[CANCER RESEARCH 46, 3574-3579, July 1986] Selective Killing of Simian Virus 40-transformed Human Fibroblasts by Parvovirus H-l1 Yong Quan Chen, Françoisede Foresta, Jacqueline Hertoghs, Bernard L. Avalosse, Jan J. Cornelis, and Jean Rommelaere2 Laboratory of Biophysics and Radiobiology, UniversitéLibre de Bruxelles, B-1640 Rhode St. Genèse,Belgium [Y. Q. C., F. d. F., J. H., B. L. A., J. J. C., J. RJ, and Laboratory of Molecular Oncology, 1NSERM UI86, Institut Pasteur de Lille, F-59019 Lille, France [B. L. A., J. J. C.. J. RJ ABSTRACT A normal strain of human foreskin fibroblasts, two SV40-transformed derivatives with finite and infinite life spans, and an established line of SV40-transformed newborn human kidney cells are compared for their susceptibility to infection with parvovirus H-l. H-l inocula, which do not detectably alter the growth of normal cells, cause a progressive degen eration of all three SV40-transformed cultures. The resistance of normal cells is not a membrane phenomenon since they adsorb and take up H-l as efficiently as the transformants. Moreover, the fraction of infected cells supporting the synthesis and nuclear migration of H-l proteins is similar in normal and SV40-transformed cultures. On the other hand, the enhanced H-l sensitivity of transformed cells correlates with a 5- to 30-fold increase in their accumulation of newly synthesized parvoviral DNA, as compared with normal cultures. This stimulation of H-l DNA replication is most pronounced for the amplification of duplex replicative forms, although the conversion of parental single-stranded DNA to replicative forms is also enhanced to a smaller extent. In addition, SV40transformed cells support productive H-l infection and release a burst of infectious virus, whereas no H-l production can be detected in the normal cell strain. The latter difference was confirmed for another series of 7 normal and 16 SV40-transformed strains of human skin fibroblasts. Altogether, these results indicate that intracellular limitations on H-l DNA replication are associated with the abortive nature of the parvoviral life cycle in normal human fibroblasts and are overcome after SV40 transformation, resulting in the selective killing of the transformants. This observation raises the possibility that oncolysis might contribute to the oncosuppressive activity displayed by parvoviruses in vivo. INTRODUCTION Parvoviruses are nuclear replicating, single-stranded DNA viruses of small size and low genetic complexity, which have been isolated, in particular, from a number of avian and mam malian species including humans (1). Parvoviruses have a lytic replicative life cycle and are devoid of detectable oncogenic activity, but they have the intriguing ability to suppress cancer formation in laboratory animals and there is speculation about their similar effect in humans (for reviews, see Refs. 2 and 3). Vertebrate parvoviruses can be divided into two subgroups, nondefective (so-called autonomous) and defective (so-called adeno-associated) members, respectively. The antineoplastic spectrum of autonomous parvoviruses is broad and includes spontaneous (4) as well as \ ¡rally(3) and chemically (5) induced cancers, whereas adeno-associated viruses specifically inhibit helper virus oncogenicity (2). The cellular and molecular bases of oncosuppression by parvoviruses are poorly understood. Parvoviruses might interfere with complex physiological proc esses conditioning tumor development (5). On the other hand, adeno-associated (6, 7) and autonomous (8) parvoviruses have both been shown to inhibit in vitro transformation of cells in culture, although they might act by different mechanisms. Thus, direct interactions between parvoviruses and transformed cells or their precursors, as occurring in vitro, might also contribute to oncosuppression. We reported previously that the autonomous parvovirus MVM3 prevents the tumor virus SV40 from transforming in vitro mouse cells which had been selected for their resistance to MVM infection (8). This inhibition could be ascribed to the specific lysis of SV40 transformants by MVM. Together with the known requirements of parvoviruses for the proliferation (3) and appropriate differentiation (1) of their host cells, this observation led us to hypothesize that malignant transforma tion may render normally resistant cells permissive to the replication of these viruses. Hence, transformed cells would be a preferential target for the lytic action of autonomous parvo viruses. The possible involvement of such an oncolysis in cancer suppression by nondefective parvoviruses remains to be deter mined. The work presented in this paper was aimed at analyzing the mechanism by which SV40 transformation sensitizes cells to the killing effect of autonomous parvoviruses and at determin ing the generality of this phenomenon. Since it was known that the nondefective parvovirus H-l can be propagated in an estab lished line of SV40-transformed newborn human kidney cells (9), it was decided to compare a normal diploid strain of human foreskin fibroblasts and two SV40-transformed derivatives with finite and infinite life spans for their susceptibility to H-l infection. Consistent with the oncolysis hypothesis, SV40 trans formation was found to correlate with an enhanced cell permis siveness to H-l. MATERIALS AND METHODS Cells. Human cell strains were grown as monolayers in Eagle's minimal essential medium supplemented with 10% fetal calf serum. NB-E is an established line of S\ 40 transformed newborn human kidney cells (10). VII 10 is a normal finite-life strain of foreskin human fibroblasts from which nonestablished (VH-10 1SV) and established (VH-10 SV), SV40 T-antigen-positive clones were independently de rived by transformation with the early region of SV40 6-17 mutant deleted within the replication origin. The VH-10 series was prepared by B. Klein and kindly provided by A. van der Eb (Leiden University, Leiden, The Netherlands). Cells were counted with a hemocytometer after trypsinization and their viability was determined by their ability to exclude 0.07% (w/v) trypan blue stain. Virus. H-l parvovirus (wild type) was propagated in NB-E cells and purified according to the method of Tattersall et al. (11). 3H- and 32Plabeled virus was produced by incubating infected cells with [3H]thymidine (5 Ci/mmol, 25 ^Ci/ml) and 32P¡ (carrier free, 0.1 mCi/ml), as Received 11/12/85; revised 3/5/86; accepted 3/26/86. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1Supported by an Action de Recherche Concertéefrom the Ministère de la Politique Scientifique and by grants from the Caisse Générale d'Epargne et de described by Rhode (12) and Rommelaere and Ward (13), respectively. Conditions for cell infection, virus harvesting, and titration by plaque assay have been described previously (14). H-l Uptake. Cells were incubated for 60 min at 37°Cor 4°Cin the Retraite, Loterie Nationale, and Fonds de la Recherche Scientifique Médicale. 2 To whom requests for reprints should be addressed. 3The abbreviations used are: MVM, minute virus of mice; SS, single-stranded; RF, replicative form. 3574 Downloaded from cancerres.aacrjournals.org on July 8, 2017. © 1986 American Association for Cancer Research. Downloaded from cancerres.aacrjournals.org on July 8, 2017. © 1986 American Association for Cancer Research. Downloaded from cancerres.aacrjournals.org on July 8, 2017. © 1986 American Association for Cancer Research. CELL TRANSFORMATION AND SUSCEPTIBILITY Table 3 H-l protein synthesis in normal and SV40-transformed human fibroblasto H-1-infected cells were tested for viral protein synthesis by an immunoradiometric assay or immunoenzymatic staining. Background radioactivity due to the immunoradiometric method (-350 cpm) and to input virus proteins (-150 cpm) was measured 2 h postinfection and was subtracted. Nuclear staining was quantitated in 200 cells and its positiveness and intensity were determined after similar background (A = 6) subtraction. The relative synthesis of viral proteins is referred to the corresponding VH-10 value considered as 1.0. Immunoradiometric Cells cpm/10* cells assay Relative synthesis TO PARVOVIRUSES Table 4 H-l virus replication in human fibroblasts Cultures of human fibroblasts (5 x 10* cells) were infected with H-l (multi plicity of infection, 10~2), incubated for 4 days, and tested for the production of infectious virus. Increases in tiler of at least 3-fold over the input virus were scored as positive. The virus titer in nonproducing cells actually decreased with time postinfection. Input virus was titered 2 h postinfection. of SV40 H-l strains transferproducRef. tion38 tested mation CellsVH-10VH-10SVGM2149 Immunoenzymatic staining % of Absorbance/ positive positive nuclei nucleus 139 +139 2 + GM2149SVGM1061 +140 3 + GM1061 SVGM1085 +140 2 + GM1085SVAT5BI +41 8 + AT5BI VA2BI a41 46BRXP30RO 4241a10+-: Relative synthesis VH-10VH-10 SVVH-10 1SVNB-E12422420325348471.01.952.63.926.5292628111621211.01.61.92.0 GM0637 B NB-ENo. : " National Institute of General Medical Sciences Human Genetic Mutant Cell Repository. DISCUSSION Abortive Interaction between Parvovirus H-l and Normal Hu man Fibroblasts 012345 Time postinfection (days) Fig. 4. H-l virus production in normal and SV40-transformed human fibro blasts. Cultures (5 x 10s cells) were infected with H-l virus (multiplicity of infection, IO"2) and analyzed at intervals for the production of infectious virus. Average values for 2 experiments (SD less than 15%). PFU, plaque-forming units. Same symbols as for Fig. 1. 2) synthesis correlated, although the former was much lower than the latter. Production of Infectious H-l Particles. Cultures of normal VH-10 cells were unable to amplify the H-l inoculum; the titer of infectious virus harvested from these cultures rather declined with time (Fig. 4). Thus, most normal fibroblasts did not appear to sustain a productive H-l infection. In contrast, SV40-transformed strains were all productively infected and released a burst of infectious H-l (Fig. 4). NB-E and transformed VH-10 cells displayed high and intermediate degrees of permissiveness compared to normal VH-10 cultures, respectively, which cor related with their relative abilities to support H-l DNA repli cation (Table 2) and susceptibilities to the lytic action of H-l (Fig. 1). The induction of permissiveness to H-l as a result of SV40 transformation is not unique to VH-10 cells. As shown by Table 4, a similar effect was observed for a number of other human skin fibroblasts. None of the normal cultures tested were able to replicate H-l whereas SV40-transformed strains were the hosts of a productive H-l infection. A series of nonpermanent cultures of normal human skin fibroblasts were found to resist productive infection with parvovirus H-l. Resistance could be ascribed to the failure of an intracellular stage of the replicative life cycle of H-l, resulting in a lack of amplification of the virus inoculum. Similar results have been reported for human amnion, embryo kidney (25), and lung (9) cells. A quantitative comparison of H-l replication was undertaken between normal skin fibroblasts and corre sponding permissive cultures, namely SV40 transformants de rived therefrom (see below). A striking difference was observed at the level of the replication of RF DNA, which was much enhanced in transformed cultures and correlated with their ability to produce infectious virus. The defect of the H-l life cycle in diploid human fibroblasts might concern RF DNA replication itself. Alternatively, another step of the viral cycle conditioning the extent of RF DNA replication might be im paired, although our data suggest that virus uptake, nuclear translocation, and parental DNA conversion are unlikely to be primarily involved. The inability of normal human fibroblasts to support RF DNA replication efficiently might result from their failure to express nonessential host functions usurped by H-l for its own growth. In addition, H-l DNA replication appears to involve virus-encoded functions (26). Nonpermissive cells might also fail to synthesize or modify these viral products, although no major impairment of H-l capsid gene expression was detected in diploid human fibroblasts. Our data indicate that the limi tation placed by normal cells on H-l replication can be reversed as a result of their in vitro transformation by SV40. A parallel can be drawn between this observation and other reports show ing that cellular changes can render normally resistant cultures susceptible to autonomous parvoviruses. Permissiveness to parvoviruses has been shown to be dependent on host cell prolif eration (27,28) and differentiation (29-31). Various physiolog- 3577 Downloaded from cancerres.aacrjournals.org on July 8, 2017. © 1986 American Association for Cancer Research. CELL TRANSFORMATION AND SUSCEPTIBILITY ical states can lead to the arrest of the parvoviral life cycle at different steps, both on the surface and on the inside of the cell (32). Therefore, there appear to be multiple conditional host factors which determine permissiveness to parvoviruses. It fol lows that the specific abortive interaction reported here for diploid human fibroblasts cannot be necessarily generalized to other cell types. TO PARVOVIRUSES ACKNOWLEDGMENTS The authors are greatly indebted to Drs. A. van der Eb and B. Klein for their generous gift of VH-10 and derived cells, to C. Kumps for technical assistance, and to Dr. P. Tattersall for critical reading of the manuscript. Some human mutant cells were kindly provided by Drs. C. Arieti, A. Lehmann, and D. Bootsma. Induction of 11-1 Sensitivity by SV40 Transformation REFERENCES The acquisition of permissiveness to H-l replication by SV40 transformants correlated with their sensitization to parvoviral lytic action. H-l inocula which had little effect on the growth of normal cultures caused a progressive degeneration of trans formed derivatives. Thus, the preferential killing of transformed cells is likely to result from their propensity to replicate H-l rather than their lower resistance to its cytopathic effect. A similar sensitization of SV40 transformants to the autonomous parvovirus M VM was reported previously for mouse cells which had been selected in vitro for their resistance to this virus (8). Therefore, SV40 transformation overcomes both natural and selected cellular protections against parvoviral attack. The enhanced susceptibility of SV40 transformants to H-l infection does not require their establishment into a permanent culture. Thus, SV40 transformation appears to act directly and not merely by facilitating cell immortalization. Since the expres sion of the SV40 genome in transformants is restricted to the early region-encoding T-antigens (33), the latter protein(s) is likely to mediate sensitization to H-l. Large T-antigen is known to activate cellular gene expression (33, 34). As stated above, cell permissiveness to parvoviruses involves host functions, some of which are not permanently expressed and might con ceivably be induced by SV40. On the other hand, a direct interaction between the H-l genome and SV40 T-antigen(s) might also potentiate H-l replication. Another tumor virus, adenovirus, was found to provide helper functions to H-l in coinfected human cells (35) and encodes a tumor antigen which could possibly interact directly with the DNA of the defective parvovirus adeno-associated virus (7). Whatever mechanism it involves, sensitization to H-l is apparently not specific for tumor virus-transformed cells. Indeed we have recently ex tended the present observation to human diploid fibroblasts transformed by 7-irradiation (36). Nonvirally transformed cells therefore appear to supply helper functions similar to those encoded or induced by SV40. Altogether, our data point to a positive interrelation between two complex cellular phenotypes each composed of multiple components, i.e., permissiveness to autonomous parvoviruses and /// vitro malignant transformation. This result raises two intriguing possibilities, (a) The lytic life cycle of parvoviruses may provide specific markers for cell transformation. We report here that SV40 transformation bypasses a limitation to H-l DNA replication. In contrast, a postreplicative step of the growth of parvovirus MVM was found to be stimulated as a result of the transformation of rat cells with the retrovirus avian erythroblastosis virus (37). An interesting issue is whether the overcoming of distinct barriers to parvovirus replication re quires the expression of different transformation traits, (b) The suppresion of cancer development by autonomous parvoviruses may result, at least in part, from oncolysis. 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W., Rhode, S. L., and Gierthy, J. F. Inhibition of 7,12-dimethylbenz(a)anthracene-induced tumors in Syrian hamsters by prior infection with H-l parvovirus. Cancer Res., 42: 2552-2555, 1982. 6. Casto, B. C., and Goodheart, C. R. Inhibition of adenovirus transformation in vitro by AAV-1. Proc. Soc. Exp. Biol. Med., 140: 72-78, 1972. 7. Ostrove, J. M., Duckworth, D. H., and Berns, K. I. Inhibition of adenovirustransformed cell oncogenicity by adeno-associated virus. Virology, 113: 521533, 1981. 8. Mousset, S., and Rommelaere, J. Minute virus of mice inhibits cell transfor mation by simian virus 40. Nature (Lond.), 300: 537-539, 1982. 9. Singer, I. I., and Rhode, S. L. Electron microscopy and cytochemistry of H1 parvovirus intracellular morphogenesis. In: D. C. Ward and P. Tattersall (eds.). Replication of Mammalian Parvoviruses, pp. 479-504. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory, Publisher, 1978. 10. Shein, H. M., and Enders, J. F. 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Carcinogenesis (Lond.), 4: 559-564, 1983. 3579 Downloaded from cancerres.aacrjournals.org on July 8, 2017. © 1986 American Association for Cancer Research. 0 Announcements MEETING OF THE RADIATION The annual meeting of the Radiation Research Socie ty will be held at the State University of Iowa, Iowa City, on June 22—24, 1953. The Society will be the guest of the University, and all meetings will be held on the campus. The program will consist of: (1) Two symposia, one on “TheEffects of Rwliation on Aqueous Solu tions,― which includes the following speakers: E. S. G. Barren, Edwin J. Hart, Warren Garrison, J. L. Magee, and A. 0. Allen. The second is “PhysicalMeasurements for Radiobiology―and companion talks by Ugo Fano, Burton J. Moyer, G. Failla, L. D. Marinelli, and Payne RESEARCH S. Harris. SOCIETY (2) On Monday night, June 22, a lecture by Dr. L. W. Alvarez on meson physics has been tentative ly scheduled. On Tuesday night, June 23, Dr. L. H. Gray of the Hammersmith Hospital, London, will speak on a topic to be announced. Dr. Gray's lecture is spon sored by the Iowa Branch of the American Cancer Soci ety. Those desiring to report original research in radia tion effects, or interested in attending or desiring addi tional information, please contact the Secretary of the Society, Dr. A. Edelmann, Biology Department, Brook haven National Laboratory, Upton, L.I., New York. ERRATUM The following correction should be made in the arti cle by Beck and Valentine, “The Aerobic Carbohydrate Metabolism Glycolysis substitute of Leukocytes in Health and Leukemia. I. and Respiration,― November, 1952, page 821; for the last paragraph: The data in Table 3 permit several interesting calcu lations. If one compares the amount of glucose actually disappearing with the sum of the amount equivalent to lactic acid produced plus that equivalent to 02 con by the glucose utilized by 16 per cent in CLL. If the as sumption is made that, in this respect, the myeloid and lymphoid celLsof leukemia are similar to those of nor ma! blood, it may be that the computed normal figure represents a summation of the myeloid (M) and lymphoid (L) cells that make up the normal leukocyte population. Thus, if M = +0.27 and L = —0.16 and the normal differential is 65 per cent M and So per cent L, then 0.65 (+0.27) + 0.35 (—0.16) = +0.12 sumption, it is seen that the amount of glucose “cleav age products―exceeds the amount of glucose utilized b a figure identical to the observed +0.12 for normal 12 per cent in N and 27 per cent in CML and is exceeded leukocytes. 308 Selective Killing of Simian Virus 40-transformed Human Fibroblasts by Parvovirus H-1 Young Quan Chen, Françoise de Foresta, Jacqueline Hertoghs, et al. Cancer Res 1986;46:3574-3579. 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