Evidence from sero-epidemiological studies and from cell culture studies supports the hypothesis that the cells of many, and perhaps all, vertebrates contain information for producing C-type RNA viruses. It is postulated that the viral information (the virogene), including that portion responsible for transforming a normal cell into a tumor cell (the oncogene), is most commonly transmitted from animal to progeny animal and from cell to progeny cell in a covert form. Carcinogens, irradiation, and the normal aging process all favor the partial or complete activation of these genes. An understanding of how normal cells and normal animals prevent expression of endogenous viral information would appear to offer one of the best hopes for the control of naturally occurring cancers.

https://www.pnas.org/content/pnas/64/3/1087.full.pdf

Oncogenes of rna tumor viruses as determinants of cancer

A new acute transforming feline retrovirus, the Hardy-Zuckerman 4 feline sarcoma virus (HZ4-FeSV), has been isolated from a feline fibrosarcoma The viral genome of HZ4-FeSV contains a new oncogene designated v-kit, has the structure 5' delta gag-kit-delta pol-delta env 3' and specifies a gag-kit polyprotein of relative molecular mass 80,000 The predicted kit amino-acid sequence displays partial homology with tyrosine-specific protein kinase oncogenes HZ4-FeSV appears to have been generated by transduction of feline c-kit sequences with feline leukaemia virus

A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family

Publisher Summary The question that whether the unit of malignancy is a gene, or an organism that grows in highly specialized protoplasmic environments, or a molecule that multiplies by virtue of integral chemical union with a molecule of protoplasm, remains unanswered. The question of whether leukemia in the mouse is caused by either genetic or viral mechanisms has taken on a new meaning with the recognition of host genetic constitution with the viral infection in leukemogenesis. The chapter covers the early studies of murine leukemia and the genetic control of friend virus susceptibility and naturally occurring leukemia viruses. It also discusses the h2 linked genetic control of leukemogenesis and the other genes responsible for leukemogenesis. Infection with ontogenic viruses is complex and malignancy is not an inevitable result of tumor virus infection; many specific events affect the interaction of leukemia virus with cells, leading to leukemogenesis.

Genetic Control Of Murine Viral Leukemogenesis

Publisher Summary The discovery of RNA-directed DNA synthesis in disrupted virions of RNA tumor viruses added strong support to the hypothesis that information transfer from RNA to DNA exists in biological system. The chapter discusses the properties of the endogenous reaction carried out by the virion DNA polymerase. To study the endogenous reaction disrupted, virions are incubated with substrates in the absence of any added template and synthesis of DNA is observed using the RNA present in the virions as template. The chapter also discusses the general implications of RNA-directed DNA synthesis in relation to tumor viruses, neoplastic cells, and normal cells. It is hypothesized that the leukovirus RNA-directed DNA polymerase activity is an integral part of the ribonucleoprotein core of the virions. The cores are synthesized in cells as precursor particles and then are incorporated into complete virions when the virions are assembled by budding at the cell surface. This core enzyme system contains not only the template-primer RNA, a DNA polymerase that can transfer information from RNA to double-stranded DNA, but ancillary enzymes, such as polynucleotide ligase and nucleases, which may aid in integrating the viral information with cellular DNA. This suggests that the virion enzyme activity is related to normal cellular DNA polymerases, and that there are homologies between the amino acid sequences of the viral enzyme and normal cellular enzymes. The relationship of RNA-directed DNA synthesis to neoplasia depends upon the relationship of RNA tumor viruses to neoplasia, which is supported by three general hypotheses: the provirus model, the oncogene model, and the protovirus model.

RNA-Directed DNA Synthesis and RNA Tumor Viruses

The major focus of cancer immunology has shifted away from arguments about the validity of the immunosurveillance theory of cancer to the more basic question of tumor-specific antigens. Despite vast effort aimed at demonstrating such antigens, their existence in the generality of cancer remains unproven. Serological analysis of three tumor types, mouse leukemia, mouse sarcoma, and human malignant melanoma, has received most attention, and a rudimentary classification of the surface antigens expressed by these tumors has begun to emerge. The prime candidates for antigens that can be considered tumor specific are the few instances of Class 1 antigens that have now been serologically defined on mouse and human tumors. These antigens show an absolute restriction to individual tumors, not being demonstrable on any other normal or malignant cell type. Biochemical and genetic characterization of Class 1 antigens represents an essential next step in evaluating the significance of these antigens. The surprising features of the Thymus Leukemia (TL) antigens of the mouse provide insight into the genetic origin of another key class of tumor antigens, in this case antigens with characteristic properties of both differentiation antigens and tumor-specific antigens. In normal mice, TL antigens are restricted to cells in the thymus, and strains differ with regard to expression versus nonexpression of TL antigens. Genetic information for TL is universal in the mouse, however, as leukemias developing in mice that normally lack TL are found to express TL. What is clear from the past two decades of research in cancer immunology is that a far more detailed knowledge of surface antigens of tumor cells will be necessary before we can begin to assess the possibility of immunological control of cancer.

https://cancerres.aacrjournals.org/content/canres/41/2/361.full.pdf

Cancer immunology: the search for specificity--G. H. A. Clowes Memorial lecture.

Subgroup classification of feline leukemia and sarcoma viruses by viral interference and neutralization tests.

An avian leucosis group-specific complement fixation reaction. application for the detection and assay of non-cytopathogenic leucosis viruses.

Tests for the group-specific antigen of the C-type RNA tumor virus showed that mouse embryos of all strains tested, at some stage of development in utero, revealed detectable titers of group-specific antigen in one or more of their tissues; younger, rather than older, embryos were likely to be positive, particularly in those strains which normally reveal little or no expression of the RNA genome postnatally. The antigens were found in embryos of low-leukemia strains, free of infectious virus. These new findings support a previously stated hypothesis that the genome of RNA tumor viruses, mostly switched off for infectious virus expression, is vertically transmitted as part of the natural genetic apparatus of normal mouse cells. Since group-specific antigens have also been described in chick embryos and immunological tolerance to homologous group-specific antigens has been demonstrated in hamsters and cats as well as in mice and chickens, the hypothesis has been extended to include vertebrate cells in general. Finally, the high incidence and titers of the group-specific antigen suggest that the genes for RNA tumor virus, which later in life act as determinants of cancer, may be important also as gene determinants in the developing embryo.

Group-Specific Antigen Expression During Embryogenesis of the Genome of the C-Type RNA Tumor Virus: Implications for Ontogenesis and Oncogenesis

* This investigation was aided by grants from the American Cancer Society and the Jane Coffin Childs Fund for Medical Research. 1 The following abbreviations are used: DMBA, dimethylbenz(a)anthracene; BA, benz(a) anthracene; 3'-Me-DAB, 3'-methyl-4-dimethylaminoazobenzene. 2 Huggins, C., L. C. Grand, and F. P. Brillantes, Nature, 189, 204 (1961). 3Huggins, C., S. Morii, and L. C. Grand, Ann. Surg., 154, Suppl. no. 6, 315 (1961). 4Huggins, C., and S. Morii, J. Exptl. Med., 114, 741 (1961). 6 Currie, A. R., J. E. Helfenstein, and S. Young, Lancet, II, 1199 (1962). 6 Dao, T. L., and Y. Tanaka, Proc. Soc. Exptl. Biol. Med., 113, 78 (1963). 7Dao, T. L., and Y. Tanaka, Cancer Res., 23, 1148 (1963). 8 Huggins, C., T. F. Deuel, and R. Fukunishi, Biochem. Z., 338, 106 (1963). 9 Huggins, C., and R. Fukunishi, J. Exptl. Med., in press. 10 We are indebted to Paul Schurr, the Upjohn Company, Kalamazoo, Michigan, for preparing a lipide emulsion of 7,12-DMBA. Prof. M. S. Newman, Ohio State University, Columbus, Ohio, generously provided 3,9-DMBA and 6,8-DMBA.

http://www.pnas.org/content/51/5/742.full.pdf

Padman S. Sarma

Papers

Subgroup classification of feline leukemia and sarcoma viruses by viral interference and neutralization tests.

An avian leucosis group-specific complement fixation reaction. application for the detection and assay of non-cytopathogenic leucosis viruses.

Group-Specific Antigen Expression During Embryogenesis of the Genome of the C-Type RNA Tumor Virus: Implications for Ontogenesis and Oncogenesis

Specific complement-fixing viral antigens in hamster and guinea pig tumors induced by the schmidt-ruppin strain of avian sarcoma.

Viral interference in feline leukemia-sarcoma complex.