Virus Oncogenesis and Tumor Immunogenicity in the Mouse Mammary Tumor System1

[CANCER RESEARCH 34, 1319 1324, June 1974] Virus Oncogenesis and Tumor Immunogenicity in the Mouse Mammary Tumor System1

Jan Vaage and Daniel Medina Department of Cancer Therapy Development, Pondville Hospital, Walpole, Massachusetts 02081 [J. K.J, and Department oj Cell Biology, Baylor College of Medicine, Houston. Texas 77025 [D. M.\

SUMMARY INTRODUCTION

Mammary tumorigenesis and mammary tumor trans Several factors are known to be involved in the etiology of plantation immunogenicity were examined in breeding fe spontaneous mammary tumors in mice; most important males of 2 syngeneic sublines of the C3H strain: in among them are viral (2, 5, 15, 16), hormonal (16), and mammary tumor virus (MTV) plus nodule-inducing virus- genetic (8, 15) factors. In the C3H strain, 2 mammary infected C3H/Sed mice; and in MTV-free, nodule-inducing tumor viruses have been recognized: the MTV3 of high and virus-infected C3Hf/Sed mice. early oncogenic activity; and the NIV, of high but late Ninety-seven % of the C3H mice (29 of 30) developed oncogenic activity (11). The oncogenic effect of the in mammary tumors at an average age of 280 days. Of 43 M/ero-transmitted NIV is distinguishable in the C3Hf different C3H tumors tested for transplantation immunoge mouse, which was established as a syngeneic subline of C3H nicity in the C3H strain of origin, 13 (30%) had non-MTV- by foster nursing to exclude the milk-transmitted MTV, and associated tumor-specific transplantation antigens (TSTA). the high but late mammary tumor incidence in C3Hf mice Of 5 primary C3H hosts that developed multiple mammary becomes apparent in animals with a very long normal tumors, 4 animals developed both TSTA-positive and life-span in the infection-free conditions of a hygienic and TSTA-negative tumors. All C3H tumors tested (20 of 20) pathogen-free environment (11). for antigenicity in the C3Hf strain had MTV-associated In MTV-induced mouse mammary tumors, immunogenic transplantation antigens. reactivity (1, 10, 13, 20, 21, 23) and immunogenic cross- Sixty-nine % of the C3Hf mice (34 of 49) developed reactivity (20, 21, 23, 24) have been demonstrated in mammary tumors at an average age of 708 days. Of 16 MTV-free syngeneic C3Hf hosts where the MTV and/or different C3Hf tumors tested for antigenicity in the C3Hf cell products controlled by the viral genome probably strain of origin, 1 (6%) had TSTA. constitute common VATA's. In contrast, C3H mice, neona- Mammary tumorigenesis and mammary tumor trans tally infected with MTV, have been shown to be immuno- plantation immunogenicity were examined in expiants of 2 logically tolerant of the MTV (10, 12), and they can separate MTV-free C3Hf/Ki hyperplastic alveolar nodule consequently be expected to respond only to mammary (HAN) outgrowth lines transplanted to the cleared mam tumor immunogens other than the viral antigens and/or cell mary fat pads of syngeneic MTV-free C3Hf/Ki mice and products controlled by the viral genome.4 Such non-MTV- transplanted to the cleared mammary fat pads of syngeneic associated and non-cross-reacting TSTA's in MTV-induced MTV-infected C3H/KÃŒmice.Tumor development in HAN mouse mammary carcinomas have been demonstrated by line 1 was 44% at 297 days in C3Hf recipients and 100% at. both in vivo (14, 20, 21, 23) and in vitro (7) test procedures. 175 days in C3H recipients. Tumor development in HAN Non-virus-associated transplantation immunogenicity may line 2 was 75% at 225 days in C3Hf recipients and 87% at be expected in about 1of 4 MTV-induced mammary tumors 142 days in C3H recipients. One of 9 HAN line 1 tumors (21, 23). C3Hf mice most probably respond like C3H mice acquired TSTA during development in the C3Hf/Ki strain: to TSTA, but in the C3Hf mice this immune response is 0 of 10 acquired TSTA during development in the C3H/KÃŒ strain. Each tumor tested had acquired virus-associated transplantation antigens during development in the C3H/KÃŒ 'The abbreviations used are: MTV, mammary tumor virus; NIV, strain. One of 14 HAN line 2 tumors acquired TSTA during nodule-inducing virus; VATA, virus-associated transplantation antigen: TSTA, tumor-specific transplantation antigen: HAN, hyperplastic alveo development in the C3Hf/Ki strain; 0 of 15 acquired TSTA lar nodule: i.d., intradermally. during development in the C3H/KÃŒstrain. 4Reported demonstrations of anti-MTV immune factors in immuni/ed MTV-infected mice are considered to be due to a complete or partial loss of tolerance to MTV-associated antigens in occasional MTV-infected mice 'This work was supported in part by USPHS Grants Ã‡A 130I8. [see review by Blair (3)) or may be due to immune factors that do not CAI 1944. and CAI326I. impede tumor growth in vivo. However, the clear difference between C3H 2Recipient of Cancer Research Scholar Award from the American and C3Hf mice in their response to VATA has shown that immune Cancer Society, Massachusetts Division, which supported part of this tolerance to the VATA is a general characteristic of the C3H strain. Both work. C3H and C3Hf mice are assumed to be tolerant of the in Â¡//era-transmitted Received November 15, 1973: accepted February 19, 1974. NIV.

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Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1974 American Association for Cancer Research. J. Vaage and D. Medina obscured by the much stronger response to the ever-present Tumor tissue was removed from freshly killed or live VATA. anesthetized donor animals, and skin and necrotic tissue The possibilities that the non-virus-associated tumor were removed before the tissue was placed in tissue culture transplantation immunogenicity could be due to medium in a sterile Petri dish kept on a bed of crushed ice. histocompatibility variation in the donor or could be due to Disruption of tumor tissue to obtain suspensions of dis the presence of antigenic variants of the MTV or even persed tumor cells was accomplished by a mechanical unrelated infectious agents were excluded by repeated procedure described in a previous publication (22). demonstrations that a mouse may develop both immuno- In all of the experiments reported here, s.c. sensitization genic and nonimmunogenic tumors at the same time (23). procedures were done on the right side of the animal and s.c. The present investigation has attempted to compare the challenge implantations were done on the left side. Chal frequency of non-virus-associated immunogenicity in mam lenge implantation s.c. of presensitized and control mice mary tumors induced by the action of the MTV with the was by injection of viable (trypan blue-negative) tumor cells frequency of non-virus-associated immunogenicity in mam suspended in tissue culture medium and consisting predomi mary tumors induced by the action of the NIV and also to nantly of single cells. The proportion of trypan blue-nega examine the frequency and variability of immunogenicity in tive cells in the tumor cell suspension was usually about mammary tumors arising in multiple expiants of mammary 25%. tissue from a single preneoplastic source. Statistical Analyses. For comparison of tumor incidence after challenge, the \2 test was used to evaluate the significance of differences in the total number of tumors MATERIALS AND METHODS between groups of mice. Differences between groups were considered significant only when p values of comparison Mice. The animals used in these experiments were as were 0.05 or smaller. follows. Group 1, was composed of 12-week-old female mice of inbred strains C3Hf/Sed and C3H/Sed from the defined-flora, pathogen-free breeding colonies (mice carry RESULTS ing only the following enteric bacteria: Closlridium sp., Peptostreptococcus sp., Bacillus sp., Bacteroides sp.) main Tumor Development in C3H/Sed and C3Hf/Sed Mice. tained by the Section of Experimental Radiotherapy at the Table 1 shows the incidence and age of mammary carci University of Texas M.D. Anderson Hospital and Tumor noma development in defined-flora, pathogen-free breeding Institute at Houston and by the Department of Radiation females of C3H/Sed and C3Hf/Sed mice. Foundation line Medicine, Massachusetts General Hospital. The C3Hf/Sed breeding mice were kept 1 pair to a cage in sterile air mice came originally from the germfree colony of Burdette isolators until retirement after 4 to 5 litters, at an average at the M.D. Anderson Hospital; he in turn had acquired his age of about 26 weeks. Retired female breeders are kept in mice from the germfree colony of Pilgrim at the University filter-top cages in filtered air environment at 74Â°Finregular of Utah, Salt Lake City, Utah. Pilgrim established his animal rooms and observed regularly for tumor develop germfree mice by cesarian section from C3Hf/Crgl mice. ment and general condition for the rest of their lives. C3H/Sed mice were established by foster nursing All the MTV-positive C3H/Sed female mice, with 1 C3Hf/Sed on C3H/PÃ•. Group 2 was composed of 8- to exception, developed a mammary carcinoma at an average 12-week-old male and female mice from inbred strains age of 280 days. No gross evidence of other pathological C3H/KÃ•and C3Hf/Ki maintained in a closed mouse colony conditions was found in these mice at postmortem examina in the Department of Cell Biology at Baylor College of tion. The exceptional C3H/Sed female mouse is at the time Medicine at Houston. of writing 650 days of age and apparently disease free. Her Tumors. Female C3H and C3Hf mice with spontaneous offspring did not enter foundation line breeding, and it is recently arisen mammary carcinomas were routinely re therefore uncertain whether she has biologically active moved from the breeding colony. The tumors were resected MTV. Her female littermate, however, died with a mam and used for experimentation when they reached a size of mary carcinoma at 313 days of age. about 10 mm. Some of the mice were kept after surgery and Of the MTV-free C3Hf/Sed female mice, 44 of 49 observed for the development of further (not recurrent) developed neoplastic disease, all without signs of other tumors, which were also resected and used for experimenta disease. Only 4 of 49 died of nonneoplastic causes. One tion. C3Hf/Sed female mouse is at the time of writing 1200 days Mammary carcinomas that developed in C3Hf/Ki HAN of age and apparently disease free. tissue transplanted to the cleared mammary fat pads of Immunogenicity Tests with C3H/Sed and C3Hf/Sed C3Hf/Ki and C3H/KÃ• mice were resected and used for Mammary Tumors. Recently arisen mammary carcinomas experimentation. were removed from the original host and implanted s.c. in Tumor Implantation. Implantation s.c. of 1-mm pieces of the right flank of 10 syngeneic mice. When the implanted living tumor tissue was the method used to initiate tumor tumors had grown to a size averaging 10 to 12 mm, they growth for the purpose of immunization. An incision was were removed surgically from all except 2 mice. The made in the skin of the flank, and a tumor piece was placed challenge implantation of tumor cells was made 2 days later under the skin by means of a trocar. The incision was closed to give the test animals some time to recover from the with wound clips. surgery and from the possible tumor effect (22). The 2

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Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1974 American Association for Cancer Research. Virus Oncogenesis and Tumor Immunogenicity remaining mice, while serving as tumor donors for the cell TSTA-negative tumors in the following proportions: 2/4, suspension used for the challenge, were also challenged and 1/5,1/1,1/1,0/2. kept in the experiment. Living tumor cells (IO5) were Tumor Development in Transplanted C3HÃ•/KÃ•HAN's. injected s.c. at the left shoulder and hip of the pretreated The tests used 2 HAN outgrowth lines which came from mice and of 10 untreated control mice. The incidence of retired C3Hf/Ki breeders. These HAN lines, designated F-l tumors at the injection sites was then checked at weekly and F-2, have been serially transplanted in the cleared intervals. mammary fat pads of young syngeneic mice. The mammary At the time of each challenge injection, a new group of carcinoma incidence in expiants of HAN line F-1 growing in C3H/Sed or C3Hf/Sed mice received immunizing implants the mammary fat pads of MTV-free C3Hf/Ki mice is 44% of the same tumor to test the tumors for immunogenicity 297 days after nodule implantation. The tumor incidence in in succeeding transplant generations. For most of the tu line F-2 is 75% in 225 days under the same conditions. If the mors, this process was repeated for 2 to 6 transplant gen nodule lines are transplanted into the cleared mammary fat erations. For the C3H tumors tested in the MTV-free pads of MTV-positive C3H/KÃŒmice,the mammary carci C3Hf mice, the MTV-associated immunogenicity of C3H noma incidence in F-l is 100% by 175 days after nodule tumors is so strong and unequivoval that a single test was implantation and in F-2 the incidence is 87% by 142 days. usually considered adequate. Immunogenicity Tests with C3Hf/Ki HAN's and Table 2 summarizes the results of these tests, showing the Mammary Tumors. The presence of transplantation-type difference in immunogenicity of C3H tumors when tested immunogens in the nodule lines F-l and F-2 was tested in in C3H hosts versus C3Hf hosts, as well as the difference in the C3Hf/Ki strain of origin by a sensitization followed by tumor-specific transplantation immunogenicity in C3H tu transplantation assay procedure: (a) the mammary paren mors compared to C3Hf tumors. chyma rudiments were removed from the 4th pair of Of the 43 C3H tumors tested for immunogenicity, 18 mammary fat pads of 3-week-old female C3Hf/Ki mice; (b) tumors came from 5 hosts that developed multiple mam pieces of HAN tissue were implanted i.d. at 10weeks of age; mary tumors. These 5 hosts developed TSTA-positive to (c) the sensitizing i.d. implants were removed after 4 weeks,

Table 1 Tumor development in breeding C3H/Sed and C3Hf/Sed female mice

age at1sttumor of mice with StrainC3H tumorMammaryof tumor/no, atrisk29/30 (days)280 (days)189-471

carcinoma (96.7)Â°-" C3Hf Mammary carcinoma 30/49(61.2)' 695 431-957 C3Hf Ovarian carcinoma 8/49(16.3) 748 431-920771-845 C3HfC3Hf Mammaryandovarian carcinoma 4/49(8.2)1/49(2.0) 809779731Range carcinomaGastric granuloma C3HfType LymphomaNo. 1/49(2.0)Av. " Numbers in parentheses, percentage of mice. 6One of 30 C3H mice still surviving, tumor free, at 650 days of age. ' Of the 30 C3Hf mice that developed a mammary carcinoma and no other tumor, 2 had a cystic ovary (average, 931 days; range, 905 to 957 days). Of the 4 of 49 C3Hf mice that died from nonneoplastic causes, 3 died from cystic ovaries (average, 789 days: range, 782 to 820 days), and 1 died from sterile endometritis (750 days). One of 49 C3Hf mice still survives, tumor free, at 1200 days of age.

Table 2 Immunogenicity of isografts of spontaneous C3H/Sed and C3Hf/Sed mammarv carcinomas in female CiH/Sed and C3Hf/Sed hosts The immunogenicity of each tumor was determined by statistical evaluation of differences in tumor incidence in sensitized versus unsensitized groups of mice. Test animals were sensitized by s.c. implants of a tumor in the right flank and challenged by s.c. implantation of IO5living cells at the left shoulder and hip 2 days after removal of the sensitizing implant. 13/43 versus 20/20. p < 0.001; 13/43 versus 1/16, 0.05 < p < 0.1. of immunogenic tumors/ originC3H/Sed(MTVStrain of strainC3H/Sed(MTV tumorstested13/43(30)"

+ ,NIV + ) + ,NIV+) C3H/Sed(MTV+, NIV + ) C3Hf/Sed(MTV-,NIV + ) 20/20(100) C3Hf/Sed(MTV-,NIV + )Recipient C3Hf/Sed(MTV-,NIV + )No. 1/16(6) " Numbers in parentheses, percentage of mice.

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Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1974 American Association for Cancer Research. J. Vaage and D. Medina and pieces of HAN tissue were implanted into the cleared F-l tissue transplanted to MTV-free C3Hf/Ki mice had fat pads of sensitized mice and into the cleared fat pads of acquired tumor-specific immunogenicity while 0 of 10 unsensitized control mice; (d) the mice were sacrificed at 18 tumors that arose in the same F-l tissue transplanted to and 22 weeks of age, the implanted fat pads removed and MTV-positive C3H/KÃŒmicehad acquired immunogenicity. stained in hematoxylin, and the extent of HAN growth was However, each of 3 tumors (randomly selected from the 10 determined using a dissecting microscope. C3H/KÃŒtumors) were strongly immunogenic in C3Hf/Ki The results of these tests are presented in Table 3 and hosts. show that pretreatment of syngeneic mice with HAN tissue The results of tests with HAN line F-2 and tumors from did not induce a state of resistance to the growth of HAN line F-2 are summarized in Chart 2. The results are subsequent orthotopic implants of the same nodule line. The similar to those obtained with HAN line F-l. Of 14 tumors nodule lines F-l and F-2 are therefore considered not to that arose in nonimmunogenic HAN line F-2 tissue trans have tissue-specific transplantation-type immunogens of planted to MTV-free C3Hf/Ki mice, 1 had acquired sufficient strength to be detectable by the techniques used in tumor-specific immunogenicity, while 0 of 15 tumors that these investigations. arose in the same F-2 tissue transplanted to MTV-positive Mammary carcinomas that arose in F-l and F-2 HAN C3H/KÃŒmice had acquired immunogenicity. None of the tissue growing in the cleared mammary fat pads of C3H/K.ÃŒtumors that arose in C3H/KÃŒhosts have been tested for and C3Hf/Ki mice were tested for immunogenicity in the immunogenicity in C3Hf/Ki hosts. same strains by the procedure already described for similar tests with spontaneous C3H/Sed and C3Hf/Sed tumors. The results of tests with HAN line F-l and tumors from DISCUSSION HAN line F-l are summarized in Chart 1. The results show that 1 of 9 tumors that arose in nonimmunogenic HAN line The primary objective of this study was to determine the frequency with which infection with the MTV can lead to Table 3 the appearance of TSTA in MTV-induced mammary Growth oforlholopic isografts ofdHf/Ki HAN tissue in syngeneic hosts carcinomas arising spontaneously in breeding female mice The nonimmunogenicity of each HAN was determined by comparison or arising in lines of MTV-free HAN outgrowths trans of HAN growth in the cleared mammary fat pads of sensitized versus planted to the cleared mammary fat pads of MTV-infected unsensitized mice. Test animals were sensitized by i.d. implants of HAN tissue and challenged by intramammary implantation of HAN tissue. syngeneic mice. By determining the proportion of such MTV-induced tumors that can elicit transplantation resist Av. HAN occupation of fat ance in MTV-tolerant mice, it was hoped that comparisons pad (%) with similar studies on mammary carcinomas arising in syngeneic MTV-free mice would provide some information TreatmentSensitized lineF-l about how often the event of virus-induced neoplastic (8)Â° transformation is associated with the appearance of what UnsensitizedSensitized F-lF-2 40(8)36(14) 78(8)87(12)85(12)may be non-virus-associated immunogenic abnormal cell products or cell components. That the appearance of new UnsensitizedHAN F-24wk42 42(11)8wk78(8) immunogenic components is closely associated with the oncogenic activity of the MTV and the neoplastic state was ' Numbers is parentheses, number of mice examined. indicated by the present and previously reported observation that new tumor immunogens will persist through at least 10 C3Hf / Ki ( MTV-, N IV + ) transplant generations in spite of immune selective pressure (21). The mouse mammary tumor system, because of the immune tolerance conditions associated with the vertical transmission of the oncogenic agent, offers a system in Nodule F-1 ( Non-onligenic ) which the occurrence of virus-induced abnormal cell gene products can be compared to the occurrence of abnormal Tronsplont F-1 to Transplant F-1 to cell gene products induced by the action of chemical C3Hf / Ki ?Â¥ C3H/KÃŒ?? (MTV + .NIV + ) oncogens. This may reveal significant differences or similar ( 44 % tumors ( 100% tumors in 175 days) ities in the oncogenic activity of different agents, which may in 297 days) lead to a better understanding of the basic process of neoplastic transformation. This study has just begun, but the results thus far indicate that, while virus-associated immunogens are always expressed in virus-induced mam tumors tested in: tumors tested in : mary tumors (Table 2; Chart 1), the appearance of non- C3Hf /Ki : Vg TSTA + C3H/KÃŒ:Â°/10TSTA+ C3Hf/Ki : 3/3 VATA+ virus-associated TSTA is an event that is only occasionally Chart 1. Test of immunogenicity of multiple tumors developed from concomitant with virally induced neoplastic transforma HAN line F-l. The tumors arose in preneoplastic nodule tissue trans tions (Table 2; Charts 1 and 2). The MTV, of high and early planted to the cleared mammary fat pads of C3Hf/Ki and C3H/KÃŒmice. oncogenic activity, induced TSTA in 30% of C3H/Sed The immunogenicity test procedure is described in Table 2. mammary tumors, whereas the NIV, of high but late

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Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1974 American Association for Cancer Research. Virus Oncogenesis and Tumor Immunogenicity C3Hf / Ki ( MTV-, NIV + ) is possible that the mature, preneoplastic HAN cells, aged in serial transplantation, are not susceptible to that effect of the MTV which may result in production of TSTA, while they remain susceptible to the oncogenic effect of the virus.

Nodule F-2 ( Non-ontigenic) REFERENCES Transplont F-2 to Transplont F-2 to 1. Attia, A. M., DeOme, K. B., and Weiss. D. W. Immunology of C3Hf /Ki ?? C3H/KÃŒ ?? ( MTV + . NIV+) Spontaneous Mammary Carcinomas in Mice. II. Resistance to ( 75% tumors ) (87% tumors in 142 days ) Rapidly and Slowly Developing Tumors. Cancer Res., 25: 451-457, in 225 days) 1965. 2. Blair, P. B. The Mammary Tumor Virus. Current Topics Microbiol. Immunol., 45: 1-69, 1968. 3. Blair, P. B. Immunological Aspects of the Relationship between Host tumors tested in: tumors tested in: and Oncogenic Virus in the Mouse Mammary Tumor System. Israel J. Med. Sci., 7: 161 186, 1971. C3 Hf / K i. V14 TSTA + C3H/ Ki : Â°/15TSTA 4- 4. DeOme, K. B., and Medina, D. A New Approach to Mammary Chart 2. Test of immunogenicity of multiple tumors developed from Tumorigenesis in Rodents. Cancer, 24: 1255 1258, 1969. HAN line F-2. For further information, see Chart I. 5. DeOme, K. B., and Nandi, S. The Mammary Tumor System in Mice. A Brief Review. In: W. J. Burdette (ed.). Viruses Inducing Cancer, pp. oncogenic activity, induced TSTA in only 6% of C3Hf/Sed 127-137. Salt Lake City, Utah: University of Utah Press, 1966. mammary tumors. In comparison, tumor-specific trans 6. Halpin, Z. T., Vaage, J., and Blair, P. B. Lack of Antigenicity of plantation immunogenicity is found in most, but not all, Mammary Tumors Induced by Carcinogens in a Nonantigenic chemically induced tumors (6, 9, 17 19), and the frequency Preneoplastic Lesion. Cancer Res., 32: 2197-2200, 1972. of expression of new immunogens has been found to vary 7. Heppner, G. H., and Pierce, G. In Vitro Demonstration of Tumor- specific Antigens in Spontaneous Mammary Tumors in Mice. Intern. with different chemical oncogenic agents (6, 17, 18). In J. Cancer, 4: 212 218, 1969. further comparison, both non-virus-associated immunogens 8. Heston, W. E., and Vlahakis, G. 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20. Vaage, J. Non-cross-reacting Resistance to Virus-induced Mouse 1973. Mammary Tumors in Virus Infected C3H Mice. Nature. 218: 23. Vaage, J., Kalinovsky, T., and Olson, R. Antigenic Differences among 101 102, 1968. Virus-induced Mouse Mammary Tumors Arising Spontaneously in 21. Vaage, J. Nonvirus-associated Antigens in Virus-induced Mouse the Same C3H/Crgl Host. Cancer Res., 29: 1452-1456, 1969 Mammary Tumors. Cancer Res., 28: 2477 2483, 1968. 24. Weiss, D. W., and Shen. A. Immunology of Spontaneous Mammary 22. Vaage, J. Influence of Tumor Antigen on Maintenance versus Tumors in Mice. Cross-reacting Immunogenicity of C3H Tumors in Depression of Tumor-specific Immunity. Cancer Res., 33: 493 505. C3Hf and C3H/2 mice. Proc. Am. Assoc. Cancer Res., 7: 75, 1966.

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Jan Vaage and Daniel Medina

Cancer Res 1974;34:1319-1324.

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