Annals of Surgical Oncology

, Volume 10, Issue 8, pp 839–851 | Cite as

Recent Insights Into Angiogenesis, Apoptosis, Invasion, and Metastasis in Colorectal Carcinoma

  • William M. BoedefeldII
  • Kirby I. Bland
  • Martin J. HeslinEmail author
Educational Review


The numerous studies profiling mechanisms in colorectal carcinoma have implicated multiple pathways in the malignant progression of a colorectal epithelial cell. Such pathways as aberrations in the cell cycle, deviation from apoptosis, neovascularization of tumors, and invasion and metastasis of malignant epithelial cells have been shown to occur in the progression of a normal epithelial cell to an adenoma and carcinoma. Today, we continue to search for communications or connections between these pathways as we try to get a more global picture of the events responsible for the adenoma-carcinoma sequence. This review focuses on the latest developments of three well-characterized pathways implicated in colorectal carcinoma: angiogenesis, apoptosis, and invasion and metastasis. We will attempt to highlight clinical correlates, when available, with some of the more interesting molecules.

Key Words

Angiogenesis Apoptosis Invasion Colorectal carcinoma 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Ellis LM, Liu W, Ahmad SA, et al. Overview of angiogenesis: biologic implications for antiangiogenic therapy. Semin Oncol 2001;28:94–104.PubMedCrossRefGoogle Scholar
  3. 3.
    Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983;219:983–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 1989;161:851–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1980;246:1306–9.CrossRefGoogle Scholar
  6. 6.
    Keck PJ, Hauser SD, Krivi G, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 1989;246:1309–12.PubMedCrossRefGoogle Scholar
  7. 7.
    Ferrara N. Vascular endothelial growth factor: molecular and biological aspects. Curr Top Microbiol Immunol 1999;237:1–30.PubMedGoogle Scholar
  8. 8.
    Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A 1991;88:9267–71.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Ogawa S, Oku A, Sawano A, Yamaguchi S, Yazaki Y, Shibuya M. A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain. J Biol Chem 1998;273:31273–82.PubMedCrossRefGoogle Scholar
  10. 10.
    Meyer M, Clauss M, Lepple-Wienhues A, et al. A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. EMBO J 1999;18:363–74.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999;13:9–22.PubMedCrossRefGoogle Scholar
  12. 12.
    Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med 1999;77:527–43.PubMedCrossRefGoogle Scholar
  13. 13.
    Shibuya M, Ito N, Claesson-Welsh L. Structure and function of vascular endothelial growth factor receptor-1 and -2. Curr Top Microbiol Immunol 1999;237:59–83.PubMedGoogle Scholar
  14. 14.
    Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 2000;60:203–12.PubMedGoogle Scholar
  15. 15.
    Lee J, Gray A, Yuan J, Luoh SM, Avraham H, Wood WI. Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Proc Natl Acad Sci U S A 1996;93:1988–92.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Joukov V, Pajusola K, Kaipainen A, et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 1996;15:1751.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Achen MG, Jeltsch M, Kukk E, et al. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci U S A 1998;95:548–53.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 1996;56:4509–15.PubMedGoogle Scholar
  19. 19.
    Brizel DM, Scully SP, Harrelson JM, et al. Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas. Cancer Res 1996;56:5347–50.PubMedGoogle Scholar
  20. 20.
    Nordsmark M, Maxwell RJ, Horsman MR, Bentzen SM, Overgaard J. The effect of hypoxia and hyperoxia on nucleoside triphosphate/inorganic phosphate, pO2 and radiation response in an experimental tumour model. Br J Cancer 1997;76:1432–9.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Minchenko A, Bauer T, Salceda S, Caro J. Hypoxic stimulation of vascular endothelial growth factor expression in vitro and in vivo. Lab Invest 1994;71:374–9.PubMedGoogle Scholar
  22. 22.
    Banai S, Shweiki D, Pinson A, Chandra M, Lazarovici G, Keshet E. Upregulation of vascular endothelial growth factor expression induced by myocardial ischaemia: implications for coronary angiogenesis. Cardiovasc Res 1994;28:1176–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Ratcliffe PJ, O’Rourke JF, Maxwell PH, Pugh CW. Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene expression. J Exp Biol 1998;201(Pt 8):1153–62.Google Scholar
  24. 24.
    Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 1995;92:5510–4.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992;12:5447–54.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Deleted in proofs.Google Scholar
  27. 27.
    Maxwell PH, Dachs GU, Gleadle JM, et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci U S A 1997;94:8104–9.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Ikeda E, Achen MG, Breier G, Risau W. Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem 1995;270:19761–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Stein I, Neeman M, Shweiki D, Itin A, Keshet E. Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes. Mol Cell Biol 1995;15:5363–8.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Levy AP, Levy NS, Goldberg MA. Hypoxia-inducible protein binding to vascular endothelial growth factor mRNA and its modulation by the von Hippel-Lindau protein. J Biol Chem 1996;271:25492–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Pertovaara L, Kaipainen A, Mustonen T, et al. Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem 1994;269:6271–4.PubMedGoogle Scholar
  32. 32.
    Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY. Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Mol Biol Cell 1993;4:121–33.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Ben Av P, Crofford LJ, Wilder RL, Hla T. Induction of vascular endothelial growth factor expression in synovial fibroblasts by prostaglandin E and interleukin-1: a potential mechanism for inflammatory angiogenesis. FEBS Lett 1995;372:83–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Cohen T, Nahari D, Cerem LW, Neufeld G, Levi BZ. Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem 1996;271:736–41.PubMedCrossRefGoogle Scholar
  35. 35.
    Gerber HP, Dixit V, Ferrara N. Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem 1998;273:13313–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Unemori EN, Ferrara N, Bauer EA, Amento EP. Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 1992;153:557–62.CrossRefPubMedGoogle Scholar
  37. 37.
    Pepper MS, Ferrara N, Orci L, Montesano R. Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun 1991;181:902–6.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Dvorak HF, Nagy JA, Feng D, Brown LF, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Curr Top Microbiol Immunol 1999;237:97–132.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995;55:3964–8.PubMedGoogle Scholar
  40. 40.
    Takahashi Y, Tucker SL, Kitadai Y, et al. Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch Surg 1997;132:541–6.PubMedCrossRefGoogle Scholar
  41. 41.
    White JD, Hewett PW, Kosuge D, et al. Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. Cancer Res 2002;62:1669–75.PubMedGoogle Scholar
  42. 42.
    Ishigami SI, Arii S, Furutani M, et al. Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer 1998;78:1379–84.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Takahashi Y, Bucana CD, Liu W, et al. Platelet-derived endothelial cell growth factor in human colon cancer angiogenesis: role of infiltrating cells. J Natl Cancer Inst 1996;88:1146–51.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Haraguchi M, Furukawa T, Sumizawa T, Akiyama S. Sensitivity of human KB cells expressing platelet-derived endothelial cell growth factor to pyrimidine antimetabolites. Cancer Res 1993;53:5680–2.PubMedGoogle Scholar
  45. 45.
    Patterson AV, Zhang H, Moghaddam A, et al. Increased sensitivity to the prodrug 5′-deoxy-5-fluorouridine and modulation of 5-fluoro-2′-deoxyuridine sensitivity in MCF-7 cells transfected with thymidine phosphorylase. Br J Cancer 1995;72:669–75.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Kato Y, Matsukawa S, Muraoka R, Tanigawa N. Enhancement of drug sensitivity and a bystander effect in PC-9 cells transfected with a platelet-derived endothelial cell growth factor thymidine phosphorylase cDNA. Br J Cancer 1997;75:506–11.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Saito S, Tsuno N, Nagawa H, et al. Expression of platelet-derived endothelial cell growth factor correlates with good prognosis in patients with colorectal carcinoma. Cancer 2000;88:42–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Takebayashi Y, Akiyama S, Akiba S, et al. Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. J Natl Cancer Inst 1996;88:1110–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Adams JC. Thrombospondins: multifunctional regulators of cell interactions. Annu Rev Cell Dev Biol 2001;17:25–51.PubMedCrossRefGoogle Scholar
  50. 50.
    Hiscott P, Schlotzer-Schrehardt U, Naumann GO. Unexpected expression of thrombospondin 1 by corneal and iris fibroblasts in the pseudoexfoliation syndrome. Hum Pathol 1996;27:1255–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Iruela-Arispe ML, Sage EH. Endothelial cells exhibiting angiogenesis in vitro proliferate in response to TGF-beta 1. J Cell Biochem 1993;52:414–30.PubMedCrossRefGoogle Scholar
  52. 52.
    Murphy-Ullrich JE, Mosher DF. Localization of thrombospondin in clots formed in situ. Blood 1985;66:1098–104.PubMedGoogle Scholar
  53. 53.
    Raugi GJ, Olerud JE, Gown AM. Thrombospondin in early human wound tissue. J Invest Dermatol 1987;89:551–4.PubMedCrossRefGoogle Scholar
  54. 54.
    Watkins SC, Raso V, Slayter HS. Immunoelectron-microscopic studies of human platelet thrombospondin, von Willebrand factor, and fibrinogen redistribution during clot formation. Histochem J 1990;22:507–18.PubMedCrossRefGoogle Scholar
  55. 55.
    Lawler J, Ferro P, Duquette M. Expression and mutagenesis of thrombospondin. Biochemistry 1992;31:1173–80.PubMedCrossRefGoogle Scholar
  56. 56.
    Streit M, Velasco P, Riccardi L, et al. Thrombospondin-1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice. EMBO J 2000;19:3272–82.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Kyriakides TR, Tam JW, Bornstein P. Accelerated wound healing in mice with a disruption of the thrombospondin 2 gene. J Invest Dermatol 1999;113:782–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Volpert OV, Lawler J, Bouck NP. A human fibrosarcoma inhibits systemic angiogenesis and the growth of experimental metastases via thrombospondin-1. Proc Natl Acad Sci U S A 1998;95:6343–8.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    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;54:6504–11.PubMedGoogle Scholar
  60. 60.
    Bleuel K, Popp S, Fusenig NE, Stanbridge EJ, Boukamp P. Tumor suppression in human skin carcinoma cells by chromosome 15 transfer or thrombospondin-1 overexpression through halted tumor vascularization. Proc Natl Acad Sci U S A 1999;96:2065–70.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Streit M, Riccardi L, Velasco P, et al. Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis. Proc Natl Acad Sci U S A 1999;96:14888–93.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Maeda K, Nishiguchi Y, Kang SM, et al. Expression of thrombospondin-1 inversely correlated with tumor vascularity and hematogenous metastasis in colon cancer. Oncol Rep 2001;8:763–6.PubMedGoogle Scholar
  63. 63.
    Maeda K, Nishiguchi Y, Yashiro M, et al. Expression of vascular endothelial growth factor and thrombospondin-1 in colorectal carcinoma. Int J Mol Med 2000;5:373–8.PubMedGoogle Scholar
  64. 64.
    Tokunaga T, Nakamura M, Oshika Y, et al. Thrombospondin 2 expression is correlated with inhibition of angiogenesis and metastasis of colon cancer. Br J Cancer 1999;79:354–9.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Peters KG. Vascular endothelial growth factor and the angiopoietins: working together to build a better blood vessel. Circ Res 1998;83:342–3.PubMedCrossRefGoogle Scholar
  66. 66.
    Suri C, Jones PF, Patan S, et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 1996;87:1171–80.PubMedCrossRefGoogle Scholar
  67. 67.
    Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997;277:55–60.PubMedCrossRefGoogle Scholar
  68. 68.
    Ahmad SA, Liu W, Jung YD, et al. The effects of angiopoietin-1 and -2 on tumor growth and angiogenesis in human colon cancer. Cancer Res 2001;61:1255–9.PubMedGoogle Scholar
  69. 69.
    Gale NW, Yancopoulos GD. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev 1999;13:1055–66.PubMedCrossRefGoogle Scholar
  70. 70.
    Easty DJ, Hill SP, Hsu MY, et al. Up-regulation of ephrin-A1 during melanoma progression. Int J Cancer 1999;84:494–501.PubMedCrossRefGoogle Scholar
  71. 71.
    Kiyokawa E, Takai S, Tanaka M, et al. Overexpression of ERK, an EPH family receptor protein tyrosine kinase, in various human tumors. Cancer Res 1994;54:3645–50.PubMedGoogle Scholar
  72. 72.
    Liu W, Ahmad SA, Jung YD, et al. Coexpression of ephrin-Bs and their receptors in colon carcinoma. Cancer 2002;94:934–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Walker NP, Talanian RV, Brady KD, et al. Crystal structure of the cysteine protease interleukin-1 beta-converting enzyme: a (p20/p10)2 homodimer. Cell 1994;78:343–52.PubMedCrossRefGoogle Scholar
  74. 74.
    Wilson KP, Black JA, Thomson JA, et al. Structure and mechanism of interleukin-1 beta converting enzyme. Nature 1994;370:270–5.PubMedCrossRefGoogle Scholar
  75. 75.
    Rotonda J, Nicholson DW, Fazil KM, et al. The three-dimensional structure of apopain/CPP32, a key mediator of apoptosis. Nat Struct Biol 1996;3:619–25.PubMedCrossRefGoogle Scholar
  76. 76.
    Cryns V, Yuan J. Proteases to die for. Genes Dev 1998;12:1551–70.PubMedCrossRefGoogle Scholar
  77. 77.
    Nicholson DW, Thornberry NA. Caspases: killer proteases. Trends Biochem Sci 1997;22:299–306.PubMedCrossRefGoogle Scholar
  78. 78.
    Cheng EH, Kirsch DG, Clem RJ, et al. Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 1997;278:1966–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Clem RJ, Cheng EH, Karp CL, et al. Modulation of cell death by Bcl-XL through caspase interaction. Proc Natl Acad Sci U S A 1998;95:554–9.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998;94:491–501.PubMedCrossRefGoogle Scholar
  81. 81.
    Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 1998;94:481–90.PubMedCrossRefGoogle Scholar
  82. 82.
    Adachi Y, Taketani S, Oyaizu H, Ikebukuro K, Tokunaga R, Ikehara S. Apoptosis of colorectal adenocarcinoma induced by 5-FU and/or IFN-gamma through caspase 3 and caspase 8. Int J Oncol 1999;15:1191–6.PubMedGoogle Scholar
  83. 83.
    Uchida H, Shinoura N, Kitayama J, Watanabe T, Nagawa H, Hamada H. 5-Fluorouracil efficiently enhanced apoptosis induced by adenovirus-mediated transfer of caspase-8 in DLD-1 colon cancer cells. J Gene Med 2003;5:287–99.PubMedCrossRefGoogle Scholar
  84. 84.
    Smith CA, Farrah T, Goodwin RG. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell 1994;76:959–62.PubMedCrossRefGoogle Scholar
  85. 85.
    Meterissian SH, Kontogiannea M, Po J, Jensen G, Ferdinand B. Apoptosis induced in human colorectal carcinoma by anti-Fas antibody. Ann Surg Oncol 1997;4:169–75.PubMedCrossRefGoogle Scholar
  86. 86.
    Itoh N, Nagata S. A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen. J Biol Chem 1993;268:10932–7.PubMedGoogle Scholar
  87. 87.
    Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 1997;90:405–13.PubMedCrossRefGoogle Scholar
  88. 88.
    Ellis HM, Horvitz HR. Genetic control of programmed cell death in the nematode C. elegans. Cell 1986;44:817–29.PubMedCrossRefGoogle Scholar
  89. 89.
    Boldin MP, Varfolomeev EE, Pancer Z, Mett IL, Camonis JH, Wallach D. A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J Biol Chem 1995;270:7795–8.PubMedCrossRefGoogle Scholar
  90. 90.
    Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998;281:1305–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Hofmann K, Bucher P, Tschopp J. The CARD domain: a new apoptotic signalling motif. Trends Biochem Sci 1997;22:155–6.PubMedCrossRefGoogle Scholar
  92. 92.
    Hague A, Moorghen M, Hicks D, Chapman M, Paraskeva C. BCL-2 expression in human colorectal adenomas and carcinomas. Oncogene 1994;9:3367–70.PubMedGoogle Scholar
  93. 93.
    Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998;281:1322–6.PubMedCrossRefGoogle Scholar
  94. 94.
    Bouillet P, Metcalf D, Huang DC, et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999;286:1735–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Sattler M, Liang H, Nettesheim D, et al. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 1997;275:983–6.PubMedCrossRefGoogle Scholar
  96. 96.
    Kroemer G. The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nat Med 1997;3:614–20.PubMedCrossRefGoogle Scholar
  97. 97.
    Muchmore SW, Sattler M, Liang H, et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 1996;381:335–41.PubMedCrossRefGoogle Scholar
  98. 98.
    Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 1997;275:1132–6.PubMedCrossRefGoogle Scholar
  99. 99.
    Baretton GB, Diebold J, Christoforis G, et al. Apoptosis and immunohistochemical bcl-2 expression in colorectal adenomas and carcinomas. Aspects of carcinogenesis and prognostic significance. Cancer 1996;77:255–64.PubMedCrossRefGoogle Scholar
  100. 100.
    Giatromanolaki A, Sivridis E, Stathopoulos GP, et al. Bax protein expression in colorectal cancer: association with p53, bcl-2 and patterns of relapse. Anticancer Res 2001;21:253–9.PubMedGoogle Scholar
  101. 101.
    Huang DC, Strasser A. BH3-Only proteins: essential initiators of apoptotic cell death. Cell 2000;103:839–42.PubMedCrossRefGoogle Scholar
  102. 102.
    Forster SJ, Talbot IC, Clayton DG, Critchley DR. Tumour basement membrane laminin in adenocarcinoma of rectum: an immunohistochemical study of biological and clinical significance. Int J Cancer 1986;37:813–7.PubMedCrossRefGoogle Scholar
  103. 103.
    Nagase H, Woessner JF Jr. Matrix metalloproteinases. J Biol Chem 1999;274:21491–4.PubMedCrossRefGoogle Scholar
  104. 104.
    Vihinen P, Kahari VM. Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets. Int J Cancer 2002;99:157–66.PubMedCrossRefGoogle Scholar
  105. 105.
    Cao J, Sato H, Takino T, Seiki M. The C-terminal region of membrane type matrix metalloproteinase is a functional transmembrane domain required for pro-gelatinase A activation. J Biol Chem 1995;270:801–5.PubMedCrossRefGoogle Scholar
  106. 106.
    Seiki M. Membrane-type matrix metalloproteinases. APMIS 1999;107:137–43.PubMedCrossRefGoogle Scholar
  107. 107.
    Kahari VM, Saarialho-Kere U. Matrix metalloproteinases and their inhibitors in tumour growth and invasion. Ann Med 1999;31:34–45.PubMedCrossRefGoogle Scholar
  108. 108.
    Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels JA. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002;87:161–7.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Bramhall SR, Hallissey MT, Whiting J, et al. Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial. Br J Cancer 2002;86:1864–70.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Tierney GM, Griffin NR, Stuart RC, et al. A pilot study of the safety and effects of the matrix metalloproteinase inhibitor marimastat in gastric cancer. Eur J Cancer 1999;35:563–8.PubMedCrossRefGoogle Scholar
  111. 111.
    Theret N, Musso O, Campion JP, et al. Overexpression of matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 in liver from patients with gastrointestinal adenocarcinoma and no detectable metastasis. Int J Cancer 1997;74:426–32.PubMedCrossRefGoogle Scholar
  112. 112.
    Poulsom R, Pignatelli M, Stetler-Stevenson WG, et al. Stromal expression of 72 kda type IV collagenase (MMP-2) and TIMP-2 mRNAs in colorectal neoplasia. Am J Pathol 1992;141:389–96.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Newell KJ, Witty JP, Rodgers WH, Matrisian LM. Expression and localization of matrix-degrading metalloproteinases during colorectal tumorigenesis. Mol Carcinog 1994;10:199–206.PubMedCrossRefGoogle Scholar
  114. 114.
    Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, Dubois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells (erratum appears in Cell 1998;94:271). Cell 1998;93:705–16.PubMedCrossRefGoogle Scholar
  115. 115.
    Zeng ZS, Huang Y, Cohen AM, Guillem JG. Prediction of colorectal cancer relapse and survival via tissue RNA levels of matrix metalloproteinase-9. J Clin Oncol 1996;14:3133–40.PubMedCrossRefGoogle Scholar
  116. 116.
    Heslin MJ, Yan J, Johnson MR, Weiss H, Diasio RB, Urist MM. Role of matrix metalloproteinases in colorectal carcinogenesis. Ann Surg 2001;233:786–92.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Pyke C, Ralfkiaer E, Tryggvason K, Dano K. Messenger RNA for two type IV collagenases is located in stromal cells in human colon cancer. Am J Pathol 1993;142:359–65.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Witty JP, McDonnell S, Newell KJ, et al. Modulation of matrilysin levels in colon carcinoma cell lines affects tumorigenicity in vivo. Cancer Res 1994;54:4805–12.PubMedGoogle Scholar
  119. 119.
    Shattuck-Brandt RL, Lamps LW, Heppner Goss KJ, Dubois RN, Matrisian LM. Differential expression of matrilysin and cyclooxygenase-2 in intestinal and colorectal neoplasms. Mol Carcinog 1999;24:177–87.PubMedCrossRefGoogle Scholar
  120. 120.
    Takeuchi N, Ichikawa Y, Ishikawa T, et al. Matrilysin gene expression in sporadic and familial colorectal adenomas. Mol Carcinog 1997;19:225–9.PubMedCrossRefGoogle Scholar
  121. 121.
    Swallow CJ, Murray MP, Guillem JG. Metastatic colorectal cancer cells induce matrix metalloproteinase release by human monocytes. Clin Exp Metastasis 1996;14:3–11.PubMedCrossRefGoogle Scholar

Copyright information

© The Society of Surgical Oncology, Inc. 2003

Authors and Affiliations

  • William M. BoedefeldII
    • 1
  • Kirby I. Bland
    • 1
  • Martin J. Heslin
    • 1
    • 2
    Email author
  1. 1.Department of SurgeryUniversity of Alabama at BirminghamBirmingham
  2. 2.Department of SurgeryUniversity of Alabama at BirminghamBirmingham

Personalised recommendations