The Impact of Oncogenes on Tumor Maintenance

  • Senji Shirasawa
  • Takehiko Sasazuki
Part of the Cancer Drug Discovery and Development book series (CDD&D)


It is now widely accepted that cancer results from an accumulation of genetic alterations, including subtle sequence changes, alterations in chromosome number, chromosomal translocation, and gene amplifications (1). These alterations result in a gain of function of oncogenes and a loss of function of tumor suppressor genes, leading to uncontrolled growth, differentiation, and apoptosis. The number of mutations required for a tumor to develop in human populations is age-dependent, and seven or eight acquired mutations in a cell are required in commonly occurring solid tumors before an overt malignancy becomes evident (2). The ectopic expression of the telomerase catalytic subunit, in combination with two oncogenes, the simian virus 40 large T and an oncogenic allele of Ha-ras, lead to direct tumorigenic conversion of normal human cells (3). Therefore, there is a succession of genetic alterations, each of which conferring one or another type of growth advantages, lead to the transformation of normal cells into malignant tissue (4). Cancer cell genotypes are a manifestation of six essential alterations in cell physiology that collectively dictate malignant growth through various mechanistic strategies: self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis (4). This classification is needed for a better understanding of molecular mechanisms involved in tumorigenesis and for designing appopriate therapy.


Vascular Endothelial Growth Factor Telomere Length Adenomatous Polyposis Coli HCT116 Cell Human Colon Cancer Cell 
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  1. 1.
    Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 1998; 396: 643–649.PubMedCrossRefGoogle Scholar
  2. 2.
    Renan MJ. How many mutations are required for tumorigenesis? Implications from human cancer data. Mol Carcinogenesis 1993; 7: 139–146.CrossRefGoogle Scholar
  3. 3.
    Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA. Creation of human tumour cells with defined genetic elements. Nature 1999; 400: 464–468.PubMedCrossRefGoogle Scholar
  4. 4.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70.PubMedCrossRefGoogle Scholar
  5. 5.
    Barbacid M. ras genes. Annu Rev Biochem 1987; 56: 779–827.PubMedCrossRefGoogle Scholar
  6. 6.
    Bos JL. ras oncogenes in human cancer: a review. Cancer Res 1989; 49:4682–4689.Google Scholar
  7. 7.
    Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-Ki-ras genes. Cell 1988; 53: 549–554.PubMedCrossRefGoogle Scholar
  8. 8.
    Koera K, Nakamura K, Nakao K, et al. K-ras is essential for the development of the mouse embryo. Oncogene 1997; 15: 1151–1159.PubMedCrossRefGoogle Scholar
  9. 9.
    Johnson L, Greenbaum D, Cichowski K, et al. K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dey 1997; 11: 2468–2481.CrossRefGoogle Scholar
  10. 10.
    James GL, Goldstein JL, Brown MS. Polylysine and CVIM sequences of K-RasB dictate specificity of prenylation and confer resistance to benzodiazepine peptidomimetic in vitro. J Biol Chem 1995; 270: 6221–6226.PubMedCrossRefGoogle Scholar
  11. 11.
    Zuber J, Tchernitsa OI, Hinzmann B, et al. A genome-wide survey of RAS transformation targets. Nat Genet 2000; 24: 144–152.PubMedCrossRefGoogle Scholar
  12. 12.
    Shirasawa S, Furuse M, Yokoyama N, Sasazuki T. Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 1993; 260: 85–88.PubMedCrossRefGoogle Scholar
  13. 13.
    Papadopoulos N, Nicolaides NC, Wei YF, et al. Mutation of a mutL homolog in hereditary colon cancer. Science 1994; 263: 1625–1629.PubMedCrossRefGoogle Scholar
  14. 14.
    Papadopoulos N, Nicolaides NC, Liu B, et al. Mutations of GTBP in genetically unstable cells. Science 1995; 268: 1915–1917.PubMedCrossRefGoogle Scholar
  15. 15.
    Ilyas M, Efstathiou JA, Straub J, Kim HC, Bodmer WF. Transforming growth factor 13 stimulation of colorectal cancer cell lines: type II receptor bypass and changes in acdhesion molecule expression. Proc Natl Acad Sci USA 1999; 96: 3087–3091.PubMedCrossRefGoogle Scholar
  16. 16.
    Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, et al. Activation of 13-catenin-Tcf signaling in colon cancer by mutations in 13-catenin or APC. Science 1997; 275: 1787–1790.PubMedCrossRefGoogle Scholar
  17. 17.
    Korinek V, Barker N, Morin PJ, et al. Constitutive transcriptional activation by a (3-catenin-Tcf complex in APC-1- colon carcinoma. Science 1997; 275: 1784–1787.PubMedCrossRefGoogle Scholar
  18. 18.
    Massague J, Pandiella A. Membrane-anchored growth factors. Annu Rev Biochem 1993; 62: 515–541.PubMedCrossRefGoogle Scholar
  19. 19.
    Toyoda H, Komurasaki T, Uchida D, Morimoto S. Distribution of mRNA for human epiregulin, a differentially expressed member of the epidermal growth factor. Biochem J 1997; 326: 69–75.PubMedGoogle Scholar
  20. 20.
    Shelly M, Pinkas-Kramarski R, Guarino BC, et al. Epiregulin is a potent pan-ErbB ligand that preferentially activates heterodimeric receptor complexes. J Biol Chem 1998; 273: 10496–10505.PubMedCrossRefGoogle Scholar
  21. 21.
    Baba I, Shirasawa S, Iwamoto R, et al. Involvement of deregulated epiregulin expression in tumorigenesis in vivo through activated Ki-ras signaling pathway in human colon cancer cells. Cancer Res 2000; 60: 6886–6889.PubMedGoogle Scholar
  22. 22.
    Little CD, Nau MM, Carney DN, Gazdar AF, Minna JD. Amplification and expression of the c-myc oncogene in human lung cancer cell lines. Nature 1983; 306: 194–196.PubMedCrossRefGoogle Scholar
  23. 23.
    Mariani-Costantini R, Escot C, Theillet C, et al. In situ c-myc expression and genomic status of the cmyc locus in infiltrating ductal carcinomas of the breast. Cancer Res 1988; 48: 199–205.PubMedGoogle Scholar
  24. 24.
    Erisman MD, Rothberg PG, Diehl RE, Morse CC, Spandorfer JM, Astrin SM. Deregulation of c-myc gene expression in human colon carcinoma is not accompanied by amplification or rearrangement of the gene. Mol Cell Biol 1985; 5: 1969–1976.Google Scholar
  25. 25.
    Escot C, Theilletet C, Lidereau R, et al. Genetic alteration of the c-myc protooncogene (MYC) in human primary breast carcinomas. Proc Nall Acad Sci USA 1986; 83: 4834–4838.CrossRefGoogle Scholar
  26. 26.
    He T-C, Sparks AB, Rago C, et al. Identification of c-MYC as a target of the APC pathway. Science 1998; 281: 1509–1512.PubMedCrossRefGoogle Scholar
  27. 27.
    Wang J, Xie LY, Allan S, Breach D, Hannon GJ. Myc activates telomerase. Genes Dev 1998; 12: 1769–1774.PubMedCrossRefGoogle Scholar
  28. 28.
    Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and pl6INK4a. Cell 1997; 88: 593–602.PubMedCrossRefGoogle Scholar
  29. 29.
    Evan G, Littlewood T. A matter of life and cell death. Science 1998; 281: 1317–1322.PubMedCrossRefGoogle Scholar
  30. 30.
    Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 2000; 14: 2501–2514.PubMedCrossRefGoogle Scholar
  31. 31.
    Dyson N. The regulation of E2F by pRB-family proteins. Genes Dev 1998; 12: 2245–2262.PubMedCrossRefGoogle Scholar
  32. 32.
    Sage J, Mulligan GJ, Attardi LD, et al. Targeted disruption of the three Rb-related genes leads to loss of G1 control and immortalization. Genes Dev 2000; 14: 3037–3050.PubMedCrossRefGoogle Scholar
  33. 33.
    Dannenberg J-H, van Rossum A, Schuijff L, to Riele H. Ablation of the retinoblastoma gene family deregulates G1 control causing immotralization and increased cell turnover under growth-restricting conditions. Genes Dev 2000; 14: 3051–3064.PubMedCrossRefGoogle Scholar
  34. 34.
    Fynan TM, Reiss M. Resistance to inhibition of cell growth by transforming growth factor-(3 and its role in oncogenesis. Crit Rev Oncog 1993; 4: 493–540.PubMedGoogle Scholar
  35. 35.
    Markowitz S, Wang J, Meyeroff L, et al. Inactivation of the type II TGF-(3 receptor in colon cancer cells with microsatellite instability. Science 1995; 268: 1336–1338.PubMedCrossRefGoogle Scholar
  36. 36.
    Campbell SL, Khosravi-Far R, Rossman KL, Clark GJ, Der CJ. Increasing complexity of Ras signaling. Oncogene 1998; 17: 1395–1413.PubMedCrossRefGoogle Scholar
  37. 37.
    Binetruy B, Smeal T, Karin M. Ha-Ras augments c-Jun activity and stimulates phosphorylation of its activation domain. Nature 1991; 351: 122–127.PubMedCrossRefGoogle Scholar
  38. 38.
    Smeal T, Binétruy B, Mercola DA, Birrer M, Karin M. Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. Nature 1991; 354: 494–496.PubMedCrossRefGoogle Scholar
  39. 39.
    Hibi M, Lin A, Smeal T, Minden A, Karin M. Identification of an oncoprotein-and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev 1993; 7: 2135–2148.PubMedCrossRefGoogle Scholar
  40. 40.
    Okumura K, Shirasawa S, Nishioka M, Sasazuki T. Activated Ki-Ras suppresses 12-O-tetradecanoylphorbol-13-acetate-induced activation of the c-Jun NH2-terminal kinase pathway in human colon cancer cells. Cancer Res 1999; 59: 2445–2450.PubMedGoogle Scholar
  41. 41.
    Downward J. Ras signalling and apoptosis. Curr Opin Genet Dev 1998; 8: 49–54.PubMedCrossRefGoogle Scholar
  42. 42.
    Khwaja A, Rodriguez-Viciana P, Wennström S, Warne PH, Downward J. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J 1997; 16: 2783–2793.PubMedCrossRefGoogle Scholar
  43. 43.
    Mayo MW, Wang C-Y, Cogswell PC, et al. Requirement of NK-KB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science 1997; 278: 1812–1815.PubMedCrossRefGoogle Scholar
  44. 44.
    Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281: 1309–1312.PubMedCrossRefGoogle Scholar
  45. 45.
    Yang J, Liu X, Bhalla K, et al. Prevention of apoptosis by Bc1–2: release of cytochrome c from mitochondria blocked. Science 1997; 275: 1129–1132.PubMedCrossRefGoogle Scholar
  46. 46.
    Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. The release of cytochrome c from mitochondria: a primary site for Bc1–2 regulation of apoptosis. Science 1997; 275: 1132–1136.PubMedCrossRefGoogle Scholar
  47. 47.
    Bossy-Wetzel E, Newmeyer DD, Green DR. Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondria] transmembrane depolarization. EMBO J 1998; 17: 37–49.PubMedCrossRefGoogle Scholar
  48. 48.
    Cardone MH, Roy N, Stennicke HR, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998; 282: 1318–1321.PubMedCrossRefGoogle Scholar
  49. 49.
    Hannun YA, Obeid LM. Ceramide: an intracellular signal for apoptosis. Trends Biochem Sci 1995; 20: 73–77.PubMedCrossRefGoogle Scholar
  50. 50.
    Ohmori M, Shirasawa S, Furuse M, Okumura K, Sasazuki T. Activated Ki-ras enhances sensitivity of ceramide-induced apoptosis without c-Jun NH2-terminal kinase/stress-activated protein kinase or extracellular signal-regulated kinase activation in human colon cancer cells. Cancer Res 1997; 57: 4714–4717.PubMedGoogle Scholar
  51. 51.
    Shay JW, Bacchetti S. A survey of telomerase activity in human cancer. Eur J Cancer 1997; 33: 787–791.PubMedCrossRefGoogle Scholar
  52. 52.
    Bryan TM, Cech TR. Telomerase and the maintenance of chromosome ends. Our Opin Cell Biol 1999; 11: 318–324.CrossRefGoogle Scholar
  53. 53.
    Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353–364.PubMedCrossRefGoogle Scholar
  54. 54.
    Bull HA, Brickell PM, Dowd PM. Src-related protein tyrosine kinases are physically associated with the surface antigen CD36 in human dermal microvascular endothelial cells. FEBS Leu 1994; 351: 41–44.CrossRefGoogle Scholar
  55. 55.
    Demeron KM, Volpert OV, Tainsky MA, Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 1994; 265: 1582–1584.CrossRefGoogle Scholar
  56. 56.
    Rak J, Mitsuhashi Y, Bayko L, et al. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 1995; 55: 4575–4580.PubMedGoogle Scholar
  57. 57.
    Okada F, Rak JW, Croix BS, et al. Impact of oncogenes in tumor angiogenesis: mutant K-ras up-regulation of vascular endothelial growth factor/vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells. Proc Natl Acad Sci USA 1998; 95: 3609–3614.PubMedCrossRefGoogle Scholar
  58. 58.
    Christofori G, Semb H. The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci 1999; 24: 73–76.PubMedCrossRefGoogle Scholar
  59. 59.
    Allgayer H, Wang H, Shirasawa S, Sasazuki T, Boyd D. Targeted disruption in an invasive colon cancer cell line down-regulates urokinase receptor expression and plasminogen-dependent proteolysis. Br J Cancer 1999; 80: 1884–1891.PubMedCrossRefGoogle Scholar
  60. 60.
    Levine AJ. p53, the cellular gatekeeper for growth and division. Cell 1997; 88: 323–331.PubMedCrossRefGoogle Scholar
  61. 61.
    Pomerantz J, Schreiber-Agus N, Liégeois NJ, et al. The Ink4a tumore suppressor gene product, p19A0, interacts with MDM2 and neutralizes MDM2’s inhibition of p53. Cell 1998; 92: 713–723.PubMedCrossRefGoogle Scholar
  62. 62.
    Picksley SM, Lane DR. The p53-mdm2 autoregulatory feedback loop: a paradigm for the regulation of growth control by p53. Bioessays 1993; 15: 689–690.PubMedCrossRefGoogle Scholar
  63. 63.
    Ries S, Biederer C, Woods D, et al. Opposing effects of ras on p53: transcriptional activation of mdm2 and induction of pl9ARF Cell 2000; 103: 321–330.PubMedCrossRefGoogle Scholar
  64. 64.
    Bunz F, Dutriaux A, Lengauer C, et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 1998; 282: 1497–1501.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2003

Authors and Affiliations

  • Senji Shirasawa
  • Takehiko Sasazuki

There are no affiliations available

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