Summary
Morphological abnormalities of both the nuclei and the cell bodies of tumour cells were described by Müller in the late 1830s. Abnormalities of mitoses and chromosomes in tumour cells were described in the late 1880s. Von Hansemann, in the 1890s, suggested that tumour cells develop from normal cells because of a tendency to mal-distribution and other changes of chromosomes occurring during mitosis. In the first decades of the 20th century, Mendelian genetics and “gene mapping” of chromosomes were established, and the dominant or recessive bases of the familial predispositions to certain tumour types were recognised. In the same period, the carcinogenic effects of ionising radiations, of certain chemicals and of particular viruses were described. A well-developed “somatic gene-mutational theory” of tumours was postulated by Bauer in 1928. In support of this, in the next three decades, many environmental agents were found to cause mitotic and chromosomal abnormalities in normal cells as well as mutations in germ-line cells of experimental animals. Nevertheless, mitotic, chromosomal, and other mutational theories were not popular explanations of tumour pathogenesis in the first half of the 20th century. Only in the 1960s did somatic mutational mechanisms come to dominate theories of tumour formation, especially as a result of the discoveries of the reactivity of carcinogens with DNA, and that the mutation responsible for xeroderma pigmentosum causes loss of function of a gene involved in the repair of DNA after damage by ultraviolet light (Cleaver in 1968). To explain the complexity of tumourous phenomena, “multi-hit” models gained popularity over “single-hit” models of somatic mutation, and “epigenetic” mechanisms of gene regulation began to be studied in tumour cells. More recently, the documentation of much larger-than-expected numbers of genomic events in tumour cells (by Stoler and co-workers, in 1999) has raised the issue of somatic genetic instability in tumour cells, a field which was pioneered in the 1970s mainly by Loeb. Here these discoveries are traced, beginning with “nuclear instability” though mitotic-and-chromosomal theories, single somatic mutation theories, “multi-hit” somatic theories, “somatic, non-chromosomal, genetic instability” and epigenetic mechanisms in tumour cells as a background to the chapters which follow.
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References
Hertwig O (1892) The Cell. Outlines of General Anatomy and Physiology. Translation by M. Campbell, 1895. Swan Sonnenschein & Co, London
Wolff J (1907) The Science of Cancerous Diseases from the Earliest Times to the Present. Translation by B Ayoub, and with an introduction by S Jarcho, 1990, Science History Publications, Sagamore Beach, MA
Wilson EB (1924) The Cell in Development and Heredity. 3rd edn., Macmillan, New York
Nordenskiöld E (1928) The History of Biology. Translation by LB Eyre, Tudor Publishing, New York
Cameron GR (1952) Pathology of the Cell. Oliver and Boyd, Edinburgh
Koller PC (1957) The genetic component of cancer. In: RW Raven (ed.): Cancer, Vol 1. Butterworth and Co, London, 335–403
Allen G (1978) Life Science in the Twentieth Century. Cambridge Univ Press, Cambridge
Shimkin MB (1979) Contrary to Nature. US Dept Health, Education and Welfare, Publication No (NIH) 79–720, Washington DC
Rather LJ (1978) The Genesis of Cancer. A study in the History of Ideas. The Johns Hopkins University Press, Baltimore
Harris HA (1995) The Cells of The Body: A History of Somatic Cell Genetics. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY
Harris HA (1999) The Birth of The Cell. Yale University Press, New Haven
Fitzgerald PJ (2000) From Demons and Evil Spirits to Cancer Genes. Armed Forces Institute of Pathology, Washington DC
Dohm G (2001) Geschichte der Histopathologie/History of Histopathology. Springer-Verlag, Berlin
Lima-de-Faria A (2003) One Hundred Years of Chromosome Research, and What Remains To Be Learned. Kluwer, Dordrecht
Carpenter WB (1891) The Microscope and its Revelations. 7th edn. J&A Churchill, London
Bradbury S (1967) The Evolution of the Microscope. Permagon Press, Oxford
Brown R (1833) On the organs and mode of fecundation in Orchideae and Asclepiadeae. Transactions Linnean Soc (London) 26: 685–745 (Communicated to the Linnean Society November 1831)
Hunter J (1837) The Works of John Hunter FRS. Translation by JF Palmer, Longman, London
Schleiden (1838) Contributions to phytogenesis. Translation by H Smith 1847, The Sydenham Society, London
Schwann T (1839) Microscopical researches into the accordance in the structure and growth of animals and plants. Translation by H Smith, 1847, The Sydenham Society, London
Bringmann WG, Lück HE, Miller R, Early CE (eds) (1997) A Pictorial History of Psychology. Quintessence Publishing Co, Carol Stream
Müller J (1838) On the Nature and Structural Characteristics of Cancer and those Morbid Growths which may be Confounded with It. G. Reimer, Berlin. Translation by C West, 1840, Sherwood, Gilbert and Piper, London
Rather LJ, Rather P, Frerichs JB (1986) Johannes Muller and the Nineteenth-Century Origins of Tumor Cell Theory. Science History Publications, Canton
Kölliker A (1852) A Manual of Human Microscopic Anatomy. Translation by G Busk, 1860, Parker, London
Hertwig O (1890) Textbook of the Embryology of Man and Mamals. Translation by EL Mark, 1899, Swan Sonnenschein & Co, London
Gaskin E (1968) Investigation into Generation 1651–1828. Hutchinson, London
Haeckel E (1907) The evolution of man: a popular scientific study. 5th edn, Translation by J McCabe, Watts, London
Bolsche W (1906) Haeckel, his life and work. With introduction and supplementary chapter by the translator, J McCabe. TF Unwin, London
Huxley JS (1958) Introduction to the Mentor edition of the Origin of Species by C Darwin, New American Library, New York, ix–xv
Barnett S (ed.) (1958) A Century of Darwin. Heinemann, London
Bowler PJ (1983) The Eclipse of Darwinism. Johns Hopkins Univ Press, Baltimore
Schwartz JF (1999) Sudden Origins: Fossils, Genes and the Emergence of Species. John Wiley and Sons, New York
Ruse M (1982) Darwinism defended: a guide to the evolution controversies. Addison-Wesley, Advanced Book Program/World Science Division, Reading, Mass, USA
Virchow R (1858) Cellular Pathology as Based Upon Physiological and Pathological Histology. 2nd edn. Translation by F Chance, reprinted 1971 by Dover Publications, New York
Virchow R (1871) Cellular Pathology as Based Upon Physiological and Pathological Histology. 4th edn. A Hirschwald, Berlin
Virchow R (1884) Ueber Metaplasie/On metaplasia. Virchow’s Archives 97: 410–430
Bignold LP (2005) Embryonic reversions and lineage infidelities in tumour cells: genome-based models and role of genetic instability. Int J Exp Pathol 86: 67–79
Cohnheim J (1882) Lectures in General Pathology. Translation by AB McKee 1889. New Sydenham Society, London
Ribbert H (1911) Das Karzinom des Menschen/Human Cancer. Friedrich Cohen, Bonn
Adami JG (1908) The Principles of Pathology, vol 1 General Pathology. Lea and Febiger, Philadelphia
Bashford RF, Murray JA, Cramer W (1905) The Growth of Cancer under Natural and Experimental Conditions. Sci Rpts Imperial Cancer Research Fund, No 2, Part II, Taylor and Francis, London
Ewing J (1940) Neoplastic diseases. 4th edn. Saunders, Philadelphia
Rather LJ (1962) Introduction; Harvey, Virchow, Bernard and the Methodology of Science. In: Disease, Life and Man. Translation and editing by LJ Rather, Collier, New York, 13–38
Ackerknecht EH (1953) Rudolph Virchow, Doctor Statesman Anthropologist. University of Wisconsin Press, Madison, USA, 98–105
Virchow R (1855) Cellular Pathology. Virchow’s Archives, 8:1. Translation by LJ Rather in Disease, Life and Man. Collier, New York, 1962, 86–115
Virchow R (1877) Standpoints in Scientific Medicine. Virchow’s Arch 70:1. Translation by L J Rather in Disease, Life and Man, Collier, New York, 1962, 156–164
Von Hansemann DP (1890) On the Asymmetrical Division of Cells in Epithelial Carcinomata and their Biological Importance. Virchow’s Arch 119:299–326
Klebs E (1889) Die allgemeine Pathologie/General Pathological. Vol 2. G Fisher, Jena
Von Hansemann D (1893) Studien über die Spezificität, den Altruismus und die Anaplasie der Zellen mit besonderer Berücksichtigung der Geschwülste/Studies of the specificity, altruism and anaplasia of cells with special reference to tumours. A Hirschwald, Berlin
Von Hansemann D (1897) Die Mikroscopische Diagnose der Bosartigen Geschwülste/The Microscopic Diagnosis of Malignant Tumours. (2nd edn, 1902). A Hirschwald, Berlin
Dunn LC (1965) A Short History of Genetics. McGraw-Hill, New York
Farley J (1982) Gametes and Spores, Ideas about Sexual Reproduction 1750–1914. Johns Hopkins University Press, Baltimore
Moore RC, Bender MA (1993) Time sequence of events leading to chromosomal aberration formation. Environ Mol Mutagen 22:208–213
O’Connor PJ, Manning FC, Gordon AT, Billett MA, Cooper DP, Elder RH, Margison GP (2000) DNA repair: kinetics and thresholds. Toxicol Pathol 28: 375–381
Klein G, Klein E (1984) Oncogene activation and tumor progression. Carcinogenesis 5: 429–435
Nowell PC (1986) Mechanisms of tumor progression. Cancer Res 46: 2203–2207
Whitman RC (1919) 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 4: 181–202
Beneke R (1900) A case of osteoid chrodrosarcoma of the urinary bladder, with comments on metaplasia. Virchow’s Arch 161: 70–114
Boveri T (1914) Zur Frage der Entstehung der Malignen Tumoren. G Fischer, Jena. Translation by M Boveri, and published as Origin of Malignant Tumors, 1929, Williams and Wilkins, Baltimore
Bauer KF (1928) Mutationstheorie der Geschwülst-Entstehung/Mutation Theory in Tumour formation. Julius Springer, Berlin
Schneider NR, Williams WR, Chaganti RS (1986) Genetic epidemiology of familial aggregation of cancer. Adv Cancer Res 47: 1–36
Warthin AS (1913) Heredity with reference to carcinoma. Arch Int Med 12: 546–555
Crowe FW, Schull JW, Neel JV (1956) A Clinical, Pathological and Genetic study of Multiple Neurofibromatosis. CC Thomas, Springfield, Illinois
Little CC (1928) Evidence that cancer is not a simple Mendelian recessive. J Cancer Res 12:30–46
Bashford EF, Murray JA (1904) The transmissibility of malignant new growths from one animal to another. Sci Rep Imperial Cancer Research Fund 1: 11–15
Tyzzer EE (1909) A series of spontaneous tumours in mice with observations on the influence of heredity on the frequency of their occurrence. J Med Res 21: 479–518
Woglom WH (1929) Immunity to transplantable tumours. Cancer Rev 4: 129–214
Loeb L (1937) The Biological Basis of Individuality. Charles C Thomas, Springfield, Illinois
Triolo VA (1964) Nineteenth century foundations of cancer research, origins of experimental research. Cancer Res 24: 4–27
Fidler IJ (1986) Rationale and methods for the use of nude mice to study the biology and therapy of human cancer metastasis. Cancer Metastasis Rev 5: 29–49
Kennaway EL, Hieger I (1930) Carcinogenic substances and their fluorescence spectra. Br Med J 1: 1044–1046
Badger GM (1954) Chemical constitution and carcinogenic activity. Adv Cancer Res 2: 73–127
Süss R, Kizel V, Scriber JD (1973) Cancer experiments and concepts. Springer-Verlag, New York
Lawley PD (1994) From fluorescence spectra to mutational spectra, a historical overview of DNA-reactive compounds. IARC Sci Publ 125: 3–22
Bignold LP (2004) Carcinogen-induced impairment of enzymes for replicative fidelity of DNA and the initiation of tumours. Carcinogenesis 25: 299–307
Murrell J (2004) Shedding light on light. Croat Chemica Acta 77: 17–30
Lea DE (1962) The Actions of Radiations on Living Cells. 2nd edn. Cambridge University Press, Cambridge, UK
Shope RE (1932) A filterable virus causing a tumor-like condition in rabbits and its relationship to myxomatosis. J Exp Med 56: 803–822
Gross L (1983) Oncogenic viruses. 3rd edn. Permagon Press, Oxford, UK
Inoue M (2001) Current molecular aspects of the carcinogenesis of the uterine endometrium. Int J Gynecol Cancer 11: 339–348
Argyris TS (1985) Regeneration and the mechanism of epidermal tumour promotion. Crit Rev Toxicol 14: 211–258
Foulds L (1969) Neoplastic development. (Vol 2, 1975), Academic Press, London
Berenblum I (1958) The study of tumours in experimental animals. In: HW Florey (ed.): General Pathology, 2nd edn. Lloyd-Luke, London, 513–549
Willis RA (1948) Pathology of Tumours, Butterworths, London
Haddow A (1972) Molecular repair, wound healing, and carcinogenesis: tumour production a possible overhealing? Adv Cancer Res 6: 181–234
Apffel CA (1976) Nonimmunological host defenses: a review. Cancer Res 36: 1527–1537
Harris H (1990) The role of differentiation in the suppression of malignancy. J Cell Sci 97: 5–10
Bignold LP (2003) The mutator phenotype theory of carcinogenesis and the complex histopathology of tumours: support for the theory from the independent occurrence of nuclear abnormality, loss of specialisation and invasiveness among occasional neoplastic lesions. Cell Mol Life Sci 60: 883–891
Prasad KN, Hovland AR, Nahreini P, Cole WC, Hovland P, Kumar B, Prasad KC. (2001) Differentiation genes: are they primary targets for human carcinogenesis? Exp Biol Med (Maywood) 226: 805–813
Yuasa Y (2003) Control of gut differentiation and intestinal-type gastric carcinogenesis. Nat Rev Cancer 3: 592–600
Lefort K, Dotto GP (2004) Notch signaling in the integrated control of keratinocyte growth/differentiation and tumor suppression. Semin Cancer Biol 14: 374–386
Verrecchia F, Mauviel A (2002) Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. J Invest Dermatol 118: 211–215
Micke P, Ostman A (2004) Tumour-stroma interaction: cancer-associated fibroblasts as novel targets in anti-cancer therapy? Lung Cancer, 45Suppl 2: S163–175
Parmar H, Cunha GR (2004) Epithelial-stromal interactions in the mouse and human mammary gland in vivo. Endocr Relat Cancer 11: 437–458
Zhang Z, Yuan XM, Li LH, Xie FP (2001) Transdifferentiation in neoplastic development and its pathological implication. Histol Histopathol 16: 1249–1262
Ber I, Shternhall K, Perl S, Ohanuna Z, Goldberg I, Barshack I, Benvenisti-Zarum L, Meivar-Levy I, Ferber S (2003) Functional, persistent, and extended liver to pancreas transdifferentiation. J Biol Chem 278: 31950–31957
Guarino M, Micheli P, Pallotti F, Giordano F (1999) Pathological relevance of epithelial and mesenchymal phenotype plasticity. Pathol Res Pract 195: 379–389
Hay ED (1995) An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 154: 8–20
Birchmeier W, Birchmeier C (1995) Epithelial-mesenchymal transitions in development and tumour progression. EXS 74: 1–15
Kerr JF (2002) History of the events leading to the formulation of the apoptosis concept. Toxicology 181–182: 471–474
De Vries H (1902) Mutation Theory. Translation by JB Farmer, AD Darbishire. 1910, Kegan Paul, Trench, Trübner & Co, London
Bateson W (1913) Problems of Genetics. Yale University Press, New Haven, CT, USA
Tyzzer EE (1916) Tumour immunology. J Cancer Res 1: 125–155
Morgan TH, Sturtevant AH, Muller HJ, Bridges CB (1915) The Mechanism of Mendelian Heredity. Constable, London
Lawley PD (1994) Historical origins of current concepts of carcinogenesis. Adv Cancer Res 65: 17–111
Berenblum I, Shubik P (1949) An experimental study of the initiating stage of carcinogenesis, and a re-examination of the somatic cell mutation theory of cancer. Br J Cancer 3: 109–118
Berenblum I (1967) Cancer Research Today. Pergamon Press, New York
Burdette WJ (1955) The significance of mutation in relation to the origin of tumours: a review. Cancer Res 15: 201–226
Earle WR (ed.) (1943) Production of malignancy in vitro. J Natl Cancer Instit 4: 131–248
Sanford KK (1965) Malignant transformation of cells in vitro. Int Rev Cytol 18: 249–311
Hayflick L (1967) Oncogenesis in vitro. Nat Cancer Inst Monograph 26: 355–385
Huebner RJ, Todaro GJ (1969) Oncogenes of RNA tumour viruses as determinants of cancer. Proc Natl Acad Sci USA 64: 1087–1094
Sporn MB, Roberts AB (1985) Autocrine growth factors and cancer. Nature 313: 745–747
Rozengurt E (1995) Polypeptide and neuropeptide growth factors: signalling pathways and role in cancer. In: M Peckham, H Pinedo, U Veronesi (eds): Oxford Textbook of Oncology, Oxford University Press, Oxford, 12–20
Moschos SJ, Mantzoros CS (2002) The role of the IGF system in cancer: from basic to clinical studies and clinical applications. Oncology 63: 317–332
Bignold LP (2004) Chaotic genomes make chaotic cells: the mutator phenotype theory of carcinogenesis applied to clinicopathological relationships of solid tumors. Cancer Invest 22: 338–343
Iversen OH (1995) Of mice and men: a critical reappraisal of the two-stage theory of carcinogenesis. Crit Rev Oncog 6: 3357–3405
McGee J O’D, Isacson PG, Wright NA (eds) (1992) Oxford Textbook of Pathology. vol. 1. Oxford University Press, Oxford 636
Rubin E, Farber JL (eds) (1992) Pathology. 2nd edition. Lippincott, Philadelphia, 144
Walter JB, Talbot IC (eds) (1996) General Pathology. Churchill Livingstone, Edinburgh, 530
Lockhart-Mummery JP (1934) The Origin of Tumours. J and A Churchill, London
Nichols EM (1969) Somatic variation and multiple neurofibromatosis. Hum Hered 19: 473–479
Comings DE (1973) A general theory of carcinogenesis. Proc Natl Acad Sci USA 70: 3324–3328
Knudson AG (2000) Chasing the cancer demon. Annu Rev Genet 34: 1–19
Knudson AG (2001) Two hits (more or less) to cancer. Nature Rev Genet 2: 157–162
Bignold LP (2004) The cell-type-specificity of inherited predispositions to tumours: review and hypothesis. Cancer Letters 216: 127–146
Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumourigenesis. Cell 61: 759–767
Vogelstein B Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9: 138–141
Bodmer W (1997) The somatic evolution of cancer. J Roy Coll Physicians Lond 31: 82–89
Fearnhead NS, Wilding JL, Bodmer WF (2002) Genetics of colorectal cancer: hereditary aspects and overview of colorectal tumourigenesis. Br Med Bull 64: 27–43
Miller EC, Miller JA (1981) Mechanisms of chemical carcinogenesis. Cancer 47(5 Suppl): 1055–1064
Slaga TJ, O’Connell J, Rotstein J, Patskan G, Morris R, Aldaz CM, Conti CJ (1986) Critical genetic determinants and molecular events in multistage skin carcinogenesis. Symp Fundam Cancer Res 39: 31–44
Pitot HC (1993) The molecular biology of carcinogenesis. Cancer 72(3 Suppl): 962–970
Steen HB (2000) The origin of oncogenic mutations: where is the primary damage? Carcinogenesis 21: 1773–1776
Chu EH, Trosko JE, Chang CC (1977) Mutational approaches to the study of carcinogenesis. J Toxicol Environ Health 2: 1317–1334
Fisher RA (1930) The Genetical Theory of Natural Selection. Clarendon Press, Oxford, UK
Nordling CE (1953) A new theory of the cancer-inducing mechanism. Br J Cancer 7: 68–72
Ashley DJB (1969) The two “hit” and multiple “hit” theories of carcinogenesis. Br J Cancer 23:313–328
Armitage P (1985) Multistage models of carcinogenesis. Environ Health Perspect 63: 195–201
Day NE (1990) The Armitage-Doll multistage model of carcinogenesis. Stat Med 9: 677–679
Slaga TJ, Budunova IV, Gimenez-Conti IB, Aldaz CM (1996) The mouse skin carcinogenesis model. J Investig Dermatol Symp Proc 1: 151–156
Rowinsky EK, Donehower RC (2001) Antimicrotubule agents. In: BA Chabner, Longo DL (eds): Cancer Chemotherapy and Biotherapy: Principles and Practice. 3rd edn. Lippincott, Williams and Wilkins, Philadelphia, 329–372
Bignold LP (2003) Initiation of genetic instability and tumour formation: a review and hypothesis of a nongenotoxic mechanism. Cell Mol Life Sci 60: 1107–1117
Cleaver JE (1968) Defective repair replication of DNA in xeroderma pigmentosum. Nature 218: 652–656
Marsh DJ, Zori RT (2002) Genetic insights into familial cancers — update and recent discoveries. Cancer Letters 181: 125–164
Mullis KB, Faloona FA (1987) Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Methods Enzymol 155: 335–350
Stoler DL, Chen N, Basik M, Kahlenberg MS, Rodriguez-Bigas MA, Petrelli NJ, Anderson GR (1999) The onset and extent of genomic instability in sporadic colorectal tumour progression. Proc Natl Acad Sci USA 96: 15121–15126
Loeb LA, Springgate CF, Battula N (1974) Errors in DNA replication as a basis of malignant changes. Cancer Res 34: 2311–2321
Loeb LA (1996) Many mutations in cancers. Cancer Surv 28: 329–342
Loeb KR, Loeb LA (2000) Significance of multiple mutations in cancer. Carcinogenesis 21: 379–385
Loeb LA (2001) A mutator phenotype in cancer. Cancer Res 61: 230–239
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Bignold, L.P., Coghlan, B.L.D., Jersmann, H.P.A. (2006). Cancer morphology, carcinogenesis and genetic instability: a background. In: Cancer: Cell Structures, Carcinogens and Genomic Instability. Experientia Supplementum, vol 96. Birkhäuser Basel. https://doi.org/10.1007/3-7643-7378-4_1
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