International Journal of Clinical Oncology

, Volume 11, Issue 2, pp 82–89

Current status and perspective of antiangiogenic therapy for cancer: hepatocellular carcinoma

REVIEW ARTICLE

Abstract

Hepatocellular carcinoma (HCC) is well known as a typical angiogenic tumor, especially in the moderately to poorly differentiated type. Such clinicopathological characteristics are not only useful for imaging diagnosis but are also applicable to the treatment of HCC. In addition, recent molecular studies have revealed that angiogenesis is closely related to hepatocarcinogenesis. In this review, the molecular mechanism of HCC angiogenesis and the antiangiogenic prevention of HCC are reviewed to introduce the latest trends in antiangiogenic treatment of cancers, including HCC.

Key words

Hepatocellular carcinoma Angiogenesis Angiogenic switch VEGF Angiopoietin Molecularly targeted antiangiogenic therapy 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Folkman, J 1971Tumor angiogenesis: therapeutic implicationsN Engl J Med28511821186PubMedGoogle Scholar
  2. 2.
    Ferrara, N, Kerbel, RS 2005Angiogenesis as a therapeutic targetNature (Lond)438967794Google Scholar
  3. 3.
    Hanahan, D, Folkman, J 1996Patterns and emerging mechanisms of the angiogenic switch during tumorigenesisCell86353364CrossRefPubMedGoogle Scholar
  4. 4.
    Carmeliet, P, Jain, RK 2000Angiogenesis in cancer and other diseasesNature (Lond)407249257Google Scholar
  5. 5.
    Asahara, T, Murohara, T, Sullivan, A,  et al. 1997Isolation of putative progenitor endothelial cells for angiogenesisScience275964967CrossRefPubMedGoogle Scholar
  6. 6.
    Kawahara, N, Ono, M, Taguchi, K,  et al. 1998Enhanced expression of thrombospondin-1 and hypovascularity in human cholangiocarcinomaHepatology2815121517CrossRefPubMedGoogle Scholar
  7. 7.
    Poon, RT, Chung, KK, Cheung, ST,  et al. 2004Clinical significance of thrombospondin 1 expression in hepatocellular carcinomaClin Cancer Res1041504157PubMedGoogle Scholar
  8. 8.
    Ferrara, N 2002VEGF and the quest for tumour angiogenesis factorsNat Rev Cancer2795803CrossRefPubMedGoogle Scholar
  9. 9.
    Mise, M, Arii, S, Higashituji, H,  et al. 1996Clinical significance of vascular endothelial growth factor and basic fibroblast growth factor gene expression in liver tumorHepatology23455464PubMedGoogle Scholar
  10. 10.
    Park, YN, Kim, YB, Yang, KM, Park, C 2000Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesisArch Pathol Lab Med12410611065PubMedGoogle Scholar
  11. 11.
    Ng, IO, Poon, RT, Lee, JM,  et al. 2001Microvessel density, vascular endothelial growth factor and its receptors Flt-1 and Flk-1/KDR in hepatocellular carcinomaAm J Clin Pathol116838845PubMedGoogle Scholar
  12. 12.
    Li, XM, Tang, ZY, Zhou, G, Liu, YK, Ye, SL 1998Significance of vascular endothelial growth factor mRNA expression in invasion and metastasis of hepatocellular carcinomaJ Exp Clin Cancer Res171317PubMedGoogle Scholar
  13. 13.
    El Assal, ON, Yamanoi, A, Soda, Y,  et al. 1998Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liverHepatology2715541562PubMedGoogle Scholar
  14. 14.
    Yamaguchi, R, Yano, H, Iemura, A,  et al. 1998Expression of vascular endothelial growth factor in human hepatocellular carcinomaHepatology286877PubMedGoogle Scholar
  15. 15.
    Sugimachi, K, Tanaka, S, Taguchi, K,  et al. 2003Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinomaJ Clin Pathol56854860CrossRefPubMedGoogle Scholar
  16. 16.
    Yasuda, S, Arii, S, Mori, A,  et al. 2004Hexokinase II and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1 alpha and its significanceJ Hepatol40117123CrossRefPubMedGoogle Scholar
  17. 17.
    von Marschall, Z, Cramer, T, Hocker, M,  et al. 2001Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinomaGut488796CrossRefPubMedGoogle Scholar
  18. 18.
    Tsukamoto, A, Kaneko, Y, Yoshida, T, Ichinose, M, Kimura, S 1999Regulation of angiogenesis in human hepatomas: possible involvement of p53-inducible inhibitor of vascular endothelial cell proliferationCancer Lett1417984PubMedGoogle Scholar
  19. 19.
    Lee, SW, Lee, YM, Bae, SK,  et al. 2000Human hepatitis B virus X protein is a possible mediator of hypoxia-induced angiogenesis in hepatocarcinogenesisBiochem Biophys Res Commun268456461PubMedGoogle Scholar
  20. 20.
    Tsujii, M, Kawano, S, Tsuji, S,  et al. 1998Cyclooxygenase regulates angiogenesis induced by colon cancer cellsCell93705716CrossRefPubMedGoogle Scholar
  21. 21.
    Schmitt, M, Horbach, A, Kubitz, R, Frilling, A, Haussinger, D 2004Disruption of hepatocellular tight junctions by vascular endothelial growth factor (VEGF): a novel mechanism for tumor invasionJ Hepatol41274283CrossRefPubMedGoogle Scholar
  22. 22.
    Arii, S 2004Role of vascular endothelial growth factor on the invasive potential of hepatocellular carcinomaJ Hepatol41333335CrossRefPubMedGoogle Scholar
  23. 23.
    Poon, RT, Ng, IO, Lau, C,  et al. 2001Correlation of serum basic fibroblast growth factor levels with clinicopathologic features and postoperative recurrence in hepatocellular carcinomaAm J Surg182298304CrossRefPubMedGoogle Scholar
  24. 24.
    Yoshiji, H, Kuriyama, S, Yoshii, J,  et al. 2002Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinomaHepatology35834842CrossRefPubMedGoogle Scholar
  25. 25.
    Ogasawara, S, Yano, H, Iemura, A, Hisaka, T, Kojiro, M 1996Expressions of basic fibroblast growth factor and its receptors and their relationship to proliferation of human hepatocellular carcinoma cell linesHepatology24198205PubMedGoogle Scholar
  26. 26.
    Kin, M, Sata, M, Ueno, T,  et al. 1997Basic fibroblast growth factor regulates proliferation and motility of human hepatoma cells by an autocrine mechanismJ Hepatol27677687CrossRefPubMedGoogle Scholar
  27. 27.
    Kage, K, Fujita, N, Oh-hara, T,  et al. 1999Basic fibroblast growth factor induces cyclooxygenase-2 expression in endothelial cells derived from boneBiochem Biophys Res Commun254259263CrossRefPubMedGoogle Scholar
  28. 28.
    Uematsu, S, Higashi, T, Nouso, K,  et al. 2005Altered expression of vascular endothelial growth factor, fibroblast growth factor-2 and endostatin in patients with hepatocellular carcinomaJ Gastroenterol Hepatol20583588CrossRefPubMedGoogle Scholar
  29. 29.
    Motoo, Y, Sawabu, N, Yamaguchi, Y, Terada, T, Nakanuma, Y 1993Sinusoidal capillarization of human hepatocellular carcinoma: possible promotion by fibroblast growth factorOncology50270274PubMedGoogle Scholar
  30. 30.
    Balkwill, F, Mantovani, A 2001Inflammation and cancer: back to Virchow?Lancet357539545CrossRefPubMedGoogle Scholar
  31. 31.
    Gorrin Rivas, MJ, Arii, S, Furutani, M,  et al. 1998Expression of human macrophage metalloelastase gene in hepatocellular carcinoma: correlation with angiostatin generation and its clinical significanceHepatology28986993PubMedGoogle Scholar
  32. 32.
    Akiba, J, Yano, H, Ogasawara, S, Higaki, K, Kojiro, M 2001Expression and function of interleukin-8 in human hepatocellular carcinomaInt J Oncol18257264PubMedGoogle Scholar
  33. 33.
    Perez-Ruiz, M, Ros, J, Morales-Ruiz, M,  et al. 1999Vascular endothelial growth factor production in peritoneal macrophages of cirrhotic patients: regulation by cytokines and bacterial lipopolysaccharideHepatology2910571063PubMedGoogle Scholar
  34. 34.
    Kawakita, T, Shiraki, K, Yamanaka, Y,  et al. 2004Functional expression of TWEAK in human hepatocellular carcinoma: possible implication in cell proliferation and tumor angiogenesisBiochem Biophys Res Commun318726733CrossRefPubMedGoogle Scholar
  35. 35.
    Jakubowski, A, Ambrose, C, Parr, M,  et al. 2005TWEAK induces liver progenitor cell proliferationJ Clin Invest11523302340CrossRefPubMedGoogle Scholar
  36. 36.
    Fausto, N 2005Tweaking liver progenitor cellsNat Med1110531054CrossRefPubMedGoogle Scholar
  37. 37.
    Tanaka, S, Mori, M, Sakamoto, Y,  et al. 1999Biologic significance of angiopoietin-2 expression in human hepatocellular carcinomaJ Clin Invest103341345PubMedGoogle Scholar
  38. 38.
    Davis, S, Aldrich, TH, Jones, PF,  et al. 1996Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloningCell8711611169CrossRefPubMedGoogle Scholar
  39. 39.
    Maisonpierre, PC, Suri, C, Jones, PF,  et al. 1997Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesisScience2775560CrossRefPubMedGoogle Scholar
  40. 40.
    Gill, KA, Brindle, NP 2005Angiopoietin-2 stimulates migration of endothelial progenitors and their interaction with endotheliumBiochem Biophys Res Commun336392396CrossRefPubMedGoogle Scholar
  41. 41.
    Mandriota, SJ, Pepper, MS 1998Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxiaCirc Res83852859PubMedGoogle Scholar
  42. 42.
    Tanaka, S, Wands, JR, Arii, S 2006Induction of angiopoietin-2 gene expression by COX-2: a novel role for COX-2 inhibitors during hepatocarcinogenesisJ Hepatol44233235CrossRefPubMedGoogle Scholar
  43. 43.
    Witzenbichler, B, Maisonpierre, PC, Jones, P, Yancopoulos, GD, Isner, JM 1998Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2J Biol Chem2731851418521CrossRefPubMedGoogle Scholar
  44. 44.
    Yancopoulos, GD, Davis, S, Gale, NW,  et al. 2000Vascular-specific growth factors and blood vessel formationNature (Lond)407242248Google Scholar
  45. 45.
    Tanaka, S, Sugimachi, K, Yamashita, Y,  et al. 2002Tie2 vascular endothelial receptor expression and function in hepatocellular carcinomaHepatology35861867CrossRefPubMedGoogle Scholar
  46. 46.
    Tanaka, S, Sugimachi, K, Yamashita, Y,  et al. 2003Angiogenic switch as a molecular target of malignant tumorsJ Gastroenterol389397PubMedGoogle Scholar
  47. 47.
    Thun, MJ, Namboodiri, MM, Heath, CW,Jr 1991Aspirin use and reduced risk of fatal colon cancerN Engl J Med32515931596PubMedGoogle Scholar
  48. 48.
    Koga, H 2003Hepatocellular carcinoma: is there a potential for chemoprevention using cyclooxygenase-2 inhibitors?Cancer (Phila)98661667Google Scholar
  49. 49.
    Tanaka, N, Ishihara, M, Lamphier, MS,  et al. 1996Cooperation of the tumour suppressors IRF-1 and p53 in response to DNA damageNature (Lond)382816818Google Scholar
  50. 50.
    Ohno, S, Nishi, T, Kojima, Y,  et al. 2002Combined stimulation with interferon alpha and retinoic acid synergistically inhibits proliferation of the glioblastoma cell line GB12Neurol Res24697704CrossRefPubMedGoogle Scholar
  51. 51.
    von Marschall, Z, Scholz, A, Cramer, T,  et al. 2003Effects of interferon alpha on vascular endothelial growth factor gene transcription and tumor angiogenesisJ Natl Cancer Inst95437448PubMedGoogle Scholar
  52. 52.
    Marler, JJ, Rubin, JB, Trede, NS,  et al. 2002Successful antiangiogenic therapy of giant cell angioblastoma with interferon alfa 2b: report of 2 casesPediatrics109E37CrossRefPubMedGoogle Scholar
  53. 53.
    Wang, L, Wu, WZ, Sun, HC,  et al. 2003Mechanism of interferon alpha on inhibition of metastasis and angiogenesis of hepatocellular carcinoma after curative resection in nude miceJ Gastrointest Surg7587594CrossRefPubMedGoogle Scholar
  54. 54.
    Wang, L, Tang, ZY, Qin, LX,  et al. 2000High-dose and long-term therapy with interferon-alfa inhibits tumor growth and recurrence in nude mice bearing human hepatocellular carcinoma xenografts with high metastatic potentialHepatology324348CrossRefPubMedGoogle Scholar
  55. 55.
    Muto, Y, Moriwaki, H, Saito, A 1999Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinomaN Engl J Med34010461047CrossRefPubMedGoogle Scholar
  56. 56.
    Sporn, MB, Suh, N 2000Chemoprevention of cancerCarcinogenesis (Oxf)21525530Google Scholar
  57. 57.
    Lingen, MW, Polverini, PJ, Bouck, NP 1996Retinoic acid induces cells cultured from oral squamous cell carcinomas to become anti-angiogenicAm J Pathol149247258PubMedGoogle Scholar
  58. 58.
    Diaz, BV, Lenoir, MC, Ladoux, A,  et al. 2000Regulation of vascular endothelial growth factor expression in human keratinocytes by retinoidsJ Biol Chem275642650CrossRefPubMedGoogle Scholar
  59. 59.
    Iurlaro, M, Benelli, R, Masiello, L,  et al. 1998Beta interferon inhibits HIV-1 Tat-induced angiogenesis: synergism with 13-cis retinoic acidEur J Cancer34570576CrossRefPubMedGoogle Scholar
  60. 60.
    Majewski, S, Szmurlo, A, Marczak, M, Jablonska, S, Bollag, W 1994Synergistic effect of retinoids and interferon alpha on tumor-induced angiogenesis: anti-angiogenic effect on HPV-harboring tumor-cell linesInt J Cancer578185PubMedGoogle Scholar
  61. 61.
    Bengtson, EM, Rigas, JR 1999New oral chemotherapeutic agents for lung cancerDrugs585769PubMedGoogle Scholar
  62. 62.
    Ribatti, D, Alessandri, G, Baronio, M,  et al. 2001Inhibition of neuroblastoma-induced angiogenesis by fenretinideInt J Cancer94314321CrossRefPubMedGoogle Scholar
  63. 63.
    Kagawa, M, Sano, T, Ishibashi, N,  et al. 2004An acyclic retinoid, NIK-333, inhibits N-diethylnitrosamine-induced rat hepatocarcinogenesis through suppression of TGF-alpha expression and cell proliferationCarcinogenesis (Oxf)25979985Google Scholar
  64. 64.
    Banerjee, P, Chatterjee, M 2003Antiproliferative role of vitamin D and its analogs: a brief overviewMol Cell Biochem253247254PubMedGoogle Scholar
  65. 65.
    Mantell, DJ, Owens, PE, Bundred, NJ, Mawer, EB, Canfield, AE 20001-Alpha, 25-dihydoxyvitamin D3 inhibits angiogenesis in vitro and in vivoCirc Res87214220PubMedGoogle Scholar
  66. 66.
    Masood, R, Nagpal, S, Zheng, T,  et al. 2000Kaposi sarcoma is a therapeutic target for vitamin D3 receptor agonistBlood9631883194PubMedGoogle Scholar
  67. 67.
    Dalhoff, K, Dancey, J, Astrup, L,  et al. 2003A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinomaBr J Cancer89252257CrossRefPubMedGoogle Scholar
  68. 68.
    Park, BH, Breyer, B, He, TC 2001Peroxisome proliferator-activated receptors: roles in tumorigenesis and chemoprevention in human cancerCurr Opin Oncol137883CrossRefPubMedGoogle Scholar
  69. 69.
    Xin, X, Yang, S, Kowalski, J, Gerritsen, ME 1999Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivoJ Biol Chem27491169121CrossRefPubMedGoogle Scholar
  70. 70.
    Bishop-Bailey, D, Hla, T 1999Endothelial cell apoptosis induced by peroxisome proliferator-activated receptor (PPAR) ligand 15-deoxy delta 12,14-prostaglandin J2J Biol Chem2741704217048CrossRefPubMedGoogle Scholar
  71. 71.
    Mueller, E, Sarraf, P, Tontonoz, P,  et al. 1998Terminal differentiation of human breast cancer through PPAR-γMol Cell1465470CrossRefPubMedGoogle Scholar
  72. 72.
    Lefebvre, AM, Chen, I, Desreumaux, P,  et al. 1998Activation of the proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ miceNat Med410531057CrossRefPubMedGoogle Scholar
  73. 73.
    Schaefer, KL, Wada, K, Takahashi, H,  et al. 2005Peroxisome proliferator-activated receptor gamma inhibition prevents adhesion to the extracellular matrix and induces anoikis in hepatocellular carcinoma cellsCancer Res6522512259CrossRefPubMedGoogle Scholar
  74. 74.
    Hurwitz, H, Fehrenbacher, L, Novotny, W,  et al. 2004Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancerN Engl J Med35023352342CrossRefPubMedGoogle Scholar
  75. 75.
    Semela, D, Dufour, JF 2004Angiogenesis and hepatocellular carcinomaJ Hepatol41864880CrossRefPubMedGoogle Scholar
  76. 76.
    Liu, Y, Poon, RT, Li, Q, Kok, TW, Lau, C, Fan, ST 2005Both antiangiogenesis- and angiogenesis-independent effects are responsible for hepatocellular carcinoma growth arrest by tyrosine kinase inhibitor PTK787/ZK222584Cancer Res6536913699PubMedGoogle Scholar
  77. 77.
    Strumberg, D, Richly, H, Hilger, RA,  et al. 2005Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumorsJ Clin Oncol23965972PubMedGoogle Scholar
  78. 78.
    Oliner, J, Min, H, Leal, J,  et al. 2004Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2Cancer Cell6507516CrossRefPubMedGoogle Scholar
  79. 79.
    Hirata, A, Ogawa, S, Kometani, T,  et al. 2002ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinaseCancer Res6225542560PubMedGoogle Scholar
  80. 80.
    Matsuo, M, Sakurai, H, Saiki, I 2003ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, shows antimetastatic activity using a hepatocellular carcinoma modelMol Cancer Ther2557561PubMedGoogle Scholar
  81. 81.
    Furumoto, K, Arii, S, Yamasaki, S,  et al. 2000Spleen-derived dendritic cells engineered to enhance interleukin-12 production elicit therapeutic antitumor immune responsesInt J Cancer87665672CrossRefPubMedGoogle Scholar
  82. 82.
    Yamashita, YI, Shimada, M, Hasegawa, H,  et al. 2001Electroporation-mediated interleukin-12 gene therapy for hepatocellular carcinoma in the mice modelCancer Res6110051012PubMedGoogle Scholar
  83. 83.
    O'Reilly, MS, Boehm, T, Shing, Y,  et al. 1997Endostatin: an endogenous inhibitor of angiogenesis and tumor growthCell88277285PubMedGoogle Scholar
  84. 84.
    Eder, JP,Jr, Supko, JG, Clark, JW,  et al. 2002Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated dailyJ Clin Oncol2037723784CrossRefPubMedGoogle Scholar
  85. 85.
    Patt, YZ, Hassan, MM, Lozano, RD,  et al. 2005Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trialCancer (Phila)103749755Google Scholar
  86. 86.
    List, A, Kurtin, S, Roe, DJ,  et al. 2005Efficacy of lenalidomide in myelodysplastic syndromesN Engl J Med352549557CrossRefPubMedGoogle Scholar
  87. 87.
    Niwano, M, Arii, S, Mori, A,  et al. 1998Inhibition of tumor growth and microvascular angiogenesis by the potent angiogenesis inhibitor, TNP-470, in ratsSurg Today28915922CrossRefPubMedGoogle Scholar
  88. 88.
    Kapadia, CR 1998Somatostatin and hepatocellular carcinomaGastroenterology11512981299CrossRefPubMedGoogle Scholar
  89. 89.
    Albini, A, Florio, T, Giunciuglio, D,  et al. 1999Somatostatin controls Kaposi's sarcoma tumor growth through inhibition of angiogenesisFASEB J13647655PubMedGoogle Scholar
  90. 90.
    St. Croix, B, Rago, C, Velculescu, V,  et al. 2000Genes expressed in human tumor endotheliumScience28911971202PubMedGoogle Scholar
  91. 91.
    Ruoslahti, E 2002Specialization of tumour vasculatureNat Rev Cancer28390CrossRefPubMedGoogle Scholar
  92. 92.
    Kerbel, RS, Kamen, BA 2004The anti-angiogenic basis of metronomic chemotherapyNat Rev Cancer4423436CrossRefPubMedGoogle Scholar
  93. 93.
    Bocci, G, Francia, G, Man, S, Lawler, J, Kerbel, RS 2003Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapyProc Natl Acad Sci U S A1001291712922CrossRefPubMedGoogle Scholar
  94. 94.
    Ma, J, Pulfer, S, Li, S,  et al. 2001Pharmacodynamic-mediated reduction of temozolomide tumor concentrations by the angiogenesis inhibitor TNP-470Cancer Res6154915498PubMedGoogle Scholar
  95. 95.
    Sengupta, S, Eavarone, D, Capila, I,  et al. 2005Temporal targeting of tumour cells and neovasculature with a nanoscale delivery systemNature (Lond)436568572Google Scholar
  96. 96.
    Gasparini, G, Longo, R, Fanelli, M, Teicher, BA 2005Combination of antiangiogenic therapy with other anticancer therapies: results, challenges, and open questionsJ Clin Oncol2312951311CrossRefPubMedGoogle Scholar
  97. 97.
    Winkler, F, Kozin, SV, Tong, RT,  et al. 2004Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinasesCancer Cell6553563PubMedGoogle Scholar
  98. 98.
    Jain, RK 2005Normalization of tumor vasculature: an emerging concept in antiangiogenic therapyScience3075862CrossRefPubMedGoogle Scholar
  99. 99.
    Greene, HSN 1941Heterologous transplantation of mammalian tumors. The transfer of human tumors of alien speciesJ Exp Med73461486Google Scholar
  100. 100.
    Algire, GH, Chalkley, HW, Legallais, FY, Park, HD 1945Vascular reactions of normal and malignant tissues in vivo. I. Vascular reactions of normal and neoplastic transplantsJ Natl Cancer Inst67385Google Scholar
  101. 101.
    Gasparini, G, Longo, R, Toi, M, Ferrara, N 2005Angiogenic inhibitors: a new therapeutic strategy in oncologyNat Clin Pract Oncol2562577PubMedGoogle Scholar

Copyright information

© The Japan Society of Clinical Oncology 2006

Authors and Affiliations

  1. 1.Department of Hepato-Biliary-Pancreatic SurgeryTokyo Medical and Dental University, Graduate School of MedicineTokyoJapan

Personalised recommendations