Liver Regeneration and Tumor Stimulation—A Review of Cytokine and Angiogenic Factors

  • Christopher Christophi
  • Nadia Harun
  • Theodora Fifis


Liver resection for metastatic (colorectal carcinoma) tumors is often followed by a significant incidence of tumor recurrence. Cellular and molecular changes resulting from hepatectomy and the subsequent liver regeneration process may influence the kinetics of tumor growth and contribute to recurrence. Clinical and experimental evidence suggests that factors involved in liver regeneration may also stimulate the growth of occult tumors and the reactivation of dormant micrometastases. An understanding of the underlying changes may enable alternative strategies to minimize tumor recurrence and improve patient survival after hepatectomy.


Colorectal carcinoma Liver resection Liver regeneration Cytokines Angiogenesis Growth factors Tumor recurrence 


  1. 1.
    Fong Y, Cohen AM, Fortner JG, et al. Liver resection for colorectal metastases. J Clin Oncol 1997;15:938–946.PubMedGoogle Scholar
  2. 2.
    Fong Y. Surgical therapy of hepatic colorectal metastasis. CA Cancer J Clin 1999;49:231–255.PubMedGoogle Scholar
  3. 3.
    Werther K, Christensen IJ, Nielsen HJ. Prognostic impact of matched preoperative plasma and serum VEGF in patients with primary colorectal carcinoma. Br J Cancer 2002;86:417–423.PubMedGoogle Scholar
  4. 4.
    Poon RT, Ng IO, Lau C, Yu WC, Fan ST, Wong J. Correlation of serum basic fibroblast growth factor levels with clinicopathologic features and postoperative recurrence in hepatocellular carcinoma. Am J Surg 2001;182:298–304.PubMedGoogle Scholar
  5. 5.
    Scheele J, Stangl R, Altendorf-Hofmann A. Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. Br J Surg 1990;77:1241–1246.PubMedGoogle Scholar
  6. 6.
    Schindel DT, Grosfeld JL. Hepatic resection enhances growth of residual intrahepatic and subcutaneous hepatoma, which is inhibited by octreotide. J Pediatr Surg 1997;32:995–997; discussion 997–998.PubMedGoogle Scholar
  7. 7.
    Liau KH, Ruo L, Shia J, et al. Outcome of partial hepatectomy for large (>10 cm) hepatocellular carcinoma. Cancer 2005;104:1948–1955.PubMedGoogle Scholar
  8. 8.
    Elias D, De Baere T, Roche A, Mducreux, Leclere J, Lasser P. During liver regeneration following right portal embolization the growth rate of liver metastases is more rapid than that of the liver parenchyma. Br J Surg 1999;86:784–788.PubMedGoogle Scholar
  9. 9.
    Kokudo N, Tada K, Seki M, et al. Proliferative activity of intrahepatic colorectal metastases after preoperative hemihepatic portal vein embolization. Hepatology 2001;34:267–272.PubMedGoogle Scholar
  10. 10.
    Togo S, Nagano Y, Masui H, et al. Two-stage hepatectomy for multiple bilobular liver metastases from colorectal cancer. Hepatogastroenterology 2005;52:913–919.PubMedGoogle Scholar
  11. 11.
    Adam R, Laurent A, Azoulay D, Castaing D, Bismuth H. Two-stage hepatectomy: A planned strategy to treat irresectable liver tumors. Ann Surg 2000;232:777–785.PubMedGoogle Scholar
  12. 12.
    von Schweinitz D, Faundez A, Teichmann B, et al. Hepatocyte growth-factor-scatter factor can stimulate post-operative tumor-cell proliferation in childhood hepatoblastoma. Int J Cancer 2000;85:151–159.Google Scholar
  13. 13.
    Slooter GD, Marquet RL, Jeekel J, Ijzermans JN. Tumour growth stimulation after partial hepatectomy can be reduced by treatment with tumour necrosis factor alpha. Br J Surg 1995;82:129–132.PubMedGoogle Scholar
  14. 14.
    de Jong KP, Lont HE, Bijma AM, et al. The effect of partial hepatectomy on tumor growth in rats: In vivo and in vitro studies. Hepatology 1995;22:1263–1272.PubMedGoogle Scholar
  15. 15.
    Picardo A, Karpoff HM, Ng B, Lee J, Brennan MF, Fong Y. Partial hepatectomy accelerates local tumor growth: Potential roles of local cytokine activation. Surgery 1998;124:57–64.PubMedGoogle Scholar
  16. 16.
    Harun N, Nikfarjam M, Muralidharan V, Christophi C. Liver Regeneration stimulates tumour metastases. J Surg Res 2007;138:284–290.PubMedGoogle Scholar
  17. 17.
    Rashidi B, An Z, Sun FX, et al. Minimal liver resection strongly stimulates the growth of human colon cancer in the liver of nude mice. Clin Exp Metastasis 1999;17:497–500.PubMedGoogle Scholar
  18. 18.
    Ikeda Y, Matsumata T, Takenaka K, Sasaki O, Soejima K, Sugimachi K. Preliminary report of tumor metastasis during liver regeneration after hepatic resection in rats. Eur J Surg Oncol 1995;21:188–190.PubMedGoogle Scholar
  19. 19.
    Mueller L, Goettsche J, Abdulgawad A, et al. Tumor growth-promoting cellular host response during liver atrophy after portal occlusion. Liver Int 2005;25:994–1001.PubMedGoogle Scholar
  20. 20.
    Kollmar O, Menger MD, Schilling MK. Macrophage inflammatory protein-2 contributes to liver resection-induced acceleration of hepatic metastatic tumor growth. World J Gastroenterol 2006;12:858–867.PubMedGoogle Scholar
  21. 21.
    Kountouras J, Boura P, Lygidakis NJ. Liver regeneration after hepatectomy. Hepatogastroenterology 2001;48:556–562.PubMedGoogle Scholar
  22. 22.
    Taub R. Liver regeneration: From myth to mechanism. Nat Rev Mol Cell Biol 2004;5:836–847.PubMedGoogle Scholar
  23. 23.
    Mangnall D, Bird NC, Majeed AW. The molecular physiology of liver regeneration following partial hepatectomy. Liver Int 2003;23:124–138.PubMedGoogle Scholar
  24. 24.
    Bucher NL. Regeneration of mammalian liver. Int Rev Cytol 1963;15:245–300.PubMedGoogle Scholar
  25. 25.
    Su AI, Guidotti LG, Pezacki JP, Chisari FV, Schultz PG. Gene expression during the priming phase of liver regeneration after partial hepatectomy in mice. Proc Natl Acad Sci U S A 2002;99:11181–11186.PubMedGoogle Scholar
  26. 26.
    White P, Brestelli JE, Kaestner KH, Greenbaum LE. Identification of transcriptional networks during liver regeneration. J Biol Chem 2005;280:3715–3722.PubMedGoogle Scholar
  27. 27.
    Fountoulakis M, Suter L. Proteomic analysis of the rat liver. J Chromatogr B Analyt Technol Biomed Life Sci 2002;782:197–218.PubMedGoogle Scholar
  28. 28.
    Michalopoulos GK, DeFrances MC. Liver regeneration. Science 1997;276:60–66.PubMedGoogle Scholar
  29. 29.
    Mitchell C, Nivison M, Jackson LF, et al. Heparin-binding epidermal growth factor-like growth factor links hepatocyte priming with cell cycle progression during liver regeneration. J Biol Chem 2005;280:2562–2568.PubMedGoogle Scholar
  30. 30.
    Leu JI, Crissey MA, Craig LE, Taub R. Impaired hepatocyte DNA synthetic response posthepatectomy in insulin-like growth factor binding protein 1-deficient mice with defects in C/EBP beta and mitogen-activated protein kinase/extracellular signal-regulated kinase regulation. Mol Cell Biol 2003;23:1251–1259.PubMedGoogle Scholar
  31. 31.
    Hayashi H, Nagaki M, Imose M, et al. Normal liver regeneration and liver cell apoptosis after partial hepatectomy in tumor necrosis factor-alpha-deficient mice. Liver Int 2005;25:162–170.PubMedGoogle Scholar
  32. 32.
    Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology 2006;43:S45–S53.PubMedGoogle Scholar
  33. 33.
    Schoen Smith JM, Lautt WW. The role of prostaglandins in triggering the liver regeneration cascade. Nitric Oxide 2005;13:111–117.PubMedGoogle Scholar
  34. 34.
    Schoen Smith JM, Lautt WW. Nitric oxide and prostaglandins potentiate the liver regeneration cascade. Can J Gastroenterol 2006;20:329–334.PubMedGoogle Scholar
  35. 35.
    Fausto N, Riehle KJ. Mechanisms of liver regeneration and their clinical implications. J Hepatobiliary Pancreat Surg 2005;12:181–189.PubMedGoogle Scholar
  36. 36.
    Cressman DE, Diamond RH, Taub R. Rapid activation of the Stat3 transcription complex in liver regeneration. Hepatology 1995;21:1443–1449.PubMedGoogle Scholar
  37. 37.
    Michalopoulos GK, Khan Z. Liver regeneration, growth factors, and amphiregulin. Gastroenterology 2005;128:503–506.PubMedGoogle Scholar
  38. 38.
    Pennisi PA, Kopchick JJ, Thorgeirsson S, LeRoith D, Yakar S. Role of growth hormone (GH) in liver regeneration. Endocrinology 2004;145:4748–4755.PubMedGoogle Scholar
  39. 39.
    LaBrecque D. Liver regeneration: A picture emerges from the puzzle. Am J Gastroenterol 1994;89:S86–S96.PubMedGoogle Scholar
  40. 40.
    Kim TH, Mars WM, Stolz DB, Petersen BE, Michalopoulos GK. Extracellular matrix remodeling at the early stages of liver regeneration in the rat. Hepatology 1997;26:896–904.PubMedGoogle Scholar
  41. 41.
    Yasuda H, Mine T, Shibata H, et al. Activin A: An autocrine inhibitor of initiation of DNA synthesis in rat hepatocytes. J Clin Invest 1993;92:1491–1496.PubMedGoogle Scholar
  42. 42.
    Wang H, Keiser JA. Hepatocyte growth factor enhances MMP activity in human endothelial cells. Biochem Biophys Res Commun 2000;272:900–905.PubMedGoogle Scholar
  43. 43.
    Maeno H, Ono T, Dhar DK, Sato T, Yamanoi A, Nagasue N. Expression of hypoxia inducible factor-1alpha during liver regeneration induced by partial hepatectomy in rats. Liver Int 2005;25:1002–1009.PubMedGoogle Scholar
  44. 44.
    Mohammed FF, Khokha R. Thinking outside the cell: Proteases regulate hepatocyte division. Trends Cell Biol 2005;15:555–563.PubMedGoogle Scholar
  45. 45.
    Fujii H, Hirose T, Oe S, et al. Contribution of bone marrow cells to liver regeneration after partial hepatectomy in mice. J Hepatol 2002;36:653–659.PubMedGoogle Scholar
  46. 46.
    Gehling UM, Willems M, Dandri M, et al. Partial hepatectomy induces mobilization of a unique population of haematopoietic progenitor cells in human healthy liver donors. J Hepatol 2005;43:845–853.PubMedGoogle Scholar
  47. 47.
    Grunewald M, Avraham I, Dor Y, et al. VEGF-induced adult neovascularization: Recruitment, retention, and role of accessory cells. Cell 2006;124:175–189.PubMedGoogle Scholar
  48. 48.
    Takayama T, Makuuchi M, Hirohashi S, et al. Early hepatocellular carcinoma as an entity with a high rate of surgical cure. Hepatology 1998;28:1241–1246.PubMedGoogle Scholar
  49. 49.
    Tsavellas G, Patel H, Allen-Mersh TG. Detection and clinical significance of occult tumour cells in colorectal cancer. Br J Surg 2001;88:1307–1320.PubMedGoogle Scholar
  50. 50.
    Yamaguchi K, Takagi Y, Aoki S, Futamura M, Saji S. Significant detection of circulating cancer cells in the blood by reverse transcriptase-polymerase chain reaction during colorectal cancer resection. Ann Surg 2000;232:58–65.PubMedGoogle Scholar
  51. 51.
    Chang YS, di Tomaso E, McDonald DM, Jones R, Jain RK, Munn LL. Mosaic blood vessels in tumors: Frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci U S A 2000;97:14608–14613.PubMedGoogle Scholar
  52. 52.
    Schluter K, Gassmann P, Enns A, et al. Organ-specific metastatic tumor cell adhesion and extravasation of colon carcinoma cells with different metastatic potential. Am J Pathol 2006;169:1064–1073.PubMedGoogle Scholar
  53. 53.
    Pilch J, Habermann R, Felding-Habermann B. Unique ability of integrin alpha(v)beta 3 to support tumor cell arrest under dynamic flow conditions. J Biol Chem 2002;277:21930–21938.PubMedGoogle Scholar
  54. 54.
    Mocellin S, Keilholz U, Rossi CR, Nitti D. Circulating tumor cells: The ‘leukemic phase’ of solid cancers. Trends Mol Med 2006;12:130–139.PubMedGoogle Scholar
  55. 55.
    Holmgren L, O’Reilly MS, Folkman J. Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995;1:149–153.PubMedGoogle Scholar
  56. 56.
    Luzzi KJ, MacDonald IC, Schmidt EE, et al. Multistep nature of metastatic inefficiency: Dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 1998;153:865–873.PubMedGoogle Scholar
  57. 57.
    Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86:353–364.PubMedGoogle Scholar
  58. 58.
    Weinstat-Saslow DL, Zabrenetzky VS, VanHoutte K, Frazier WA, Roberts DD, Steeg PS. Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential, and angiogenesis. Cancer Res 1994;54:6504–6511.PubMedGoogle Scholar
  59. 59.
    O’Reilly MS, Boehm T, Shing Y, et al. Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 1997;88:277–285.PubMedGoogle Scholar
  60. 60.
    llard WJ, Matera J, Miller MC, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 2004;10:6897–6904.Google Scholar
  61. 61.
    Da Costa ML, Redmond HP, Bouchier-Hayes DJ. Taurolidine improves survival by abrogating the accelerated development and proliferation of solid tumors and development of organ metastases from circulating tumor cells released following surgery. J Surg Res 2001;101:111–119.PubMedGoogle Scholar
  62. 62.
    Jin H, Aiyer A, Su J, et al. A homing mechanism for bone marrow-derived progenitor cell recruitment to the neovasculature. J Clin Invest 2006;116:652–662.PubMedGoogle Scholar
  63. 63.
    Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003;15:740–746.PubMedGoogle Scholar
  64. 64.
    Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006;6:392–401.PubMedGoogle Scholar
  65. 65.
    Yamagami H, Moriyama M, Tanaka N, Arakawa Y. Detection of serum and intrahepatic human hepatocyte growth factor in patients with type C liver diseases. Intervirology 2001;44:36–42.PubMedGoogle Scholar
  66. 66.
    Guirouilh J, Castroviejo M, Balabaud C, Desmouliere A, Rosenbaum J. Hepatocarcinoma cells stimulate hepatocyte growth factor secretion in human liver myofibroblasts. Int J Oncol 2000;17:777–781.PubMedGoogle Scholar
  67. 67.
    Huh CG, Factor VM, Sanchez A, Uchida K, Conner EA, Thorgeirsson SS. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci U S A 2004;101:4477–4482.PubMedGoogle Scholar
  68. 68.
    Borowiak M, Garratt AN, Wustefeld T, Strehle M, Trautwein C, Birchmeier C. Met provides essential signals for liver regeneration. Proc Natl Acad Sci U S A 2004;101:10608–10613.PubMedGoogle Scholar
  69. 69.
    Tsubouchi H. Hepatocyte growth factor for liver disease. Hepatology. 1999;30:333–334.PubMedGoogle Scholar
  70. 70.
    Thaler FJ, Michalopoulos GK. Hepatopoietin A: partial characterization and trypsin activation of a hepatocyte growth factor. Cancer Res 1985;45:2545–2549.PubMedGoogle Scholar
  71. 71.
    Zarnegar R, Michalopoulos GK. The many faces of hepatocyte growth factor: From hepatopoiesis to hematopoiesis. J Cell Biol 1995;129:1177–1180.PubMedGoogle Scholar
  72. 72.
    Vila MR, Nakamura T, Real FX. Hepatocyte growth factor is a potent mitogen for normal human pancreas cells in vitro. Lab Invest 1995;73:409–418.PubMedGoogle Scholar
  73. 73.
    Lamszus K, Jin L, Fuchs A, et al. Scatter factor stimulates tumor growth and tumor angiogenesis in human breast cancers in the mammary fat pads of nude mice. Lab Invest 1997;76:339–353.PubMedGoogle Scholar
  74. 74.
    Matsumoto K, Kagoshima M, Nakamura T. Hepatocyte growth factor as a potent survival factor for rat pheochromocytoma PC12 cells. Exp Cell Res 1995;220:71–78.PubMedGoogle Scholar
  75. 75.
    Tamatani T, Hattori K, Iyer A, Tamatani K, Oyasu R. Hepatocyte growth factor is an invasion/migration factor of rat urothelial carcinoma cells in vitro. Carcinogenesis 1999;20:957–962.PubMedGoogle Scholar
  76. 76.
    Nakamura T, Matsumoto K, Kiritoshi A, Tano Y. Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells: In vitro analysis of tumor-stromal interactions. Cancer Res 1997;57:3305–3313.PubMedGoogle Scholar
  77. 77.
    Matsumoto K, Date K, Ohmichi H, Nakamura T. Hepatocyte growth factor in lung morphogenesis and tumor invasion: Role as a mediator in epithelium-mesenchyme and tumor-stroma interactions. Cancer Chemother Pharmacol 1996;38(Suppl):S42–S47.PubMedGoogle Scholar
  78. 78.
    Rahimi N, Tremblay E, McAdam L, Park M, Schwall R, Elliott B. Identification of a hepatocyte growth factor autocrine loop in a murine mammary carcinoma. Cell Growth Differ 1996;7:263–270.PubMedGoogle Scholar
  79. 79.
    Bottaro DP, Rubin JS, Faletto DL, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 1991;251:802–804.PubMedGoogle Scholar
  80. 80.
    Di Renzo MF, Narsimhan RP, Olivero M, et al. Expression of the Met/HGF receptor in normal and neoplastic human tissues. Oncogene 1991;6:1997–2003.PubMedGoogle Scholar
  81. 81.
    Joseph A, Weiss GH, Jin L, et al. Expression of scatter factor in human bladder carcinoma. J Natl Cancer Inst 1995;87:372–377.PubMedGoogle Scholar
  82. 82.
    Arkonac BM, Foster LC, Sibinga NE, et al. Vascular endothelial growth factor induces heparin-binding epidermal growth factor-like growth factor in vascular endothelial cells. J Biol Chem 1998;273:4400–4405.PubMedGoogle Scholar
  83. 83.
    Di Renzo MF, Olivero M, Giacomini A, et al. Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin Cancer Res 1995;1:147–154.PubMedGoogle Scholar
  84. 84.
    Bauer TW, Fan F, Liu W, et al. Insulinlike growth factor-I-mediated migration and invasion of human colon carcinoma cells requires activation of c-Met and urokinase plasminogen activator receptor. Ann Surg 2005;241:748–756; discussion 756–748.PubMedGoogle Scholar
  85. 85.
    Todd R, Wong DT. Epidermal growth factor receptor (EGFR) biology and human oral cancer. Histol Histopathol 1999;14:491–500.PubMedGoogle Scholar
  86. 86.
    Spano JP, Lagorce C, Atlan D, et al. Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol 2005;16:102–108.PubMedGoogle Scholar
  87. 87.
    Schiffer E, Housset C, Cacheux W, et al. Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology 2005;41:307–314.PubMedGoogle Scholar
  88. 88.
    Saeki T, Salomon DS, Johnson GR, et al. Association of epidermal growth factor-related peptides and type I receptor tyrosine kinase receptors with prognosis of human colorectal carcinomas. Jpn J Clin Oncol 1995;25:240–249.PubMedGoogle Scholar
  89. 89.
    Brabender J, Danenberg KD, Metzger R, et al. Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer Is correlated with survival. Clin Cancer Res 2001;7:1850–1855.PubMedGoogle Scholar
  90. 90.
    Park DI, Kang MS, Oh SJ, et al. HER-2/neu overexpression is an independent prognostic factor in colorectal cancer. Int J Colorectal Dis 2006;17:5758–5770.Google Scholar
  91. 91.
    Jiang JG, Zarnegar R. A novel transcriptional regulatory region within the core promoter of the hepatocyte growth factor gene is responsible for its inducibility by cytokines via the C/EBP family of transcription factors. Mol Cell Biol 1997;17:5758–5770.PubMedGoogle Scholar
  92. 92.
    Ellis LM. Epidermal growth factor receptor in tumor angiogenesis. Hematol Oncol Clin North Am 2004;18:1007–1021.PubMedGoogle Scholar
  93. 93.
    Baker CH, Kedar D, McCarty MF, et al. Blockade of epidermal growth factor receptor signaling on tumor cells and tumor-associated endothelial cells for therapy of human carcinomas. Am J Pathol 2002;161:929–938.PubMedGoogle Scholar
  94. 94.
    De Luca A, Arra C, D’Antonio A, et al. Simultaneous blockage of different EGF-like growth factors results in efficient growth inhibition of human colon carcinoma xenografts. Oncogene 2000;19:5863–5871.PubMedGoogle Scholar
  95. 95.
    Ciardiello F, Caputo R, Bianco R, et al. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 2001;7:1459–1465.PubMedGoogle Scholar
  96. 96.
    Iivanainen E, Kahari VM, Heino J, Elenius K. Endothelial cell–matrix interactions. Microsc Res Tech 2003;60:13–22.PubMedGoogle Scholar
  97. 97.
    Yen L, Benlimame N, Nie ZR, et al. Differential regulation of tumor angiogenesis by distinct ErbB homo- and heterodimers. Mol Biol Cell 2002;13:4029–4044.PubMedGoogle Scholar
  98. 98.
    De Jong KP, Stellema R, Karrenbeld A, et al. Clinical relevance of transforming growth factor alpha, epidermal growth factor receptor, p53, and Ki67 in colorectal liver metastases and corresponding primary tumors. Hepatology 1998;28:971–979.PubMedGoogle Scholar
  99. 99.
    Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002;20:4368–4380.PubMedGoogle Scholar
  100. 100.
    Barbera-Guillem E, Nyhus JK, Wolford CC, Friece CR, Sampsel JW. Vascular endothelial growth factor secretion by tumor-infiltrating macrophages essentially supports tumor angiogenesis, and IgG immune complexes potentiate the process. Cancer Res 2002;62:7042–7049.PubMedGoogle Scholar
  101. 101.
    Harmey JH, Dimitriadis E, Kay E, Redmond HP, Bouchier-Hayes D. Regulation of macrophage production of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor beta-1. Ann Surg Oncol 1998;5:271–278.PubMedGoogle Scholar
  102. 102.
    Kaur B, Khwaja FW, Severson EA, Matheny SL, Brat DJ, Van Meir EG. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro-oncol 2005;7:134–153.PubMedGoogle Scholar
  103. 103.
    Dvorak HF, Detmar M, Claffey KP, Nagy JA, van de Water L, Senger DR. Vascular permeability factor/vascular endothelial growth factor: an important mediator of angiogenesis in malignancy and inflammation. Int Arch Allergy Immunol 1995;107:233–235.PubMedCrossRefGoogle Scholar
  104. 104.
    Byrne AM, Bouchier-Hayes DJ, Harmey JH. Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med 2005;9:777–794.PubMedGoogle Scholar
  105. 105.
    Kremer C, Breier G, Risau W, Plate KH. Up-regulation of flk-1/vascular endothelial growth factor receptor 2 by its ligand in a cerebral slice culture system. Cancer Res 1997;57:3852–3859.PubMedGoogle Scholar
  106. 106.
    Shing Y, Folkman J, Sullivan R, Butterfield C, Murray J, Klagsbrun M. Heparin affinity: Purification of a tumor-derived capillary endothelial cell growth factor. Science 1984;223:1296–1299.PubMedGoogle Scholar
  107. 107.
    Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med 2000;342:1350–1358.PubMedGoogle Scholar
  108. 108.
    Shim KS, Kim KH, Han WS, Park EB. Elevated serum levels of transforming growth factor-beta1 in patients with colorectal carcinoma: Its association with tumor progression and its significant decrease after curative surgical resection. Cancer 1999;85:554–561.PubMedGoogle Scholar
  109. 109.
    Shirai Y, Kawata S, Tamura S, et al. Plasma transforming growth factor-beta 1 in patients with hepatocellular carcinoma. Comparison with chronic liver diseases. Cancer 1994;73:2275–2279.PubMedGoogle Scholar
  110. 110.
    Salvucci M, Lemoine A, Saffroy R, et al. Microsatellite instability in European hepatocellular carcinoma. Oncogene 1999;18:181–187.PubMedGoogle Scholar
  111. 111.
    Teramoto T, Kiss A, Thorgeirsson SS. Induction of p53 and Bax during TGF-beta 1 initiated apoptosis in rat liver epithelial cells. Biochem Biophys Res Commun 1998;251:56–60.PubMedGoogle Scholar
  112. 112.
    Desbois-Mouthon C, Wendum D, Cadoret A, et al. Hepatocyte proliferation during liver regeneration is impaired in mice with liver-specific IGF-1R knockout. Faseb J 2006;20:773–775.PubMedGoogle Scholar
  113. 113.
    Daughaday WH. Growth hormone axis overview-somatomedin hypothesis. Pediatr Nephrol 2000;14:537–540.PubMedGoogle Scholar
  114. 114.
    Rajaram S, Baylink DJ, Mohan S. Insulin-like growth factor-binding proteins in serum and other biological fluids: Regulation and functions. Endocr Rev 1997;18:801–831.PubMedGoogle Scholar
  115. 115.
    Yakar S, Pennisi P, Wu Y, Zhao H, LeRoith D. Clinical relevance of systemic and local IGF-I. Endocr Dev 2005;9:11–16.PubMedCrossRefGoogle Scholar
  116. 116.
    Butler AA, LeRoith D. Minireview: Tissue-specific versus generalized gene targeting of the igf1 and igf1r genes and their roles in insulin-like growth factor physiology. Endocrinology 2001;142:1685–1688.PubMedGoogle Scholar
  117. 117.
    Wu Y, Yakar S, Zhao L, Hennighausen L, LeRoith D. Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res 2002;62:1030–1035.PubMedGoogle Scholar
  118. 118.
    Long L, Navab R, Brodt P. Regulation of the Mr 72,000 type IV collagenase by the type I insulin-like growth factor receptor. Cancer Res 1998;58:3243–3247.PubMedGoogle Scholar
  119. 119.
    Wolk A, Mantzoros CS, Andersson SO, et al. Insulin-like growth factor 1 and prostate cancer risk: A population-based, case-control study. J Natl Cancer Inst 1998;90:911–915.PubMedGoogle Scholar
  120. 120.
    Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 2000;92:1472–1489.PubMedGoogle Scholar
  121. 121.
    Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 1995;95:1789–1797.PubMedGoogle Scholar
  122. 122.
    Bermont L, Lamielle F, Fauconnet S, Esumi H, Weisz A, Adessi GL. Regulation of vascular endothelial growth factor expression by insulin-like growth factor-I in endometrial adenocarcinoma cells. Int J Cancer 2000;85:117–123.PubMedGoogle Scholar
  123. 123.
    Shigematsu S, Yamauchi K, Nakajima K, Iijima S, Aizawa T, Hashizume K. IGF-1 regulates migration and angiogenesis of human endothelial cells. Endocr J 1999;46(Suppl)S59–62.PubMedGoogle Scholar
  124. 124.
    Rabinovsky ED, Draghia-Akli R. Insulin-like growth factor I plasmid therapy promotes in vivo angiogenesis. Mol Ther 2004;9:46–55.PubMedGoogle Scholar
  125. 125.
    Gille H, Kowalski J, Li B, et al. Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem 2001;276:3222–3230.PubMedGoogle Scholar
  126. 126.
    Price JA, Kovach SJ, Johnson T, et al. Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma. Hepatology 2002;36:1089–1097.PubMedGoogle Scholar
  127. 127.
    Overall CM, Dean RA. Degradomics: Systems biology of the protease web. Pleiotropic roles of MMPs in cancer. Cancer Metastasis Rev 2006;25:69–75.PubMedGoogle Scholar
  128. 128.
    Stetler-Stevenson WG. Progelatinase A activation during tumor cell invasion. Invasion Metastasis 1994;14:259–268.PubMedGoogle Scholar
  129. 129.
    Nagase H, Woessner JF, Jr. Matrix metalloproteinases. J Biol Chem 1999;274:21491–21494.PubMedGoogle Scholar
  130. 130.
    Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002;2:161–174.PubMedGoogle Scholar
  131. 131.
    Portier G, Elias D, Bouche O, et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol 2006;24:4976–4982.PubMedGoogle Scholar
  132. 132.
    Van Cutsem E, Nordlinger B, Adam R, et al. Towards a pan-European consensus on the treatment of patients with colorectal liver metastases. Eur J Cancer 2006;42:2212–2221.PubMedGoogle Scholar
  133. 133.
    Zorzi D, Laurent A, Pawlik TM, Lauwers GY, Vauthey JN, Abdalla EK. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg 2007;94:274–286.PubMedGoogle Scholar
  134. 134.
    Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 2004;9(Suppl 1):2–10.PubMedGoogle Scholar
  135. 135.
    Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 2007;96:1788–1795.PubMedGoogle Scholar
  136. 136.
    Ellis LM, Curley SA, Grothey A. Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J Clin Oncol 2005;23:4853–4855.PubMedGoogle Scholar
  137. 137.
    Los M, Roodhart JM, Voest EE. Target practice: Lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. Oncologist 2007;12:443–450.PubMedGoogle Scholar
  138. 138.
    Gasparini G, Longo R, Toi M, Ferrara N. Angiogenic inhibitors: A new therapeutic strategy in oncology. Nat Clin Pract Oncol 2005;2:562–577.PubMedGoogle Scholar
  139. 139.
    Relf M, LeJeune S, Scott PA, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 1997;57:963–969.PubMedGoogle Scholar
  140. 140.
    Jayson GC, Mulatero C, Ranson M, et al. Phase I investigation of recombinant anti-human vascular endothelial growth factor antibody in patients with advanced cancer. Eur J Cancer 2005;41:555–563.PubMedGoogle Scholar
  141. 141.
    Riely GJ, Miller VA. Vascular endothelial growth factor trap in non small cell lung cancer. Clin Cancer Res. 2007;13:s4623–4627.PubMedGoogle Scholar
  142. 142.
    Brekken RA, Overholser JP, Stastny VA, Waltenberger J, Minna JD, Thorpe PE. 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. Cancer Res 2000;60:5117–5124.PubMedGoogle Scholar
  143. 143.
    Whitehurst B, Flister MJ, Bagaitkar J, et al. Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. Int J Cancer 2007 (in press).Google Scholar
  144. 144.
    Cabebe E, Wakelee H. Role of anti-angiogenesis agents in treating NSCLC: Focus on bevacizumab and VEGFR tyrosine kinase inhibitors. Curr Treat Options Oncol 2007;8:15–27.PubMedGoogle Scholar
  145. 145.
    Hutson TE, Bukowski RM. A phase II study of GW786034 using a randomized discontinuation design in patients with locally recurrent or metastatic clear-cell renal cell carcinoma. Clin Genitourin Cancer 2006;4:296–298.PubMedGoogle Scholar
  146. 146.
    Scott EN, Meinhardt G, Jacques C, Laurent D, Thomas AL. Vatalanib: The clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours. Exp Opin Investig Drugs 2007;16:367–379.Google Scholar
  147. 147.
    Cohen RB, Langer CJ, Simon GR, et al. A phase I/randomized phase II, non-comparative, multicenter, open label trial of CP-547,632 in combination with paclitaxel and carboplatin or paclitaxel and carboplatin alone as first-line treatment for advanced non-small cell lung cancer (NSCLC). Cancer Chemother Pharmacol 2007;60:81–89.PubMedGoogle Scholar
  148. 148.
    Trump DL. Sorafenib in advanced clear-cell renal-cell carcinoma Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM, TARGET Study Group, Department of Medicine, Institut Gustave Roussy, Villejuif, France. Urol Oncol 2007;25:443–445.Google Scholar
  149. 149.
    Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001;344:1038–1042.PubMedGoogle Scholar
  150. 150.
    van Oosterom AT, Judson IR, Verweij J, et al. Update of phase I study of imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal tumors: A report of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2002;38:(Suppl 5)S83–87.PubMedGoogle Scholar
  151. 151.
    Heymach JV, Nilsson M, Blumenschein G, Papadimitrakopoulou V, Herbst R. Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. Clin Cancer Res 2006;12:4441s–4445s.PubMedGoogle Scholar
  152. 152.
    Sessa C, Vigano L, Grasselli G, et al. Phase I clinical and pharmacological evaluation of the multi-tyrosine kinase inhibitor SU006668 by chronic oral dosing. Eur J Cancer 2006;42:171–178.PubMedGoogle Scholar
  153. 153.
    Ellis AG, Doherty MM, Walker F, et al. Preclinical analysis of the analinoquinazoline AG1478, a specific small molecule inhibitor of EGF receptor tyrosine kinase. Biochem Pharmacol 2006;71:1422–1434.PubMedGoogle Scholar
  154. 154.
    Gridelli C, Bareschino MA, Schettino C, Rossi A, Maione P, Ciardiello F. Erlotinib in non-small cell lung cancer treatment: Current status and future development. Oncologist 2007;12:840–849.PubMedGoogle Scholar
  155. 155.
    Hofheinz RD, Kubicka S, Wollert J, Arnold D, Hochhaus A. Gefitinib in combination with 5-fluorouracil (5-FU)/folinic acid and irinotecan in patients with 5-FU/oxaliplatin- refractory colorectal cancer: A phase I/II study of the Arbeitsgemeinschaft fur Internistische Onkologie (AIO). Onkologie 2006;29:563–567.PubMedGoogle Scholar
  156. 156.
    Zhu Z. Targeted cancer therapies based on antibodies directed against epidermal growth factor receptor: Status and perspectives. Acta Pharmacol Sin 2007;28:1476–1493.PubMedGoogle Scholar
  157. 157.
    Gibson TB, Ranganathan A, Grothey A. Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer. Clin Colorectal Cancer 2006;6:29–31.PubMedGoogle Scholar
  158. 158.
    Zhou Y, Brattain MG. Synergy of epidermal growth factor receptor kinase inhibitor AG1478 and ErbB2 kinase inhibitor AG879 in human colon carcinoma cells is associated with induction of apoptosis. Cancer Res 2005;65:5848–5856.PubMedGoogle Scholar
  159. 159.
    Zhou Y, Li S, Hu YP, et al. Blockade of EGFR and ErbB2 by the novel dual EGFR and ErbB2 tyrosine kinase inhibitor GW572016 sensitizes human colon carcinoma GEO cells to apoptosis. Cancer Res 2006;66:404–411.PubMedGoogle Scholar
  160. 160.
    Hopfner M, Sutter AP, Huether A, Baradari V, Scherubl H. Tyrosine kinase of insulin-like growth factor receptor as target for novel treatment and prevention strategies of colorectal cancer. World J Gastroenterol 2006;12:5635–5643.PubMedGoogle Scholar
  161. 161.
    Miyamoto S, Nakamura M, Shitara K, et al. Blockade of paracrine supply of insulin-like growth factors using neutralizing antibodies suppresses the liver metastasis of human colorectal cancers. Clin Cancer Res 2005;11:3494–3502.PubMedGoogle Scholar
  162. 162.
    Hirte H, Vergote IB, Jeffrey JR, et al. A phase III randomized trial of BAY 12-9566 (tanomastat) as maintenance therapy in patients with advanced ovarian cancer responsive to primary surgery and paclitaxel/platinum containing chemotherapy: A National Cancer Institute of Canada Clinical Trials Group Study. Gynecol Oncol 2006;102:300–308.PubMedGoogle Scholar
  163. 163.
    Chu QS, Forouzesh B, Syed S, et al. A phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomas. Invest New Drugs 2007;25:359–367.PubMedGoogle Scholar
  164. 164.
    Heath EI, Burtness BA, Kleinberg L, et al. Phase II, parallel-design study of preoperative combined modality therapy and the matrix metalloprotease (mmp) inhibitor prinomastat in patients with esophageal adenocarcinoma. Invest New Drugs 2006;24:135–140.PubMedGoogle Scholar
  165. 165.
    Sparano JA, Bernardo P, Stephenson P, et al. Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J Clin Oncol 2004;22:4683–4690.PubMedGoogle Scholar
  166. 166.
    Leighl NB, Paz-Ares L, Douillard JY, et al. Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada—Clinical Trials Group Study BR.18. J Clin Oncol 2005;23:2831–2839.PubMedGoogle Scholar
  167. 167.
    Itasaka S, Komaki R, Herbst RS, et al. Endostatin improves radioresponse and blocks tumor revascularization after radiation therapy for A431 xenografts in mice. Int J Radiat Oncol Biol Phys 2007;67:870–878.PubMedGoogle Scholar
  168. 168.
    Kulke MH, Bergsland EK, Ryan DP, et al. Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors. J Clin Oncol 2006;24:3555–3561.PubMedGoogle Scholar
  169. 169.
    Kurup A, Lin CW, Murry DJ, et al. Recombinant human angiostatin (rhAngiostatin) in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer: A phase II study from Indiana University. Ann Oncol 2006;17:97–103.PubMedGoogle Scholar
  170. 170.
    Hariharan S, Gustafson D, Holden S, et al. Assessment of the biological and pharmacological effects of the {alpha}{nu}{beta}3 and {alpha}{nu}{beta}5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors. Ann Oncol 2007;18:1400–1407.PubMedGoogle Scholar
  171. 171.
    Tran HT, Blumenschein GR, Jr., Lu C, et al. Clinical and pharmacokinetic study of TNP-470, an angiogenesis inhibitor, in combination with paclitaxel and carboplatin in patients with solid tumors. Cancer Chemother Pharmacol 2004;54:308–314.PubMedGoogle Scholar
  172. 172.
    Cernaianu G, Frank S, Erbstosser K, et al. TNP-470 fails to block the onset of angiogenesis and early tumor establishment in an intravital minimal disease model. Int J Colorectal Dis 2006;21:143–154.PubMedGoogle Scholar
  173. 173.
    Patel SR, Jenkins J, Papadopolous N, et al. Pilot study of vitaxin—an angiogenesis inhibitor—in patients with advanced leiomyosarcomas. Cancer 2001;92:1347–1348.PubMedGoogle Scholar
  174. 174.
    McNeel DG, Eickhoff J, Lee FT, et al. Phase I trial of a monoclonal antibody specific for alphavbeta3 integrin (MEDI-522) in patients with advanced malignancies, including an assessment of effect on tumor perfusion. Clin Cancer Res 2005;11:7851–7860.PubMedGoogle Scholar
  175. 175.
    Biswas S, Guix M, Rinehart C, et al. Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J Clin Invest 2007;117:1305–1313.PubMedGoogle Scholar
  176. 176.
    Hau P, Jachimczak P, Schlingensiepen R, et al. Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: From preclinical to phase I/II studies. Oligonucleotides 2007;17:201–212.PubMedGoogle Scholar
  177. 177.
    Schlingensiepen KH, Schlingensiepen R, Steinbrecher A, et al. Targeted tumor therapy with the TGF-beta2 antisense compound AP 12009. Cytokine Growth Factor Rev 2006;17:129–139.PubMedGoogle Scholar
  178. 178.
    Yin JJ, Selander K, Chirgwin JM, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 1999;103:197–206.PubMedGoogle Scholar
  179. 179.
    Rowland-Goldsmith MA, Maruyama H, Kusama T, Ralli S, Korc M. Soluble type II transforming growth factor-beta (TGF-beta) receptor inhibits TGF-beta signaling in COLO-357 pancreatic cancer cells in vitro and attenuates tumor formation. Clin Cancer Res 2001;7:2931–2940.PubMedGoogle Scholar
  180. 180.
    Yingling JM, Blanchard KL, Sawyer JS. Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov 2004;3:1011–1022.PubMedGoogle Scholar
  181. 181.
    Chalmers CR, Wilson DJ, Ward J, Robinson PJ, Toogood GJ, Hull MA. Antiangiogenic activity of the selective cyclooxygenase 2 inhibitor rofecoxib in human colorectal cancer liver metastases. Gut 2006;55:1058–1059.PubMedGoogle Scholar
  182. 182.
    Ren Y, Chan HM, Fan J, et al. Inhibition of tumor growth and metastasis in vitro and in vivo by targeting macrophage migration inhibitory factor in human neuroblastoma. Oncogene 2006;25:3501–3508.PubMedGoogle Scholar
  183. 183.
    Berkenblit A, Matulonis UA, Kroener JF, et al. A6, a urokinase plasminogen activator (uPA)-derived peptide in patients with advanced gynecologic cancer: A phase I trial. Gynecol Oncol 2005;99:50–57.PubMedGoogle Scholar
  184. 184.
    Burgess T, Coxon A, Meyer S, et al. Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors. Cancer Res 2006;66:1721–1729.PubMedGoogle Scholar
  185. 185.
    Sun X, Liu M, Wei Y, et al. Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1alpha eradicates gliomas. Cancer Gene Ther 2006;13:428–435.PubMedGoogle Scholar
  186. 186.
    Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G, Powis G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther 2004;3:233–244.PubMedGoogle Scholar
  187. 187.
    Heideman DA, Overmeer RM, van Beusechem VW, et al. Inhibition of angiogenesis and HGF-cMET-elicited malignant processes in human hepatocellular carcinoma cells using adenoviral vector-mediated NK4 gene therapy. Cancer Gene Ther 2005;12:954–962.PubMedGoogle Scholar
  188. 188.
    Shinomiya N, Gao CF, Xie Q, et al. RNA interference reveals that ligand-independent met activity is required for tumor cell signaling and survival. Cancer Res 2004;64:7962–7970.PubMedGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2007

Authors and Affiliations

  • Christopher Christophi
    • 1
  • Nadia Harun
    • 1
  • Theodora Fifis
    • 1
  1. 1.Department of SurgeryUniversity of MelbourneMelbourneAustralia

Personalised recommendations