CANCER BIOLOGY: VIRAL AND EPIGENETIC*
Authors: HUXLEY JULIAN 
Published: January 2008

I. Viruses, in the sense of filterable, replicable and transmissible (infective) particles in the cytoplasm, containing nucleoprotein, cause a number of tumours, such as Rous sarcoma in fowls, avian leukosis, some mammary cancers and some leukaemias in mice, Shope papilloma in rabbits, and Lucké adenocarcinoma in frogs.

2 Virus tumours cannot be understood without considering the nature and properties of viruses in general. These include insect viruses, vertebrate viruses, plant viruses, bacterial viruses (bacteriophages), rickettsias and non‐pathogenic viruses (carbon dioxide sensitivity agent in Drosophila).

3 The replicating properties of viruses depend on nucleic acids. Plant viruses are based on ribonucleic acid (RNA), perhaps because they multiply only in non‐ dividing cells. Most others are based solely or mainly on desoxyribonucleic acid (DNA), though the main nucleic acid component of influenza virus is RNA. Insect viruses always cause crystal formation in the host cells, and many are intranuclear, while others begin development in nuclei but multiply mainly in the cytoplasm. Rickettsias are intermediate between other viruses and bacteria and are probably true parasites. Other viruses form part of a compound metabolic system involvinghost components, one of whose properties is the synthesis of more virus. The composition’ of viruses, notably as regards proteins, may thus vary with the host's physiological state and genetic properties and with the stage of the virus cycle (e.g. plant viruses can be obtained outside the plant as pure crystalline nucleoprotein, their infective properties then depending solely on their RNA; influenza virus in one phase incorporates host proteins).

4. Viruses are one type of the larger category of nucleoprotein‐containing replicating units other than nuclear genes, e.g. plasmagenes, plant plastids and Kappa particles in Paramecium. Lederberg calls all these plasmids: I suggest the term paragene. All appear capable of mutation.

5. Some viruses are transmitted through the egg (carbon dioxide sensitivity in Drosophilu, some mouse leukaemias), others through the mother's milk and (to a lesser extent) the father's sperm (Bittner milk agent in mice).

6. Many viruses in certain conditions become masked or latent, no longer producing host symptoms. Some plant viruses remain wholly masked in certain host strains (e.g. paracrinkle in King Edward potatoes). In phages latency is achieved through the virus (prophage) becoming attached to a specific locus in the bacterial gene complex. Some tumour viruses (e.g. Shope papilloma) become masked (non‐extractable and non‐infective) in rapidly proliferating and highly malignant host tissues, presumably owing to closer association with host components; others (e.g. Rous sarcoma) become masked in tumours grafted into old hosts. Some viruses (e.g. adenoidal‐pharyngeal‐conjunctivitis) become unmasked by repeated passage on solid media. Viruses may produce quite different symptoms in old and very young hosts.

7. Active phages and probably other viruses do not replicate by duplication, but by breaking down into numerous sub‐units, all capable of replication (and of deviating host proteins to their own use). Recombination occurs between sub‐ units of different strains. The replication of latent phages (prophages) is synchronized with that of the host genome. This behaviour of prophages has points of resemblance to the genetic ‘transformation’ of bacteria by means of pure DNA, units of which apparently replace normal recessive alleles in the ‘host's' gene complex; and also to the ‘infective inheritance’ (sometimes at least mediated by a heavily masked virus‐like agent) found in, for example, Pneumococcus and Salmonella.

8. In Paramecium the inheritance of ‘Killer’ properties through Kappa particles capable of replication and mutation (but under partial nuclear genetic control), and the cytoplasmic modulation of antigenic properties within a gene‐determined range of antigenic spectrum, are discussed in their relevance to problems of tumorigenesis. One important point is that almost all host gent mutations permit an increase in Kappa number (and lethal properties), presumably by weakening the host's control over Kappa multiplication. Another is that increase of the number of host K alleles by polyploidy (K is a dominant allele which is necessary for infection by Kappa) also increases the number and the lethality of the Kappa particles in the cell.

9. With most tumour viruses: (a) infection is much easier in embryos or very young animals, notably of other species, and then often causes haemorrhagic or other non‐neoplastic disease instead of tumours, (b) adaptation of the virus to a different host species, subspecies or strain usually alters it in various ways, notably its specific infectivity, and the site and type of tumour which it induces. It is possible that inoculation of tumour cells or filtrates into newborn or embryonic hosts will reveal the presence of (masked) viruses in many tumours now considered non‐ viral.

10. There are various theories concerning the origin of viruses. (a) Altenburg's theory. This regards viruses as derived from ‘viroids’, supposed to be present in all organisms, and to be representatives of the precellular (‘naked gene’) stage of evolution, which have survived through adopting a symbiotic habit. (b) The autogenous theory, of which Darlington is the protagonist. This regards viruses as originating from normal cytoplasmic nucleoproteins which have become abnormal, autonomous, and eventually infective. (c) The parasite theory. This regards viruses as having originally been independent organisms which have become ‘metabolic parasites' of a peculiarly intimate kind, utilizing or incorporating some of the host's metabolic processes or products. Some supporters of this theory consider that viruses were always of precellular type, others that they are degraded bacteria.

Theory (c) appears to be true for rickettsias; (a) is highly speculative, but might account for some cases of progressive ‘unmasking’ of viral properties; (b) has not yet been proved for any specific case, but seems probably true of a number of viruses. The liberation of antigenic substances consisting of DNA nucleoproteins by healthy grafts and presumably by normal tissues, discovered by Medawar and his associates, and the probable liberation of specific growth antitemplates' by different tissues, indicated by Weiss, suggest ways in which an autogenous evolution of viruses could have occurred. In any case, investigation of tumour viruses and other paragenes is revealing many facts concerning non‐nuclear and somatic replication, and illuminating the relations between genetics, development (epigenetics) and transmissibility (infection).

11. Epigenetics (Waddington's term for the analytical study of individual development) can shed light on the process of tumorigenesis, and vice versa.

12. Metaplasia is a purely descriptive term, denoting various switches of differentiation (tissue transformation), including the irreversible transformation of undifferentiated cells of epidermis into mucous epithelium or of mesenchyme into bone or cartilage in mesenchymal tumours, and the redifferentiation of tissues in regeneration after dedifferentiation to pluripotency as well as the reversible transformations of cell form in tissue cultures. The alleged transformation of carcinomas to sarcomas is probably only apparent, and due to the acquisition of higher proliferation rate and consequent greater visible dedifferentiation. Tumour tissue may exert an effect on the growth rate of other tissues, both tumorous (as in mixed and composite tumours) and normal.

13. Dedifferentiation is a loose term comprising (a) reversal of determination (dedetermination, pluripotent dedifferentiation) as in regeneration blastemas; (b) loss of histological and functional differentiation, but without loss of primary differentiation, as in rapidly replicating tissues and those with high glycolytic metabolism (hypoplastic dedifferentiation); (c) anabiotic dedifferentiation, involving the reduction of general vital activities and entry into a resistant resting state, as in protozoan cysts and some tumour cells subjected to deep freezing, especially when combined with dehydration and anaerobiosis. If such anabiotic dedifferentiation could be induced by anaerobiosis alone, it might account for the recurrence of operated cancers after long periods.

14. Tumorigenesis is not an abnormal type of differentiation, since (1) it may be reversible in early stages, (2) tumours retain their original determination, though in hypoplastic form, but depends on a metabolic deviation leading to breakdown of the normal mechanism controlling growth, and so to autonomy. It does not depend on escape from a local individuation field.

15. Tumorigenic metabolic deviation also differs from processes of normal differentiation in depending on a series of irreversible steps, and in the series not always being similar in different cell strains, even of the same tissue. Each step is mutation‐like in being a chance event and not the regular result of a statistical process, though differing in that multiple foci may be involved.

16. Berenblum distinguishes two main early steps in chemical carcinogenesis, a sudden initiation and a long latent period of promotion: the latter can be induced by cocarcinogens which are incapable of inducing initiation. Nordling claims that at least six distinct steps are needed for a tissue to reach malignancy. Warburg also considers that a number of steps occur, but involving two main processes (i) irreversible damage to the respiratory mechanism, followed by (ii) a compensatory increase in glycolytic metabolism, both aerobic and anaerobic.

17. Malignancy is associated with a change in the surface properties of tumour cells, including electrical properties and lower calcium content, and leading to absence of adhesiveness.

18. Environmental carcinogenic agencies are of very various nature, including several types of radiation, many specific chemical compounds, certain types of prolonged irritation and certain parasites. Genetic carcinogenesis also occurs, due either to gross genetic imbalance in wide crosses or to single genes or systems of genes.

19. Some experimental carcinogens are also mutagenic; many inhibit growth, which might account for the long latent period in promotion. The action of some chemical carcinogens may be due to their combination with the nucleoprotein fibres of chromosomes. It has also been suggested that carcinogens may exert their effect by enzyme deletion, by the progressive elimination of key proteins, or by damage to the cells' oxidative respiratory mechanism.

20. Endocrine‐dependent tumours are caused by excess or defect of some normal endocrine activity, which may induce tumours in an endocrine‐dependent tissue (e.g. mammary gland), or may upset an endocrine feed‐back mechanism with resultant tumours in the same or another endocrine tissue.

21. In most tumorigenic processes there appear to be three main phases: (i) irreversible initiation and subsequent promotion (latent period); (ii) the conditioned phase–manifestation of a tumour but without irreversible autonomy; (iii) the fully autonomous phase. Before (i) we may prevent cancer but cannot (as yet) apply any treatment: after the onset of (iii) we cannot prevent but may treat it.

22. The chief methods of treatment, apart from operation, are (i) irradiation, (ii) serological (immunological), (iii) chemotherapeutic. The discovery of the distinctive surface properties of malignant cells may lead to more effective serological treatment. Chemotherapy may operate (a) by differential toxicity, (b) by interfering with DNA or RNA synthesis by supplying analogues of nucleic acid components, and (c) by cytostatic agents.

23. Tumour regression (resorption) can best be understood as an effect of alteration in a metabolic (physiological) balance system. Studies of the regression and resorption of denervated, reversed, ultraviolet‐irradiated and xenoplastic urodele limbs, and of the various tissues during insectan and amphibian metamorphosis, should shed light on tumour regression. All larval tumours in Drosophila, and tumour grafts at some sites in amphibian larvae, regress at metamorphosis: Helff has caused regression of some tumours by extracts of metamorphosing amphibian tissues undergoing autolysis. Thyroxin appears to reduce the risk of recurrence of operated breast‐cancer, presumably owing to a change in the body's metabolic balance.

24. The study of occupational, dietary, habitudinal, and other environmental cancers can point the way to measures of cancer prevention.

25. Cancer is a biological problem. The future organization of cancer research should include comparative studies, cytogenetics, epigenetics, allometric growth studies, and human ecology and demography, in addition to intensive biochemical analysis and the usual established disciplines of oncology.