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[CANCER RESEARCH 26 Part 1, 2018-2024,September 1966] Virus Tumor Antigens: Specific Fingerprints? KARL HABEL Laboratory of Biology of Viruses, Xational Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland Summary Immunologically new antigens of at least 2 general types have been demonstrated in cells transformed, both in vivo and in vitro, by viruses. In fact, this now appears to be true in all virusinduced tumors. The specificity of these antigens is determined by the inducing virus and is the same in tumors of a variety of histologie types and in different species. These antigens are foreign to the immunologically competent host and are reacted to by either homograft rejection or antibody formation, or both. Certain of these antigens are also produced early in the course of a lytic infection by the tumor viruses and may well represent virus-coded specific enzymes required for replication of certain viral constituents, such as their nucleic acids. There are a number of experimental facts consistent with the interpretation that the existence of these antigens reflects the continuing presence of viral genetic material in the transformed cell even when infec tious virus cannot be demonstrated. Introduction Although it has been known for over 50 years that certain viruses can induce the formation of tumors, it is only in the last few years that evidence has shown this induction to be the direct effect of virus infection of the single cell it transforms. This new knowledge has naturally led to the secondary question of what happens to the virus after transformation of the cell. In the case of UNA tumor viruses, it has become apparent that, in most cases, virus replication and release continue along with survival and multiplication of the transformed cell. However, in many cases the cell transformed by a DNA tumor virus is free of demonstrable infectious virus. This has led to the very fundamental question whether persistence of the DNA virus or viral materials occurs at all or is essential to the continuation of the transformed state or whether the virus has had a sort of "hit and run" relationship to the cell it transformed. There is currently being accumulated more and more evidence that viral material, specifically viral genome, does indeed persist in these situations. Thus, induction of infectious virus replication (4), extraction of infectious viral nucleic acid (17), and indirect demonstration of the presence of viral genome in association with cell genome (2) have established this as a fact in some systems. One additional piece of evidence supporting the thesis that viral genome persists has been the demonstration of specific antigens in cells transformed by viruses. That these antigens are the fingerprints of the viral genomes persisting in the tumor cells seems a logical conclusion at the present state of our knowledge. It is the purpose of this report to discuss the biologic nature of these antigens and their relationship to the virus and the cell, 2018 as well as their implications in oneogenesis. Major emphasis will be placed on the antigens associated with cells transformed by DNA tumor virus, and detailed results will be presented only for recent studies with the CF1 antigen in the polyoma-infected or transformed cell. Biologic Properties of Antigens How many different new specific antigens may be present in virus-transformed cells is not known. In the case of the DNA virus-induced tumors, at the present time there appear to be at least 2 types of new antigens based on the methods used to demonstrate them—the Homotransplantation and the serologie types. The homotransplantation antigen can be demonstrated only in the intact animal by showing resistance to tumor chal lenge (7, 30), whereas the serologie antigen can be measured in vitro through the use of antibodies produced by tumor-bearing or tumor-immunized animals. Cytotoxicity (3, 22, 31), comple ment-fixation (16), and immunofluorescence (18, 24) are some of the technics used to demonstrate the serologie type antigens. In Table 1 are summarized some of the important biologic properties of the 2 types of antigens in DNA tumor virus sys tems. 13oth types are found in tumors of various organs (29), and in tissue culture cells transformed by the viruses (9, 12). One of the intriguing aspects of these tumor antigens is the fact that the serologie type antigen is also made during the course of lytic infection (5, 26, 27). More detailed experimental results on this will be presented later. Thus far, there is no evidence available concerning the presence or absence of the homotrans plantation type antigen during lytic infection. Perhaps the most significant property of these new antigens is their specificity. The specific determinant is the virus that originally caused the tumor (12, 16) or cell transformation, and this specificity is not influenced by the histologie type of the tumor, the strain of animal, or even the species of animal whose cells are involved. Both types of antigens can be demonstrated to cross-react in cells transformed by 1 virus in such widely disparate species as hamster and man (6, 13). However, CF antigens present in hamster tumors induced by certain types of adenoviruses cross-react (16), as do the CF antigens produced in several different RNA virus avian (1) and mouse leukoses (14) and those involved in some cytotoxic tests of mouse leu kemia cells (23). 1The abbreviations used are: CF, complement-fixing or comple ment fixation; FUDR, 5-fluorodeoxyuridine; METC, mouse embryo tissue culture; HETC, hamster embryo tissue culture; PFU, plaque-forming units. CANCER RESEARCH VOL. 26 Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1966 American Association for Cancer Research. Virus Tumor Antigens TABLE 1 PROPERTIESOF 2 TYPES OF ANTIGENSPRODUCED BY I)\A TUMORVIRUSES HOMOTRANS PLANTATION ANTIGEN CF°ANTIGEN infectious virus appearing after about 24-48 hr (35). Cell lysis is usually not 100%, and a small fraction of the cells may be morphologically transformed. This transformation is demon strated by the ability of single cells to form clones showing a lack of contact inhibition (28). On prolonged cultivation of such infected mass cultures a "carrier culture" is frequently estab lished in which virus replication continues along with cell divi sion and culture growth (9). As has been found with lytic infec tion of monkey kidney cells with SV-40 virus (27) and of KB cells with adeno 12 virus (5), we have shown that during the Surface Nucleus lytic infection cycle of polyoma there appears a new antigen (T-antigen), \vhich reacts with antibodies against the serologie antigen of polyoma tumors. These lytic antigens have been demonstrated both by the fluorescent antibody staining technic and by CF. It has been typical of these new antigens in the 3 systems that they appear early in the lytic cycle, even before the appearance of new infectious virus or viral coat antigens. In fact, they tend " CF, complement-fixation. to decrease in amount or disappear in the later stages of the lytic infection when new virus is reaching its peak level. Chart 1 Evidence concerning the intracellular location of the tumor shows our results in the polyoma-mouse embryo culture system. In order to obtain some information concerning the relation antigens is limited. However, the CF antigen in SV-40 and ship between these early lytic antigens and the various stages polyoma cells appears to be in the nucleus, as demonstrated of the virus replicative cycle, the effect of various metabolic by fluorescent antibody staining (Ref. 24, and data to be pub inhibitors on the appearance of the antigen has been studied. lished by K. K. Takemoto, R. A. Malmgren, and K. Habel) and the homotransplantation antigen in the cell wall (33). In In the SV-40-monkey kidney culture system, Rapp et al. (25) systems where the cytotoxic test is effective, the antigen is also have postulated a sequence for the time of effect of various located in the cell wall (31). In fact, in cells transformed by the inhibitors and have shown a lack of inhibition of T-antigen production with inhibitors of DNA synthesis. Gilead and GinsRNA tumor viruses, which, in general, appear to be myxovirusburg (5) have confirmed the lack of requirement of DNA syn like in maturing at the cell surface, it is not surprising that thesis for antigen formation in the adenovirus lytic infection, specific viral antigen, as well as tumor antigens, has been demon and we have shown the same in the case of polyoma (Chart 2). strated in the cell wall (36). In our studies with polyoma, both FUDR and cytosine arabinoThis introduces the question of the nature of these antigens side showed the same results—an inhibition of production of and their relationship to the virus itself. In the DNA tumor virus systems, all the evidence is that neither type of new antigen is infectious virus and viral antigen but no inhibition of the tumor CF antigen. We have also used ultraviolet irradiation-inactivated present in the structure of the virus particle (8, 11). Furthermore, polyoma virus to test whether intact DNA of the virus inoculum in the case of polyoma and SV-40 tumors, the homotransplanta is required for T-antigen production, and apparently it is, since tion antigen and the CF antigen appear to be separate and dis no antigen was produced in cells inoculated with the inactivated tinct entities in the same cell (11). Much more is known con cerning the CF antigen because of the ease of quantitative virus. testing compared with the homotransplantation type. In our hands, inhibitors of RNA and protein synthesis de The reactions of the tumor-bearing and the virus-infected creased the production of infectious virus, viral antigen, and animals to the 2 types of antigens differ in the polyoma system. T-antigen in the polyoma system. This was found with actinoWhereas the CF antigen calls forth a serum antibody, the trans mycin D, mitomycin, and puromycin (see Charts 3-5). In the plantation antigen produces a lymphocyte-mediated cellular case of puromycin, when increasing amounts of inhibitors were reaction such as is seen in graft rejection. Yet both reactions used there appeared to be a greater sensitivity to inhibitor on the occur as the result of tumor inoculation. However, on inoculation part of the synthetic apparatus for viral antigen than in that for of the animal with virus, the transplant rejection response is tumor antigen. Actinomycin and puromycin appeared to exert consistently present, but the appearance of antibodies against their inhibitory effect when added any time up to 12 hr after the CF antigen is variable and is frequently absent unless the infection in a system where the tumor antigen usually appeared animal develops a tumor of its own. Occasionally CF antibodies will appear and subsequently disappear, apparently, in response by 18 hr in infected control cultures. to antigen produced by lytic viral multiplication in the mouse. Two important difficulties have limited the inhibitor studies. First, it is difficult to infect 100% of the cells in the polyoma Formation of CF Tumor Antigen in Lytic Polyoma Infec system, even with high multiplicities of infection; and secondly, tion the growth cycle is relatively so long that the inhibitors may exert a toxic effect on the cells before they are harvested for When jjolyoma virus is used to infect secondary cultures of mouse embryos, a lytic cycle of virus replication occurs with new- antigen titrations. Present in tumor cells Present in in vitro transformed cells Present in lytic infection Location in cell Specificity Cross-reacting between species Animal reaction Cell mediated Serum antibody Produced by virus inoculation Produced by tumor inoculation Involved in viral oncogenesis SEPTEMBER 1966 Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1966 American Association for Cancer Research. 2019 Karl Hobel o =VIRAL ANTIGEN CF •= TUMOR ANTIGEN CF - 2 18 24 28 36 42 48 3+ CPE CHART 1. Secondary mouse embryo 4 cultures inoculated with polyoma virus (MOI = 100), adsorbed times, and incubated in medium. Titers are for 0.2 ml of a 10% cell extract. The abbreviations tion; PFU, plaque-forming units; MOI, multiplicity of infection; CPE, cytopathic effect. used are: 3 hr at 37°C,washed CF, complement 3 fixa TABLE 2 SECONDARYHAMSTER EMBRYOCULTURES INOCULATEDWITH POLYOMAVIRUS (MOI = 100)" Cultures were trypsinized and divided 2 to 1 at 60 days and 4 to 1 at 67, 74, and 80 days. CF results are reciprocals of dilution of a 10% cell extract giving 3+ end points. PFU are the number of infectious virus plaques formed by inoculating 0.2 ml of 10% cell extract onto mouse embryo cultures. AVS POSTINTECTION CFTumor Virus CFPFU X IO602<113i16<124216<1931629516<1881612.812814.917410.424<420.2604266722174<1<180<1<10.03 MOI, multiplicity of infection; CF, complement-fixation; PFU, plaque-forming unit. CF Tumor Antigen Production in Transforming Polyoma System When hamster embryo cultures are infected with polyoma virus, only limited virus replication takes place with no apparent cell destruction, and transformation occurs in up to 10% of the cells (28, 32). Preliminary experiments on the appearance of the T-antigen in hamster embryo cultures infected with polyoma virus give a somewhat different picture from that seen with mouse embryo cultures. The CF antigen appears early, although not as early as in the mouse embryo cultures, and persists in spite of only limited viral replication. In Table 2 are shown the results when secondary hamster embryo cultures were inoculated with approximately 10 PFU of polyoma virus per cell and the culture medium was changed twice weekly without subdivision of the cultures for 60 days. Both infectious virus and viral CF antigen persisted at low levels. The tumor antigen was first demonstrable at 3 days and con tinued at low levels. However, when these cultures were trypsi 2020 nized and divided 4 to 1 at weekly intervals, starting at 60 days, there was a progressive drop in both types of CF antigen and infectious virus. In Table 3 a comparison can be made between the events in the predominantly lytic virus cycle in mouse embryo cultures and the nonlytic response of hamster embryo cultures. In the lytic mouse embryo system viral multiplication was evidenced by early and sharp increases in viral CF antigen and infectious virus and by cytopathic effect on the cells, whereas the T-antigen production was at its height at 1 day and not demonstrable at 6 days. Antigen and infectious virus production in the nonlytic hamster culture was not found until the 2nd day, was quantita tively low, and tended to persist at about the same levels. After virus carrier cultures had teen established in both cell systems at 22 days, there was not any marked difference between the 2. It is of interest to compare the T-antigen levels in relation to the amount of new virus production in the early stages of infection in the 2 systems. For instance, at 2 days in the mouse cell cultures there were 40 X IO6 PFU/CF unit of T-antigen, but in the hamster system only 0.6 X IO6 PFU. CANCER RESEARCH VOL. 26 Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1966 American Association for Cancer Research. Virus Tumor Antigens These results are consistent with the higher efficiency of virus replication in the METC and of transformation in the HETC, with T-antigen production accompanying both types of cell response to infection. The previously demonstrated rapid appear ance and subsequent loss of T-antigen during lytic infection and its persistence at low levels in transforming infection can explain these comparative results with the eventual similar findings in CF 64 Pfu xio6 80 Controls | FUDR H evi m 32 ¡6 40 20 10 Pfu VIRUS CF 30 TUMOR CF HR POST-INFECTION CHART 2. Secondary mouse embryo tissue culture inoculated with polyoma virus (MOI = 20). Inhibitors present during 3 hr of virus adsorption and in medium after washing 3 times. FUDR was used at 10~5 M and CYT at 10~3 5 M. The abbreviations used are: CF, complement fixation; PFU, plaque-forming units; MOI, multiplicity of infection; FUDR, 5-fluorodeoxyuridine; and CYT, cytosine arabinoside. both systems on more prolonged culture. The findings are similar to those obtained by Hoggan et al. (15) on shorter term culture of adenovirus 12 in the lytic KB cell system versus the trans forming hamster embryo culture. Evidence that Viral Genome Antigens Reflect Message Originating in Direct evidence is yet to be produced to establish that the appearance of the 2 types of new antigen in cells transformed by the DNA tumor viruses is due to protein formation coded by the persisting viral genome. Yet a number of experimental facts strongly suggest that this may be true, (a) The antigens are virus specific, or where cross reactions occur with the serologie antigens, there are other biologic characteristics in common between the cross-reacting viruses. (6) The antigens occurring in transformed cells and tumors of different histologie types and even in different species appear to be immunologically the same. (c) In the polyoma virus marker rescue experiments reported by Ting (34), the genetic marker demonstrated in the virus progeny produced after superinfection of a "virus-free" polyoma-transformed cell was associated with homotransplantation antigen production, (d) Both types of antigen persist in tumors through many transplant passages and in cells transformed in vitro through multiple cell generations, both with RNA viruses where continuation of virus replication can be readily demonstrated and with DXA viruses where infectious virus disappears, (è) In the non-virus-producing Rous tumor cells induced in mam mals, which are analogous to tumors induced by DNA viruses, the CF antigen persists and infectious virus can again be demon strated when the tumors are transferred to chickens. (/) It has been shown that a single mouse embryo culture cell already morphologically transformed by 1 DNA tumor virus (polyoma) can be "supertransformed" by a 2nd DNA tumor virus (SV-40). The doubly transformed cells contain the specific C'F tumor antigens for both viruses (to be published by G. .1. Todaro, K. Habel, and H. Green). Likewise, a hamster SV-40 tumor cell has been "supertransformed" by infection with polyoma virus with the production of T-antigens for both (to be published bv K. K. Takemoto and K. Habel). TABLE 3 SECONDARY MOUSEANDHAMSTEREMBRYOCULTURESINOCULATED WITHPOLYOMA VIRUS (MOI = 10)" POSTINFECTION0<1<10.40112.4018107.60112.7026483202+885.1046423+821106128<111002+02242201+3223.10 CUI/TUREMouse embryoHamster CF°Tumor CFPFU IO6CPEViral X embryoTESTViral CFTumor CFPFU 10"CPEDAYS X • MOI, multiplicity pathic effect. SEPTEMBER 1966 of infection; CF, complement fixation; PFU, plaque-forming units; CPE, cyto- 2021 Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1966 American Association for Cancer Research. Karl Hobel Implications Oncogenirity of Virus-induced Tumor Antigens for That the new Homotransplantation type of antigen produced in polyoma virus-induced tumor cells and the animal's immuno logie reaction to it are important determinants of tumor produc tion is now well established (8,10). The hypothesized mechanism is as follows. When the virus transforms normal cells to tumor cells in vivo, these cells contain the new foreign antigen to which the immunologically competent normal adult animal reacts, rejecting the tumor cells in a homograft reaction and thus pre- fj.q OF ACTINOMYCIN D CF 150 8 1 OJ 0§ 75 5C 'Ao.o.i. VIRUS CF THYMIDINE-3H TUMOR CF 27 HR UPTAKE POST VALINE-I4C UPTAKE INFECTION CHART3. Secondary mouse embryo tissue culture inoculated with polyoma virus (MOI = 100).Actinomycin D present from 0 time Figures at tops of columns give ¿ig of inhibitor per ml. Uptake of labeled precursors is expressed as % of that in infected control culture. Cell extract TCA precipitated before and after DNase treatment and counted in scintillation counter. The abbreviations used are MOI, multiplicity of infection; CF, Complement fixation; and TCA, trichloracetic acid. 10 THYMIDINE-3H VALINE-I4C 27 HR POST - 50 - 25 UPTAKE INFECTION CHART4. Secondary mouse embryo tissue culture inoculated with polyoma virus (MOI = 100). Mitomycin C was present from 0 time until time of harvest at 27 hr. The concentration of inhibitor in ¿ig/mlis given above each column. The uptakes of labeled precur sors into DNA and protein were proportionately so similar that they are plotted together. The abbreviations used are: MOI, multi plicity of infection; CF, complement fixation; and PFU, plaque-forming units. 2022 CANCER RESEARCH VOL. 26 Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1966 American Association for Cancer Research. Virus Tumor Antigens CF 32 16 0 fj.q OF inhibition, cell division, intercellular exchange of materials and immunologie reactions, the significance of these antigens to oncogenesis may be found greater than is now apparent. PUROMYCIN l % 100 l Ãœ 1.0 0 10 80 60 W// 30 40 20 3.0 3.0. VIRUS TUMOR THYMIDINE-JH VALINE-14C CF CF UPTAKE UPTAKE 29 HR POST INFECTION CHART5. Secondary mouse embryo tissue culture inoculated with polyoma virus (MOI = 100). Puromycin was present from 0 time. Figures at the tops of columns show /ig of inhibitor per ml. The abbreviations used are: MOI, multiplicity of infection; and CF, complement fixation. venting gross tumor production and rendering the animal immune to later tumor challenge. When this same transformation takes place in an immunologically immature newborn or an adult made immunologically incompetent by early thymectomy (21) or whole-body X-irradiation (20), gross tumors do develop. There is good reason to believe that this immunologie mecha nism explains the extreme rarity of polyoma-induced tumors in mouse colonies heavily infected under natural conditions of exposure. However, Law (19) has shown that under these condi tions of natural exposure thymectomized mice do indeed develop spontaneous polyoma tumors. There is as yet no evidence that the CF antigen in DNA virustransformed cells is responsible for the tumor properties of the cell or influences tumor development in the animal. The results of experiments demonstrating its early appearance in lytic virus infection would suggest by analogy with other lytic virus systems that this antigen may represent an early enzyme required for some stage of virus replication. Its demonstrated persistence in the transformed cell in spite of no production of complete in fectious virus suggests that it may be required for the replication of that part of the viral genome which may be integrated into the cell genome. In the case of UNA virus-transformed cells where the viral antigens are present in the cell wall, and especially in leukemias where lysis of cells can be accomplished by cytotoxic antibodies against new cell wall antigens, it is certainly possible that the serologie antigens and antibodies to them may help control tumor development. Since both types of the new tumor antigens can occur in the cell surface of certain virus-induced tumors and since the cell membrane is obviously important in such phenomena as contact References Armstrong, D., Okuyan, M., and Huebner, R. J. Complementfixing Antigens in Tissue Cultures of Avian Leukosis Viruses. Science, 144: 1584, 1964. Axelrod, D., Habel, K., and Bolton, E. T. Polyoma Genetic Material in a Virus-free Polyoma Induced Tumor. Ibid., 146: 1466-09, 1964. Bases, II. Antigenic Differences between Normal and Polyoma Virus-transformed Cells. II. In vitro Evidence for a Virusinduced Antigen. Cancer Res., 24: 1216-21, 1964. Gerber, P. Virogenic Hamster Tumor Cells : Induction of Virus Synthesis. Science, 145: 833, 1964. Gilead, Z., and Ginsberg, H. S. Characterization of a Tumorlike Antigen in Type 12and Type 18Adenovirus Infected Cells. J. Bacterio!., 90: 120-25, 1965. Girardi, A. J. Prevention of SV 40 Virus Oncogenesis in Ham sters. I. Tumor Resistance Induced by Human Cells Trans formed by SV 40. Proc. Nati. Acad. Sci., U.S., 54: 445-51, 1965. Habel, K. Resistance of Polyoma Virus Immune Animals to Transplanted Polyoma Tumors. Proc. Soc. Expt!. Biol. Med., 106: 722-25, 1961. —.Immunologie-ai Determinants of Polyoma Virus Onco genesis. J. Exptl. Med., 115: 181-93, 1962. Polyoma Tumor Antigen in Cells Transformed in 9. vitro by Polyoma Virus. Virology, 18: 553-58, 1962. —.The Relationship between Polyoma Virus Multiplica 10. tion, Immunologioal Competence, and Resistance to Tumor Challenge in the Mouse. Ann. N. Y. Acad. Sci., 101: 173-79, 1962. 11. —- . Specific Complement-fixing Antigens in Polyoma Tumors and Transformed Cells. Virology, 25: 55-61, 1965. 12. Habel, K., and Eddy, B. E. Specificity of Resistance to Tumor Challenge of Polyoma and SV 40 Virus-immune Hamsters. Proc. Soc. Exptl. Biol. Med., 113:1-12, 1963. 13. Habel, K., Jensen, F., Pangan»,J. S., and Koprowski, H. Specific Complement-fixing Tumor Antigen in SV 40 Trans formed Human Cells. Ibid., 118: 4-9, 1965. 14. Hartley, J. W., Rowe, W. P., Capps, W. I., and Huebner, R. J. Complement-fixation and Tissue Culture Assays for Mouse Leukemia Viruses. Proc. Nat!. Acad. Sci., U.S., 53: 931-38, 1965. 15. Hoggan, M. D., Rowe, W. P., Black, P. H., and Huebner, R. J. Production of "Tumor-specific" Antigens by Oncogenic Viruses during Acute Cytolytic Infections. Ibid., S3: 12-19, 1965. 16. Huebner, R. J., Rowe, W. P., Turner, H. C., and Lane, W. T. Specific Adenovirus Complement-fixing Antigens in Virusfree Hamster and Rat Tumors. Ibid., 50: 379-89, 1963. 17. Ito, Y. A Tumor-producing Factor Extracted by Phenol from Papillomatous Tissue (Shope) of Cottontail Rabbits. Virology, /a: 596-601, 1960. 18. Klein, E., and Klein, G. Antigenic Properties of Lymplioina.s Induced by the Moloney Agent. J. Nati. Cancer Inst., SS: 547-68, 1964. 19. Law, L. W. Neoplasms in Thymectomized Mice following Room Infection with Polyoma Virus. Nature, 205: 672-73, 1965. 20. Law, L. W., and Dawe, C. J. Influence of Total Body X-irradi ation on Tumor Induction by Parotid Tumor Agent in Adult Mice. Proc. Soc. Exptl. Biol. Med., 105: 414-19, 1960. SEPTEMBER 1966 Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1966 American Association for Cancer Research. 2023 Karl Habd to Polyoma-virus-induced Tumors. III. Transplantation 21. Malmgren, R. A., Rabson, A. S., and Carney, P. G. Immunity and Viral Carcinogenesis. Effect of Thymectomy on Polyoma Resistance to Genetically Compatible Polyoma Tumors In Virus Carcinogenesis in Mice. J. Nati. Cancer Inst., 33: 101-4, duced by Polyoma Tumor Homografts. J. Nati. Cancer Inst., 23: 645-66, 1964. 1964. 22. Old, L. J., Boyse, E. A., and Lilly, F. Formation of Cytotoxic 30. Sjögren,H. O., Hellström,L, and Klein, G. Transplantation of Polyoma Virus Induced Tumors in Mice. Cancer Res., 21: Antibody against Leukemias Induced by Friend Virus. Can 329-37, 1961. cer Res., 23: 1063-C8,1963. 23. Old, L. J., Boyse, E. A., and Stockert, E. Typing of Mouse 31. Slettenmark, B., and Klein, E. Cytotoxic and Neutralization Leukemias by Serological Methods. Nature, 201: 201-2, 1904. Tests with Serum and Lymph Node Cells of Isologous Mice with Induced Resistance against Gross Lymphomas. Ibid., 24. Pope, J. H., and Rmve, W. P. Detection of Specific Antigen in 22: 947-54, 1962. SV 40 Transformed Cells by Immunofluorescence. J. Exptl. Med., 120: 121-27, 1964. 32. Stoker, M., and Macpherson, I. Studies on Transformation of Hamster Cells by Polyoma Virus in vitro. Virology, 14: 35925. Rapp, F., Butel, J. S., Feldman, L. A., Kitahara, T., and Melnick, J. L. Differential Effects of Inhibitors on the Steps Lead 70, 1961. ing to the Formation of SV 40 Tumor and Virus Antigens. 33. Tevethia, S. S., Katz, M., and Rapp, F. New Surface Antigen Ibid., 121: 935-44, 1905. in Cells Transformed by Simian Papovavirus SV 40. Proc. Soc. Exptl. Biol. Med., 119: 896-901, 1965. 26. Rapp, F., Kitahara, T., Butel, J. S., andMelnick, J. L. Synthe sis of SV 40 Tumor Antigen during Replication of Simian 34. Ting, R. C. A New Approach for the Demonstration of Viral Papovavirus (SV 40). Proc. Xatl. Acad. Sci., U.S., 52: 1138-42, Genes in Virus-free Polyoma Tumor Cells. Virology, 24: 227-28, 1964. 1904. 35. Vogt, M., and Dulbecco, R. Virus-cell Interaction with a 27. Sabin, A. B., and Koch, M. A. Source of Genetic Information Tumor-producing Virus. Proc. Nati. Acad. Sci., U.S., #?: for Specific Complement-fixing Antigens in SV 40 Virusinduced Tumors. Ibid., 52: 1131-38, 1964. 305-70, 1960. 28. Sachs, L., Medina, IX, and Berwald, Y. Cell Transformation 36. Vogt, P. K., and Rubin, H. Localization of Infectious Virus by Polyoma Virus in Clones of Hamster and Mouse Cells. and Viral Antigen in Chick Fibroblasts during Successive Virology, 17: 491-93, 1962. Stages of Infection with Rous Sarcoma Virus. Virology, IS: 528-44,1961. 29. Sjögren,H. O. Studies on Specific Transplantation Resistance 2024 CANCER RESEARCH VOL. 26 Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1966 American Association for Cancer Research. Virus Tumor Antigens: Specific Fingerprints? Karl Habel Cancer Res 1966;26:2018-2024. Updated version E-mail alerts Reprints and Subscriptions Permissions Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/26/9_Part_1/2018 Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected]. Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1966 American Association for Cancer Research.