Advertisement

Aneuploidy theory explains tumor formation, the absence of immune surveillance, and the failure of chemotherapy

      Abstract

      The autocatalyzed progression of aneuploidy accounts for all cancer-specific phenotypes, the Hayflick limit of cultured cells, carcinogen-induced tumors in mice, the age distribution of human cancer, and multidrug-resistance. Here aneuploidy theory addresses tumor formation. The logistic equation, φn+1 = rφn (1 − φn), models the autocatalyzed progression of aneuploidy in vivo and in vitro. The variable φn+1 is the average aneuploid fraction of a population of cells at the n+1 cell division and is determined by the value at the nth cell division. The value r is the growth control parameter. The logistic equation was used to compute the probability distribution for values of φ after numerous divisions of aneuploid cells. The autocatalyzed progression of aneuploidy follows the laws of deterministic chaos, which means that certain values of φ are more probable than others. The probability map of the logistic equation shows that: 1) an aneuploid fraction of at least 0.30 is necessary to sustain a population of cancer cells; and 2) the most likely aneuploid fraction after many population doublings is 0.70, which is equivalent to a DNAindex=1.7, the point of maximum disorder of the genome that still sustains life. Aneuploidy theory also explains the lack of immune surveillance and the failure of chemotherapy.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Cancer Genetics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hansemann D.
        Ueber asymmetrische Zelltheilung in epithel Krebsen und deren biologische Bedeutung.
        Virschows Arch Pathol Anat. 1890; 119 ([On asymmetric mitoses in epithelial cancers and their biological significance]): 299-326
        • Mitelman F.
        Catalogue of chromosome aberrations in cancer. Wiley-Liss, New York1994
        • Sandberg A.A.
        The chromosomes in human cancer and leukemia. Elsevier Science Publishing, New York1990
        • Gebhart E.
        • Liehr T.
        Patterns of genomic imbalances in human solid tumors (review).
        Int J Oncol. 2000; 16: 383-399
        • Mertens F.
        • Johansson B.
        • Hoglund M.
        • Mitelman F.
        Chromosomal imbalance maps of malignant solid tumors.
        Cancer Res. 1997; 57: 2765-2780
        • Levan A.
        Chromosome abnormalities and carcinogenesis.
        in: Lima-de-Faria A. Handbook of molecular cytology. American Elsevier Publishing Co, New York1969: 716-731
        • Boveri T.
        Zur Frage der Entstehung maligner Tumoren. Fischer, Jena1914 ([On the question of the origin of malignant tumors])
        • Duesberg P.
        • Rasnick D.
        Aneuploidy, the somatic mutation that makes cancer a species of its own.
        Cell Motil Cytoskeleton. 2000; 47: 81-107
        • Li R.
        • Sonik A.
        • Stindl R.
        • Rasnick D.
        • Duesberg P.
        Aneuploidy versus gene mutation hypothesis.
        Proc Natl Acad Sci (USA). 2000; 97: 3236-3241
        • Rasnick D.
        • Duesberg P.H.
        How aneuploidy affects metabolic control and causes cancer.
        Biochem J. 1999; 340: 621-630
        • Rasnick D.
        Auto-catalyzed progression of aneuploidy explains the Hayflick limit of cultured cells, carcinogen-induced tumours in mice, and the age distribution of human cancer.
        Biochem J. 2000; 348: 497-506
        • Liu P.
        • Zhang H.
        • McLellan A.
        • Vogel H.
        • Bradley A.
        Embryonic lethality and tumorigenesis caused by segmental aneuploidy on mouse chromosome 11.
        Genetics. 1998; 150: 1155-1168
        • Sell S.
        • Pierce G.B.
        Biology of disease.
        Lab Invest. 1994; 70: 6-22
        • Anderson G.H.
        Chapter 3. W. B. Saunders Co, Philadelphia1991
        • Atkin N.B.
        • Baker M.C.
        Are human cancers ever diploid–or often trisomic? Conflicting evidence from direct preparations and culture.
        Cytogenet Cell Genet. 1990; 53: 58-60
        • Lindsley D.L.
        • Sandler L.
        • et al.
        Segmental aneuploidy and the genetic gross structure of the drosophila genome.
        Genetics. 1972; 71: 157-184
        • Sandler L.
        • Hecht F.
        Genetic effects of aneuploidy.
        Am J Hum Genet. 1973; 25: 332-339
        • Steel G.G.
        • Lamerton L.F.
        Cell population kinetics and chemotherapy. I. The kinetics of tumor cell populations.
        Natl Cancer Inst Monogr. 1969; 30: 29-42
        • Shackney S.E.
        • Berg G.
        • Simon S.R.
        • Cohen J.
        • Amina S.
        • et al.
        Origins and clinical implications of aneuploidy in early bladder cancer.
        Cytometry. 1995; 22: 307-316
        • Oksala T.
        • Therman E.
        Mitotic abnormalities and cancer.
        in: German J. Chromosomes and cancer. John Wiley & Sons, New York1974: 239-263
        • Giaretti W.
        • Santi L.
        Tumor progression by DNA flow cytometry in human colorectal cancer.
        Int J Cancer. 1990; 45: 597-603
        • Shackney S.E.
        • Smith C.A.
        • Miller B.W.
        • Burholt D.R.
        • Murtha K.
        • et al.
        Model for the genetic evolution of human solid tumors.
        Cancer Res. 1989; 49: 3344-3354
        • Shackney S.E.
        • Singh S.G.
        • Yakulis R.
        • Smith C.A.
        • Pollice A.A.
        • et al.
        Aneuploidy in breast cancer.
        Cytometry. 1995; 22: 282-291
        • Shankey T.V.
        • Kallioniemi O.-P.
        • Koslowski J.M.
        • Lieber M.L.
        • Mayall B.H.
        • et al.
        Consensus review of the clinical utility of DNA content cytometry in prostate cancer.
        Cytometry. 1993; 14: 497-500
        • Rous P.
        • Kidd J.G.
        Conditional neoplasms and subthreshold neoplastic states. A study of the tar tumors of rabbits.
        J Exp Med. 1941; 73: 365-389
        • Auer G.U.
        • Caspersson T.O.
        • Wallgren A.S.
        DNA content and survival in mammary carcinoma.
        Anal Quant Cytol Histol. 1980; 2: 161-165
        • Hering B.
        • Horn L.-C.
        • Nenning H.
        • Kühndel K.
        Predictive value of DNA cytometry in CIN 1 and 2.
        Anal Quant Cytol Histol. 2000; 22: 333-337
        • Rzymowska J.
        • Skierski J.
        • Kurylcio L.
        • Dyrda Z.
        DNA index as prognostic factor in breast cancer.
        Neoplasma. 1995; 42: 239-242
        • Lengauer C.
        • Kinzler K.W.
        • Vogelstein B.
        Genetic instabilities in human cancers.
        Nature. 1998; 396: 643-649
        • Levan A.
        • Biesele J.J.
        Role of chromosomes in cancerogenesis, as studied in serial tissue culture of mammalian cells.
        Ann NY Acad Sci. 1958; 71: 1022-1053
      1. Lucas C. Complexity philosophy as a computing paradigm. In: Self-organizing systems—future prospects for computing. Manchester, UK: UMIST Workshop, 1999. Available at: http://www.calresco.org/lucas/compute.htm.

        • Kato A.
        • Kubo K.
        • Kurokawa F.
        • Okita K.
        • Oga A.
        • Murakami T.
        Numerical aberrations of chromosomes 16, 17, and 18 in hepatocullular carcinoma.
        Dig Dis Sci. 1998; 43: 1-7
        • Jensen R.V.
        Classical chaos.
        Am Sci. 1987; 75: 168-181
        • Duesberg P.
        • Li R.
        • Rasnick D.
        • Rausch C.
        • Willer A.
        • et al.
        Aneuploidy precedes and segregates with chemical carcinogenesis.
        Cancer Genet Cytogenet. 2000; 119: 83-93
      2. Heylighen F. The science of self-organization and adaptivity. Center “Leo Apostel”, Free University of Brussels, Belgium, Brussels1999
        • Stutman O.
        Immunodepression and malignancy.
        Adv Cancer Res. 1975; 22: 261-422
        • Edinburgh
        Report of the medical committee of the society for investigating the nature and cure of cancer.
        Edinburgh Medical Surgery Journal. 1806; 2: 382
        • Burnet F.M.
        Cancer—a biological approach.
        Br Med J. 1957; 1: 779-786
        • Thomas L.
        Cellular and humoral aspects of the hypersensitive state (discussion). Harper, New York1959
        • Burnet F.M.
        Immunological surveillance in neoplasia.
        Transplant Rev. 1971; 7: 3-25
        • Gold M.
        A conspiracy of cells. State University of New York Press, New York1986
        • Herberman R.B.
        Possible role of natural killer cells and other effector cells in immune surveillance against cancer.
        J Invest Dermatol. 1984; 83: 137s-140s
        • Hewitt H.B.
        • Blake E.R.
        • Walder A.S.
        A critique of the evidence for active host defence against cancer, based on personal studies of 27 murine tumours of spontaneous origin.
        Br J Cancer. 1976; 33: 241-259
      3. Tannock IF. Conventional cancer therapy: promise broken or promise delayed? Lancet 1998;351(Suppl 2):SII9–16.

        • Epstein S.S.
        The politics of cancer revisited. East Ridge Press, New York1998
        • Whitman R.C.
        Somatic mutation as a factor in the production of cancer; a critical review of v. Hansemann's theory of anaplasia in the light of modern knowledge of genetics.
        J Cancer Res. 1919; 4: 181-202
        • Duesberg P.
        • Stindl R.
        • Hehlmann R.
        Explaining the high mutation rates of cancer cells to drug and multidrug resistance by chromosome reassortments that are catalyzed by aneuploidy.
        Proc Natl Acad Sci USA. 2000; 97: 14295-14300
        • Li C.I.
        • Malone K.E.
        • Weiss N.S.
        • Daling J.R.
        Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer.
        J Natl Cancer Inst. 2001; 93: 1008-1013
        • Gorre M.E.
        • Mohammed M.
        • Ellwood K.
        • Hsu N.
        • Paquette R.
        • et al.
        Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.
        Science. 2001; 293: 876-880
        • Nowell P.
        • Rowley J.
        • Knudson A.
        Cancer genetics, cytogenetics—defining the enemy within.
        Nat Med. 1998; 4: 1107-1111
        • Boveri T.
        Die Blastomerenkerne von Ascaris megalocephala und die Theorie der Chromosomenindividualität.
        Archiv Zellforschung. 1909; 3 ([The nuclei of blastomeres of (from) Ascaris megalocephalia and the theory of chromosomal individuality]): 181-268
        • Hayflick L.
        The limited in vitro lifetime of human diploid cell strains.
        Experimental Cell Res. 1965; 37: 614-636
        • Foulds L.
        The experimental study of tumor progression.
        Cancer Res. 1954; 14: 327-339
        • Niakan B.
        A mechanism of the spontaneous remission and regression of cancer.
        Cancer Biother Radiopharm. 1998; 13: 209-210
        • Challis G.B.
        • Stam H.J.
        The spontaneous regression of cancer.
        Acta Oncologica. 1990; 29: 545-550
        • Kappauf H.
        • Gallmeier W.M.
        • Wunsch P.H.
        • Mittelmeier H.O.
        • Birkmann J.
        • et al.
        Complete spontaneous remission in a patient with metastatic non-small-cell lung cancer. Case report, review of the literature, and discussion of possible biological pathways involved.
        Ann Oncol. 1997; 8: 1031-1039