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. 1999 Jun 15;340(Pt 3):621–630.

How aneuploidy affects metabolic control and causes cancer.

D Rasnick 1, P H Duesberg 1
PMCID: PMC1220292  PMID: 10359645

Abstract

The complexity and diversity of cancer-specific phenotypes, including de-differentiation, invasiveness, metastasis, abnormal morphology and metabolism, genetic instability and progression to malignancy, have so far eluded explanation by a simple, coherent hypothesis. However, an adaptation of Metabolic Control Analysis supports the 100-year-old hypothesis that aneuploidy, an abnormal number of chromosomes, is the cause of cancer. The results demonstrate the currently counter-intuitive principle that it is the fraction of the genome undergoing differential expression, not the magnitude of the differential expression, that controls phenotypic transformation. Transforming the robust normal phenotype into cancer requires a twofold increase in the expression of thousands of normal gene products. The massive change in gene dose produces highly non-linear (i.e. qualitative) changes in the physiology and metabolism of cells and tissues. Since aneuploidy disrupts the natural balance of mitosis proteins, it also explains the notorious genetic instability of cancer cells as a consequence of the perpetual regrouping of chromosomes. In view of this and the existence of non-cancerous aneuploidy, we propose that cancer is the phenotype of cells above a certain threshold of aneuploidy. This threshold is reached either by the gradual, stepwise increase in the level of aneuploidy as a consequence of the autocatalysed genetic instability of aneuploid cells or by tetraploidization followed by a gradual loss of chromosomes. Thus the initiation step of carcinogenesis produces aneuploidy below the threshold for cancer, and the promotion step increases the level of aneuploidy above this threshold. We conclude that aneuploidy offers a simple and coherent explanation for all the cancer-specific phenotypes. Accordingly, the gross biochemical abnormalities, abnormal cellular size and morphology, the appearance of tumour-associated antigens, the high levels of secreted proteins responsible for invasiveness and loss of contact inhibition, and even the daunting genetic instability that enables cancer cells to evade chemotherapy, are all the natural consequence of the massive over- and under-expression of proteins.

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Selected References

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  1. Aardema M. J., Albertini S., Arni P., Henderson L. M., Kirsch-Volders M., Mackay J. M., Sarrif A. M., Stringer D. A., Taalman R. D. Aneuploidy: a report of an ECETOC task force. Mutat Res. 1998 Feb;410(1):3–79. doi: 10.1016/s1383-5742(97)00029-x. [DOI] [PubMed] [Google Scholar]
  2. Albino A. P., Le Strange R., Oliff A. I., Furth M. E., Old L. J. Transforming ras genes from human melanoma: a manifestation of tumour heterogeneity? Nature. 1984 Mar 1;308(5954):69–72. doi: 10.1038/308069a0. [DOI] [PubMed] [Google Scholar]
  3. Alderman E. M., Lobb R. R., Fett J. W. Isolation of tumor-secreted products from human carcinoma cells maintained in a defined protein-free medium. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5771–5775. doi: 10.1073/pnas.82.17.5771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ames B. N., Durston W. E., Yamasaki E., Lee F. D. Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc Natl Acad Sci U S A. 1973 Aug;70(8):2281–2285. doi: 10.1073/pnas.70.8.2281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barbacid M. ras genes. Annu Rev Biochem. 1987;56:779–827. doi: 10.1146/annurev.bi.56.070187.004023. [DOI] [PubMed] [Google Scholar]
  6. Bos J. L., Fearon E. R., Hamilton S. R., Verlaan-de Vries M., van Boom J. H., van der Eb A. J., Vogelstein B. Prevalence of ras gene mutations in human colorectal cancers. 1987 May 28-Jun 3Nature. 327(6120):293–297. doi: 10.1038/327293a0. [DOI] [PubMed] [Google Scholar]
  7. Brown G. C. Control analysis applied to the whole body: control by body organs over plasma concentrations and organ fluxes of substances in the blood. Biochem J. 1994 Jan 1;297(Pt 1):115–122. doi: 10.1042/bj2970115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brown G. C. Total cell protein concentration as an evolutionary constraint on the metabolic control distribution in cells. J Theor Biol. 1991 Nov 21;153(2):195–203. doi: 10.1016/s0022-5193(05)80422-9. [DOI] [PubMed] [Google Scholar]
  9. CASPERSSON T., FOLEY G. E., KILLANDER D., LOMAKKA G. CYTOCHEMICAL DIFFERENCES BETWEEN MAMMALIAN CELL LINES OF NORMAL AND NEOPLASTIC ORIGINS. CORRELATION WITH HETEROTRANSPLANT- ABILITY IN SYRIAN HAMSTERS. Exp Cell Res. 1963 Dec;32:553–565. doi: 10.1016/0014-4827(63)90193-9. [DOI] [PubMed] [Google Scholar]
  10. COOPER H. L., BLACK P. H. Cytogenetic studies of hamster kidney cell cultures transformed by the simian vacuolating virus (SV40). J Natl Cancer Inst. 1963 May;30:1015–1043. [PubMed] [Google Scholar]
  11. Cha R. S., Thilly W. G., Zarbl H. N-nitroso-N-methylurea-induced rat mammary tumors arise from cells with preexisting oncogenic Hras1 gene mutations. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3749–3753. doi: 10.1073/pnas.91.9.3749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Donehower L. A., Harvey M., Slagle B. L., McArthur M. J., Montgomery C. A., Jr, Butel J. S., Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992 Mar 19;356(6366):215–221. doi: 10.1038/356215a0. [DOI] [PubMed] [Google Scholar]
  13. Duesberg P. H. Oncogenes and cancer. Science. 1995 Mar 10;267(5203):1407–1408. doi: 10.1126/science.7794335. [DOI] [PubMed] [Google Scholar]
  14. Duesberg P., Rausch C., Rasnick D., Hehlmann R. Genetic instability of cancer cells is proportional to their degree of aneuploidy. Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13692–13697. doi: 10.1073/pnas.95.23.13692. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fell D. A. Metabolic control analysis: a survey of its theoretical and experimental development. Biochem J. 1992 Sep 1;286(Pt 2):313–330. doi: 10.1042/bj2860313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fell D. A., Thomas S. Physiological control of metabolic flux: the requirement for multisite modulation. Biochem J. 1995 Oct 1;311(Pt 1):35–39. doi: 10.1042/bj3110035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fields C., Adams M. D., White O., Venter J. C. How many genes in the human genome? Nat Genet. 1994 Jul;7(3):345–346. doi: 10.1038/ng0794-345. [DOI] [PubMed] [Google Scholar]
  18. Finney R. E., Bishop J. M. Predisposition to neoplastic transformation caused by gene replacement of H-ras1. Science. 1993 Jun 4;260(5113):1524–1527. doi: 10.1126/science.8502998. [DOI] [PubMed] [Google Scholar]
  19. Foley G. E., Handler A. H., Lynch P. M., Wolman S. R., Stulberg C. S., Eagle H. Loss of neoplastic properties in vitro. II. Observations on KB sublines. Cancer Res. 1965 Sep;25(8):1254–1261. [PubMed] [Google Scholar]
  20. Fulton A. B. How crowded is the cytoplasm? Cell. 1982 Sep;30(2):345–347. doi: 10.1016/0092-8674(82)90231-8. [DOI] [PubMed] [Google Scholar]
  21. Giaretti W., Santi L. Tumor progression by DNA flow cytometry in human colorectal cancer. Int J Cancer. 1990 Apr 15;45(4):597–603. doi: 10.1002/ijc.2910450404. [DOI] [PubMed] [Google Scholar]
  22. Gunby P. Battles against many malignancies lie ahead as federal 'war on cancer' enters third decade. JAMA. 1992 Apr 8;267(14):1891–1891. [PubMed] [Google Scholar]
  23. Heinrich R., Rapoport T. A. A linear steady-state treatment of enzymatic chains. General properties, control and effector strength. Eur J Biochem. 1974 Feb 15;42(1):89–95. doi: 10.1111/j.1432-1033.1974.tb03318.x. [DOI] [PubMed] [Google Scholar]
  24. Heinrich R., Rapoport T. A. Linear theory of enzymatic chains; its application for the analysis of the crossover theorem and of the glycolysis of human erythrocytes. Acta Biol Med Ger. 1973;31(4):479–494. [PubMed] [Google Scholar]
  25. Heppner G. H., Miller F. R. The cellular basis of tumor progression. Int Rev Cytol. 1998;177:1–56. doi: 10.1016/s0074-7696(08)62230-5. [DOI] [PubMed] [Google Scholar]
  26. Holliday R. Chromosome error propagation and cancer. Trends Genet. 1989 Feb;5(2):42–45. doi: 10.1016/0168-9525(89)90020-6. [DOI] [PubMed] [Google Scholar]
  27. Hua V. Y., Wang W. K., Duesberg P. H. Dominant transformation by mutated human ras genes in vitro requires more than 100 times higher expression than is observed in cancers. Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9614–9619. doi: 10.1073/pnas.94.18.9614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Jen J., Powell S. M., Papadopoulos N., Smith K. J., Hamilton S. R., Vogelstein B., Kinzler K. W. Molecular determinants of dysplasia in colorectal lesions. Cancer Res. 1994 Nov 1;54(21):5523–5526. [PubMed] [Google Scholar]
  29. Kacser H., Burns J. A. MOlecular democracy: who shares the controls? Biochem Soc Trans. 1979 Oct;7(5):1149–1160. doi: 10.1042/bst0071149. [DOI] [PubMed] [Google Scholar]
  30. Kacser H., Burns J. A. The control of flux. Biochem Soc Trans. 1995 May;23(2):341–366. doi: 10.1042/bst0230341. [DOI] [PubMed] [Google Scholar]
  31. Kacser H., Burns J. A. The control of flux. Symp Soc Exp Biol. 1973;27:65–104. [PubMed] [Google Scholar]
  32. Kacser H., Burns J. A. The molecular basis of dominance. Genetics. 1981 Mar-Apr;97(3-4):639–666. doi: 10.1093/genetics/97.3-4.639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kacser H. Recent developments beyond metabolic control analysis. Biochem Soc Trans. 1995 May;23(2):387–391. doi: 10.1042/bst0230387. [DOI] [PubMed] [Google Scholar]
  34. Kahn D., Westerhoff H. V. Control theory of regulatory cascades. J Theor Biol. 1991 Nov 21;153(2):255–285. doi: 10.1016/s0022-5193(05)80426-6. [DOI] [PubMed] [Google Scholar]
  35. Kinzler K. W., Vogelstein B. Cancer-susceptibility genes. Gatekeepers and caretakers. Nature. 1997 Apr 24;386(6627):761–763. doi: 10.1038/386761a0. [DOI] [PubMed] [Google Scholar]
  36. Kinzler K. W., Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996 Oct 18;87(2):159–170. doi: 10.1016/s0092-8674(00)81333-1. [DOI] [PubMed] [Google Scholar]
  37. Lengauer C., Kinzler K. W., Vogelstein B. Genetic instability in colorectal cancers. Nature. 1997 Apr 10;386(6625):623–627. doi: 10.1038/386623a0. [DOI] [PubMed] [Google Scholar]
  38. Li R., Yerganian G., Duesberg P., Kraemer A., Willer A., Rausch C., Hehlmann R. Aneuploidy correlated 100% with chemical transformation of Chinese hamster cells. Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14506–14511. doi: 10.1073/pnas.94.26.14506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Lijinsky W. A view of the relation between carcinogenesis and mutagenesis. Environ Mol Mutagen. 1989;14 (Suppl 16):78–84. doi: 10.1002/em.2850140615. [DOI] [PubMed] [Google Scholar]
  40. Lindsley D. L., Sandler L., Baker B. S., Carpenter A. T., Denell R. E., Hall J. C., Jacobs P. A., Miklos G. L., Davis B. K., Gethmann R. C. Segmental aneuploidy and the genetic gross structure of the Drosophila genome. Genetics. 1972 May;71(1):157–184. doi: 10.1093/genetics/71.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Miller J. A., Miller E. C. Chemical carcinogenesis: mechanisms and approaches to its control. J Natl Cancer Inst. 1971 Sep;47(3):V–XIV. [PubMed] [Google Scholar]
  42. Mitelman F., Mertens F., Johansson B. A breakpoint map of recurrent chromosomal rearrangements in human neoplasia. Nat Genet. 1997 Apr;15(Spec No):417–474. doi: 10.1038/ng0497supp-417. [DOI] [PubMed] [Google Scholar]
  43. Moorhead P. S., Saksela E. The sequence of chromosome aberrations during SV 40 transformation of a human diploid cell strain. Hereditas. 1965;52(3):271–284. doi: 10.1111/j.1601-5223.1965.tb01960.x. [DOI] [PubMed] [Google Scholar]
  44. NORDLING C. O. A new theory on cancer-inducing mechanism. Br J Cancer. 1953 Mar;7(1):68–72. doi: 10.1038/bjc.1953.8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Nowell P. C. The clonal evolution of tumor cell populations. Science. 1976 Oct 1;194(4260):23–28. doi: 10.1126/science.959840. [DOI] [PubMed] [Google Scholar]
  46. Ono S. Genetic implication of karyological instability of malignant somatic cells. Physiol Rev. 1971 Jul;51(3):496–526. doi: 10.1152/physrev.1971.51.3.496. [DOI] [PubMed] [Google Scholar]
  47. Plattner R., Anderson M. J., Sato K. Y., Fasching C. L., Der C. J., Stanbridge E. J. Loss of oncogenic ras expression does not correlate with loss of tumorigenicity in human cells. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6665–6670. doi: 10.1073/pnas.93.13.6665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Prehn R. T. Cancers beget mutations versus mutations beget cancers. Cancer Res. 1994 Oct 15;54(20):5296–5300. [PubMed] [Google Scholar]
  49. Sandler L., Hecht F. Annotation: genetic effects of aneuploidy. Am J Hum Genet. 1973 May;25(3):332–339. [PMC free article] [PubMed] [Google Scholar]
  50. Schuster S., Kahn D., Westerhoff H. V. Modular analysis of the control of complex metabolic pathways. Biophys Chem. 1993 Nov;48(1):1–17. doi: 10.1016/0301-4622(93)80037-j. [DOI] [PubMed] [Google Scholar]
  51. Sennerstam R., Kato H., Auer G. U. Dissociation of cellular protein and DNA content in mild and moderate dysplasia as a reflection of the degree of aneuploidy in cancer. Anal Quant Cytol Histol. 1989 Aug;11(4):255–260. [PubMed] [Google Scholar]
  52. Shackney S. E., Berg G., Simon S. R., Cohen J., Amina S., Pommersheim W., Yakulis R., Wang S., Uhl M., Smith C. A. Origins and clinical implications of aneuploidy in early bladder cancer. Cytometry. 1995 Dec 15;22(4):307–316. doi: 10.1002/cyto.990220407. [DOI] [PubMed] [Google Scholar]
  53. Shackney S. E., Singh S. G., Yakulis R., Smith C. A., Pollice A. A., Petruolo S., Waggoner A., Hartsock R. J. Aneuploidy in breast cancer: a fluorescence in situ hybridization study. Cytometry. 1995 Dec 15;22(4):282–291. doi: 10.1002/cyto.990220404. [DOI] [PubMed] [Google Scholar]
  54. Shackney S. E., Smith C. A., Miller B. W., Burholt D. R., Murtha K., Giles H. R., Ketterer D. M., Pollice A. A. Model for the genetic evolution of human solid tumors. Cancer Res. 1989 Jun 15;49(12):3344–3354. [PubMed] [Google Scholar]
  55. Shankey T. V., Kallioniemi O. P., Koslowski J. M., Lieber M. L., Mayall B. H., Miller G., Smith G. J. Consensus review of the clinical utility of DNA content cytometry in prostate cancer. Cytometry. 1993;14(5):497–500. doi: 10.1002/cyto.990140508. [DOI] [PubMed] [Google Scholar]
  56. Shapiro B. L. Down syndrome--a disruption of homeostasis. Am J Med Genet. 1983 Feb;14(2):241–269. doi: 10.1002/ajmg.1320140206. [DOI] [PubMed] [Google Scholar]
  57. Shibata D., Schaeffer J., Li Z. H., Capella G., Perucho M. Genetic heterogeneity of the c-K-ras locus in colorectal adenomas but not in adenocarcinomas. J Natl Cancer Inst. 1993 Jul 7;85(13):1058–1063. doi: 10.1093/jnci/85.13.1058. [DOI] [PubMed] [Google Scholar]
  58. Small J. R., Kacser H. Responses of metabolic systems to large changes in enzyme activities and effectors. 1. The linear treatment of unbranched chains. Eur J Biochem. 1993 Apr 1;213(1):613–624. doi: 10.1111/j.1432-1033.1993.tb17801.x. [DOI] [PubMed] [Google Scholar]
  59. Small J. R., Kacser H. Responses of metabolic systems to large changes in enzyme activities and effectors. 2. The linear treatment of branched pathways and metabolite concentrations. Assessment of the general non-linear case. Eur J Biochem. 1993 Apr 1;213(1):625–640. doi: 10.1111/j.1432-1033.1993.tb17802.x. [DOI] [PubMed] [Google Scholar]
  60. Srere P. A. 17th Fritz Lipmann Lecture. Wanderings (wonderings) in metabolism. Biol Chem Hoppe Seyler. 1993 Sep;374(9):833–842. [PubMed] [Google Scholar]
  61. Stanbridge E. J. Human tumor suppressor genes. Annu Rev Genet. 1990;24:615–657. doi: 10.1146/annurev.ge.24.120190.003151. [DOI] [PubMed] [Google Scholar]
  62. Strausberg R. L., Dahl C. A., Klausner R. D. New opportunities for uncovering the molecular basis of cancer. Nat Genet. 1997 Apr;15(Spec No):415–416. doi: 10.1038/ng0497supp-415. [DOI] [PubMed] [Google Scholar]
  63. Strauss B. S. The origin of point mutations in human tumor cells. Cancer Res. 1992 Jan 15;52(2):249–253. [PubMed] [Google Scholar]
  64. TODARO G. J., WOLMAN S. R., GREEN H. RAPID TRANSFORMATION OF HUMAN FIBROBLASTS WITH LOW GROWTH POTENTIAL INTO ESTABLISHED CELL LINES BY SV40. J Cell Physiol. 1963 Dec;62:257–265. doi: 10.1002/jcp.1030620305. [DOI] [PubMed] [Google Scholar]
  65. Wolman S. R. Karyotypic progression in human tumors. Cancer Metastasis Rev. 1983;2(3):257–293. doi: 10.1007/BF00048481. [DOI] [PubMed] [Google Scholar]
  66. Zhang L., Zhou W., Velculescu V. E., Kern S. E., Hruban R. H., Hamilton S. R., Vogelstein B., Kinzler K. W. Gene expression profiles in normal and cancer cells. Science. 1997 May 23;276(5316):1268–1272. doi: 10.1126/science.276.5316.1268. [DOI] [PubMed] [Google Scholar]
  67. de Grouchy J., de Nava C. A chromosomal theory of carcinogenesis. Ann Intern Med. 1968 Aug;69(2):381–391. doi: 10.7326/0003-4819-69-2-381. [DOI] [PubMed] [Google Scholar]

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