; 19(9): 1525-1531.
49. Chiou HE, Wang TE, Wang YY, et al. Efficacy and safety of thalidomide in patients with hepatocellular carcinoma. World J Gastroenterol, 2006; 12(43): 6955-6960.
50. Chuah B, Lim R, Boyer M, et al. Multi-centre phase Ⅱ trial of Thalidomide in the treatment of unresectable hepatocellular carcinoma [Ｊ]. Acta Oncol, 2007; 46(2): 234-238.
51. Celik I, Sürücü O, Dietz C, et al. Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve [Ｊ]. Cancer Res, 2005; 65(23): 11044-11050.
52. Mauriz JL, Gonzalez P, Duran MC, et al. Cell-cycle inhibition by TNP-470 in an in vivo model of hepatocarcinoma is mediated by a p53 and p21WAF1/CIP1 mechanism [Ｊ]. Transl Res, 2007; 149(1): 46-53.
53. Bu W, Tang ZY, Sun FX, et al. Effects of matrix metalloproteinase inhibitor BB-94 on liver cancer growth and metastasis in a patient-like orthotopic model LCI-D20 [Ｊ]. Hepatogastroenterology, 1998; 45(22): 1056-1061.
54. Zhao QT, Yue SQ, Cui Z, et al. Potential involvement of the cyclooxygenase-2 pathway in hepatocellular carcinoma-associated angiogenesis [Ｊ]. Life Sci, 2007; 80(5): 484-492.
55. Baek JY, Hur W, Wang JS, et al. Selective COX-2 inhibitor, NS-398, suppresses cellular proliferation in human hepatocellular carcinoma cell lines via cell cycle arrest [Ｊ]. World J Gastroenterol, 2007; 13(8): 1175-1181.
56. Lin SM, Yu ML, Lee CM, et al. Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma [Ｊ]. J Hepatol, 2007; 46(1): 45-52.
57. Wada H, Nagano H, Yamamoto H, et al. Combination therapy of interferon-alpha and 5-fluorouracil inhibits tumor angiogenesis in human hepatocellular carcinoma cells by regulating vascular endothelial growth factor and angiopoietins [Ｊ]. Oncol Rep, 2007; 18(4): 801-809.
58. Treiber G, Wex T, Rcken C, et al. Impact of biomarkers on disease survival and progression in patients treated with octreotide for advanced hepatocellular carcinoma [Ｊ]. J Cancer Res Clin Oncol, 2006; 132(11): 699-708.
59. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy [Ｊ]. Nat Rev Cancer, 2004; 4(6): 423-436.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Advances of Study on Angiogenesis and Antiangiogenic Therapy in Hepatocellular Carcinoma

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