The Coming of Age of Tumor Virology: Presidential Address1

[CANCER RESEARCH 37, 1255-1263, May 19771 The Coming of Age of Tumor Virology: Presidential Address1

Charlotte Friend

The Center for Experimental Cell Biology, The Mollie B. Roth Laboratory, Mount Sinai School of Medicine, New York, New York

mary carcinoma that bears his name. Nevertheless, investi gations along these lines were not completely abandoned. In 1908, the Danish scientists Ellerman and Bang (32) re ported that leukemia in chickens was caused by a filterable agent, but their findings received little attention since leu kemia was not then considered to be a neoplastic disease. Three years later, Rous described a malignant chicken sar coma caused by a virus (96). This paper, which was to become a classic, met with such â€œdownrightdisbeliefâ€•(97) that 55 years were to pass before the author, then well over 90, was to be awarded the Nobel Prize for his work. After spending several discouraging years in a fruitless search for similar viruses in transplantable mouse tumors, Rous gave up his study of cancer for almost 20 years. He returned to this first love in 1934, when Richard Shope (105), who had discovered a virus that induced papillomas in rabbits, of fered it to him. He could not resist the study of a virus that caused neoplastic changes in the epithelial cells of a mam malian host. From then to the end of his long and produc tive life, he continued to explore the mechanisms involved in carcinogenesis, but he never again worked on the chicken sarcoma virus that he discovered (RSV).2 Although the climate did not improve much even after Bittner (13) found the virus that causes mammary tumors in mice, a small number of men and women persisted in inves tigating the role that viruses might play in causing a cancer cell to march to a different bugle. As evidence accumulated, scientists with an infinite variety of disciplines were drawn to the challenge, and doors began to open to efforts to Dr. Creech, members of the American Association for resolve the question of whether viruses were indeed in Cancer Research, and distinguished guests: Tonight I volved in the genesis of cancer. would like to discuss the tumor viruses and the paths of It was at this stage that I made my debut in viral oncology discovery that led from their consideration as figments of at the American Association for Cancer Research meeting the imaginations of mad scientists to their acceptance as 20 years ago and inadvertently got a ringside seat to the causative agents of cancers. opening of the Golden Age. I describe it somewhat in detail The turbulent history that began at the turn of the century to give you an idea of how strong was the reluctance to illustrates so well the wisdom of Thomas Huxley's state accept tumor viruses as a reality. Although Ludwik Gross's ment, â€œThosewhorefuse to go beyond fact rarely get as far (51) study on the virus he had recently isolated from leu as fact.â€•Perhaps because most pathologists and oncolo kemic AKR mice had not received the attention it deserved, gists of the period were completely opposed to any theory and others in the area were working against odds, I naÃ¯vely of an infectious origin of cancer, virologists were consid believed that the bitter resistance was softening and would ered the pariahs of oncological research. Work suggesting soon yield to the indisputable evidence accumulating. Cer a viral etiology for tumors was either ignored or relegated to tainly, Dr. C. P. Rhoads, then the director of Sloan-Kettering the scrap heap by derisive critics. Virchow's opinion that Institute and my boss, had not been a proponent of the viral Omnus cellula e cellula (â€œWhereacell arises, there a cell etiology of cancer, yet he encouraged and enthusiastically must previously have existedâ€•)dominated the field. Even supported my efforts. With his blessings, I packed my slides the eminent microbiologist Paul Ehrlich was convinced that and went off to Atlantic City to present my paper (38, 40). there could be no transmissible agent involved in the etiol At dinner the evening before I was to speak, I was in ogy of cancer, since he himself had repeatedly failed to formed, by a most reliable source, that there would be induce tumors with cell-free filtrates of the murine mam

2 The abbreviations used are: RSV, Rous sarcoma virus; MMTV, mouse â€˜Presentedon May 6. 1976, at the Sixty-seventh Annual Meeting of the mammary tumor virus; MuLV, murine leukemia virus; EBV, Epstein-Barr American Association for Cancer Research, Toronto, Ontario, Canada. virus; HSV, herpes simplex virus; DMSO, dimethyl sulfoxide.

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serious objections raised to the data I was to present. This Do not let this account lead you to believe that the life of was not a happy prospect for any scientist, let alone one not the viral oncologist was dismal. Common interest and dedi long out of graduate school, but at least I was prepared for a cation had drawn together a group of men and women that less than favorable reception. However, by no stretch of the could not have been more heterogeneous. We were full of imagination could the violent storm of controversy that sharp humor and excitement and felt as if we were surfers erupted after my presentation have been anticipated . A on the tide of history. Every day held a new adventure, number of you may remember the virologists in the audi especially when the old prohibitions began to relax and the ence who sprang into action to disown what I had cau attitude prevailed that it might be worthwhile to take an tiously called a â€œvirus-likeagentâ€•;it could not be a virus unjaundiced look at the tumor viruses. because it induced a frankly malignant disease. The pathol Since cancer remained among the foremost of killing ogists were equally vocal in disclaiming the disease as diseases, an increasing number of investigators were being malignant because it was obviously induced by cell-free attracted to the challenge. Armed with the technology that filtrates. To Dr. Rous, who had heard these arguments for had been developed over many years of research in various over 40 years, this did not come as a surprise. I regret that I fields of endeavor, they set out to pursue any promising do not recall the precise words he spoke in my support, for avenue that might lead to finding its cause(s) and control. his eloquence was inimitable. In essence, he said that can As the search gained momentum, the number of identified cer was the most formidable of human diseases and, in the virus-induced tumors grew. After the years of futility, it face of our abysmal ignorance of what makes a normal cell seemed as if some huge bacterium had burst, releasing begin to proliferate without restraint to form a tumor, we viruses with oncogenic potential for almost every species of should keep open minds and wait to see what further stud animal. Table 1 lists some, but by no means all, of the ies would reveal. Dr. Rous's rationality did little to cool the oncogenic viruses that have now been identified. Once the heated atmosphere, and I have never fully understood why existence of tumor viruses became fact, sights were turned my friend who chaired the session did not bring it to a close toward defining the mechanisms involved in causing an at this point. I like to imagine it was because he was sure infected cell to become malignant. that I would emerge unbowedâ€”if a little bloodiedâ€”and I The keys to open what some may liken to Pandora's box did. were forged primarily through the use of inbred mice and The next year, our colleagues were more receptive to the the techniques of tissue culture, immunology, and molecu data I presented on the effectiveness of vaccination with the lar biology. With these sensitive tools, we began to realize inactivated virus in protecting mice against the develop the astonishing complexities of the virus-host cell associa ment of leukemia (40, 41), perhaps because Dr. Jacob Furth tion. (76) stated that my findings had been confirmed in his The most important lesson that was learned was that the laboratory. behavior of tumor viruses cannot be predicted on the basis

Table 1 animalsYearRNAYearDNA1898-19501908FowlSomeoncogenic virusesof

(Sanarelli)191leukemia (Ellerman and Bang)1898Rabbit myxomatosis (Magelhaes)1933Fowl1Fowl sarcoma (Rous)1920Bovine papilloma lymphomatosis (Furth)1932Canine oral papilloma (DeMonbreun and Goodpas ture)1934Canine (Shope)ture)1936Mouselymphosarcoma(DeMonbreunand Goodpas 1932Rabbit fibroma

(Shope)1946Fowlmammarycarcinoma (Bittner)1933Rabbit papilloma lymphoid tumors (Burmesteret al.)1936 oral papilloma (Parsonsand Kidd) (LuckÃ©)1 1938RabbitFrog kidney carcinoma

950-19721951Mouse Olsen)1955Mouseleukemia(Gross)1951Equine cutaneous papilloma (Crook and (Gross)1956Mouseleukemia(Graffi)1953Mouse â€œparotidâ€•tumor al.)1959 leukemia (Friend)1953Squirrel fibroma (Kelhanet leukemia (Liebermanand Kaplan) fibroma (Shopeet al) (Durfee)1962Mouse1960MouseMouseleukemia(Moloney)1955 1956DeerFrog renal tumor Eddy)1963Mouseleukemia(Rauscher)1957Mouse polyomavirus (Stewart and al.)1964Felineleukemia(Rich)1962Human adenovirus(Trentin et al.)1966Mouseleukemia(Jarret)1962Primate SV4O(Eddyet al.)1966 osteosarcoma(Finkel)1964Human EBV (Epsteinet sarcoma(Moloney) Marek'sdiseasevirus (Churchill and Biggs) al.)19691967MouseMousesarcoma(Kirsten and Mayer)1967 1969ChickenPrimateHerpesvirussaimiri (Melendezet al.)1971Woollyleukemia(Abelsonand Rabstein) Herpesvirusateles (Melendezet 1969MouseFeline fibrosarcoma (Snyderand Theilen)1972Primate al)1972Gibbon monkey fibrosarcoma-SiSV (Theilen et apelymphosarcoma-GaLV(Kawakamieta!.)

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1977 American Association for Cancer Research. Coming of Age of Tumor Virology of what is known about â€œordinaryâ€•viruses.Frequently, certain types of adenovirus, common in human popula special conditions are necessary to demonstrate oncogenic tions, and SV4Ovirus, which is of monkey origin, are highly activity. The Bittner mammary tumor virus (MMTV) and the oncogenic when inoculated into newborn rodents. The pap Gross lymphatic leukemia virus (MuLV) each had to be illoma and polyoma viruses share this property in some introduced into newborn mice of specific inbred strains for respects. Polyoma is widely spread in the mouse popula the respective neoplasms to be produced. The age of the tions as is papilloma among wild rabbits, yet those viruses host may also be important in determining the type of dis also rarely cause malignant tumors in their natural hosts. A ease induced. RSV causes a fatal hemorrhagic disease, similar phenomenon is observed with the endogenous RNA rather than a neoplasm, when inoculated into baby chicks C-type viruses prevalent in normal animals. (28). The incubation period may be excessively long, and Finally, the tropism that is characteristic of â€˜â€˜ordinaryâ€• the disease may not manifest itself until the animals are well viruses may not be strictly adhered to by some tumor vi into middle age. The apparently normal infected mice can ruses. Stewart and Eddy showed that the polyoma virus, be viremic. The mode of transmission in nature may be isolated from parotid tumors of mice, after propagation in unsuspected. Both Bittner MMTV and Gross MuLV are tissue culture, is capable of inducing a stunning variety of transmitted from mother to offspring, the MMTV through tumors when inoculated into newborn hamsters. Among the milk and MuLV vertically through the ovum. There are a these are medullary adrenal tumors, epithelial thymic tu number of other strains of murine leukemia viruses that mors, mammary carcinomas, renal carcinomas, heman have less strict requirements for the induction of the dis giomas of the liver, and fibrosarcomas (30, 112, 113). ease. Still other factors may be involved in influencing a Ten years ago, when Shope was ill with the cancer that benign virus-induced tumor to undergo malignant changes, wasto kill him a few months later, he wrote of these â€œslyand as was demonstrated with the rabbit papilloma exposed to devious waysâ€•oftumor viruses (107). Sly and devious they carcinogenic tar (98). have remained, for the precise mechanisms by which they While it was possible to isolate these viruses once the initiate malignant alterations are still, for the most part, in prerequisites of the system were met, there are virus-in the realm of the unknown. duced tumors from which no infectious virus can be re Nevertheless, the remarkable advances that have been covered. Shope had first made this observation in his stud made have brought us to new frontiers. Let us consider es of the papilloma virus of the wild cottontail rabbit. Al some of those that will serve us well in pinpointing a puta though this virus induced morphologically identical tumors tive human tumor virus. in the cottontail and in the domestic rabbits used in the The structure and composition of many of the tumor experiments, infectious virus could be recovered only from viruses have been characterized, and their functions in the the tumors of the cottontail . He concluded that the virus had cells they transform in vitro are being defined. Many of the assumed a â€œmaskedâ€•statein the domestic rabbit tumors molecular events that occur from the moment an exoge because viral antigen was still present in them (106). A nous virus attaches to the cell are well documented, al similar observation was made on the tumors developing in though all the steps are by no means completely under young turkeys inoculated with RSV, from which no infec stood. Infection leads to complex alterations in the macro tious virus could be obtained (53). molecular synthesis of the cell, and the cell acquires new That these were not unique phenomena became clear in virus-specific antigenic determinants whether or not prog studies with the parotid tumor virus (52), subsequently eny virus is made. Molecular hybridization can be used to called polyoma (109, 112), and SV4Oviruses (29, 30, 48), for demonstrate the homology between viral and cell nucleic which the use of newborn animals was also essential to acid and to estimate how much of the viral genome is demonstrate oncogenicity. Stewart and Eddy made the incorporated into the cell. study of the replication of these DNA viruses feasible when Of prime importance to the understanding of the mecha they developed methods for culturing them. In permissive nism of RNA tumor virus infection was the discovery that cells, the virus replicates as a lytic virus (31). In cells non these viruses possess RNA-directed DNA polymerases. In permissive for viral replication, transformation occurs (126). studies on the effects of metabolic inhibitors on RSV repli The â€œCâ€•-typeRNAviruses also replicate in vitro, but they cation, compounds that affect DNA synthesis were found to are not lytic and generallydo nottransform cellsin vitro (5). block the multiplication of the virus as well as its ability to The defective RNA viruses, which are unable to synthesize transform. To account for these puzzling results, Temin their coat protein, are also unable to replicate infectious (117) suggested the possibility that the RNA genome of the virus. infecting virus was being used as a template to make DNA With these systems at hand to provide large quantities of genome, which could then be integrated as provirus into virus for characterization, the molecular biologists brought chromosomal elements. His provirus theory was received their skills into the field. The DNA-type viruses were found with skepticism until he (119) and Baltimore (7) independ to leave vital traces of their presence in the tumors they ently isolated reverse transcriptases and theory became induced and the cells they transformed in vitro, since virus fact. The template for the synthesis of viral DNA is the 60 to DNA sequences were incorporated into the genome of the 70 S RNA component of the virus. These RNA-dependent infected cells (103, 130). The genome of the RNA viruses DNA polymerases have provided a valuable means of prob can also find its way into the host cell DNA (5). ing cells for evidence of tumor virus infection. It was for this Another property of tumor viruses that makes them so fundamental work that Temin and Baltimore were awarded elusive is that they may be oncogenic only in hosts other the 1975 Nobel Prize. than the one from which they were isolated. For instance, Another unexpected finding, the significance of which is

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1977 American Association for Cancer Research. C. Friend yet to be realized, is that C-type virus genetic information is sified into subgroups based on host range, patterns of viral present in almost all normal animals studied. Progeny virus interference, and the antigenicity of the virus particle, prop can be induced in cells exposed to 5-bromo-2'-deoxyuridine erties determined by the envelope glycoprotein of the virus (4, 72) in a way similar to that in which temperate phage is (126). The genetic control ofsusceptibility and resistance to activated in lysogenic bacteria. Some cells harbor genetic the murine viruses is exerted mainly by 2 genes, the FV-1 determinants for more than one type of endogenous virus, and the FV-2, which determine whether or not the cells will and these have been distinguished by their ability to grow in permit viral replication (71). The H-2, Tla, and G,@loci, different cells, the mouse-tropic viruses in cells of the same which are involved in determining the cell surface antigens, species and the xenotropic ones in cells of foreign hosts exert an influence on endogenous viral leukemogenesis, (69, 70). In general, these viruses do not appear to be particularly on the development of lymphoid neoplasms pathogenic (3). The mechanisms that control the repression (15). The G,@locus in the mouse is of particular interest or the expression of such endogenous viral information since it carries the virus-activating genes of the AKR ge remain an intriguing problem, especially in view of the nome, AKV-1 and AKV-2, which are necessary for the pro possibility that phenotypic mixing or genetic recombination duction of complete virus (114). Evidence for the inherit with exogenous viruses may occur (110). Circulating anti ance of the virus genome comes from studies on crosses bodies to these endogenous C-type viruses found in appar between high-virus-yielding and nonvirus-yielding mouse ently normal animals bind to both mouse-tropic and xeno strains (1, 99, 100, 101, 109, 116). The capacity to produce tropic viruses, but only the antibody against the xenotropic virus segregates according to Mendelian prediction and the variant neutralizes (2). While the exogenous MuLV's have number of loci for infective virus varies in mouse strains an immunosuppressive effect (18), the mice harboring the according to whether they are low or high virus yielding. endogenous viruses are immunologically competent (82). The high-ieukemic strains, which have a larger number of Two theories have been proposed to explain the origin of virus-inducing loci, also have a larger number of complete the RNA tumor viruses. The oncogene theory of Huebner sequences of viral DNA than do the low-leukemic strains. In and Todaro (59) suggests that all cells contain in their DNA a series of elegant experiments, mice partially congenic for the information necessary to specify the complete genome the AKV-1 gene have been developed by breeding the AKR of the virus, and this is passed vertically through the cell chromosomal segment carrying this locus into the low genome. A part of the viral genome contains oncogenic leukemic NIH Swiss mouse background. Such hybrid mice information that, when expressed , leads to the development have about one-half the number of complete viral genome of cancers. Temin's theory (120) differs in that it proposes sequences that are found in the high-virus-yielding parent that the continual transfers of endogenous and exogenous strain, indicating that the chromosomal loci are viral ge information by transcription and reverse transcription, as nomes (20). well as through genetic accidents, are contributing factors Advantage has also been taken of the antigenic properties in viral carcinogenesis. of the structural proteins that are distinguishing features of Evidence to support the possibility that the ANA viruses the RNA viruses to investigate immunological responses may have evolved from normal cellular components stems (14). The glycoprotein antigen gp69/71 is associated with from studies indicating that there is some degree of homol the viral envelope. It is expressed on the surface of infected ogy between tumor virus and normal host cell DNA (8, 55, cells, whether or not they are transformed or synthesizing 80). The relationship between the different RNA viruses virus. Antiserum to it may neutralize viral infectivity. The appears to reflect the relationship among the cellular com major viral envelope glycoprotein and the smaller sized core ponents from which the viruses evolved (10, 102, 118). proteins (p30, p15, p12) have been extensively studied, and Recent data demonstrate that the DNA from normal chick all show varying degrees of type, group, and interspecies ens contains nucleic acid sequences closely related to a specificity. Cell surface determinants resembling gp69/71 portion of the transforming gene sequence of the avian have also been detected on apparently normal cells (23, 24). sarcoma virus (108). Complementary DNA prepared from The antigenic markers in viral-induced tumors, whether this small â€œsarcâ€•sequenceof about 1600 nucleotides hy they arise in the natural or in different hosts, are specific bridized to the DNA from a variety of other avian species. and are directly attributable to the infecting virus. This is in The extent of the homology indicated a divergence of the contrast to the carcinogen-induced antigens. A given chem sarc sequences that paralleled speciation. All the normal ical carcinogen induces tumors that may be antigenically avian cells examined had the sarc sequence preserved but distinct even in syngeneic hosts (87). Do these differences were lacking the portion neededfor replication. Thus, evo in antigenic responses imply that chemical carcinogens lutionary events may now be traced by following footprints may modify genetic material at a number of different sites, left by viruses that have acquired the ability to induce neo whereas the tumor viruses cause changes only at a limited plastic diseases. number of chromosomal sites? Considerable progress has also been made in the area of While we have only begun to fathom the complex mecha genetics, particularly in the analysis of the C-type RNA nism that controls oncogenic expression, we have come a tumor viruses. As you recall, these viruses can be transmit long way in a relatively short time. The animal systems have ted horizontally from animal to animal, congenitally through been unbelievably rich in the amount of information they the mother, or vertically through either parent in whose have reluctantly yielded. They do provide reasonable coun genome the viral information is integrated. terparts for some human cancers, particularly leukemia, The avian sarcoma and leukemia viruses have been clas lymphomatous diseases, sarcoma, and mammary carci

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1977 American Association for Cancer Research. Coming of Age of Tumor Virology noma. Although no human oncogenic viruses have been 1 and HSV-2, after inactivation by irradiation to prevent definitively identified so far, we have become much better cytolytic activity, transform cells that produce highly malig equipped for the pursuit of such putative culprits. nant carcinomas when inoculated into hamsters (90). EBV, Fertile fields for the search might very well be found in which is the chief suspect in the cause of two human neo cancer patients in whom second neoplasms arise after plasms, transforms cells in culture and is oncogenic in chemotherapy and in organ transplant recipients who de animals (33). The human papovaviruses are also of great velop cancers after immunosuppressive treatment (17). In interest. The JC strains have been recovered from the brain Penn's series of such patients (85), the striking feature was cells of patients with progressive multifocal leukoencepha the high incidence of leukemia and lymphoid neoplasms lopathy and appear to be closely related to SV4O (84, 128, that suggests viral involvement. Years ago, Dr. Rhoads fre 129). The BK strains isolated from the urine of immunosup quently pointed out the paradox that â€œeverycureis a cause pressed kidney transplant patients (47), malignantly trans and every cause is a cure.â€•Thus, the problem of whether form hamster fibroblasts (73). the effective chemotherapeutic agents cause as well as cure If what we have learned from the study of tumor viruses in cancers deserves more attention . These agents may have a animals is relevant to the behavior of a putative tumor virus modulating effect on endogenous viruses, inducing them to in humansâ€”and we have no reason to doubt that it will not express oncogenicity. beâ€”thenthere are many obstacles to overcome before vi Currently, several human viruses are being investigated in ruses can be assigned a definitive role in the causation of the light of the knowledge and sophisticated technologies human cancer. Early infection, genetic susceptibility, and that continue to emerge from the studies on the avian and route of transmission were among the critical factors neces murine tumor viruses. Since the RNA viruses have given rise sary to demonstrate viral transmission of malignant disease to cancers in so many species, the possibility that they may in the animals. For obvious reasons, it is not possible to be associated with human neoplasms cannot be excluded. carry out such studies in humans. Therefore, we must rely The 70 5 RNA and reverse transcriptase activity, with prop on the epidemiology and natural history of infection with erties similar to those of the animal viruses, have been the suspected virus, and it will take at least a generation to detected in the cells of various human neoplasms (9). Mo carry out such encompassing studies. A major effort is Iecular hybridization experiments demonstrated that the under way to define the precise role of EBV in just such a homology between the DNA of the viruses causing Ieu manner (25, 58, 66, 132). This virus, which is associated kemia, sarcoma, and mammary tumor to the RNA of the with two malignant diseases, Burkitt's lymphoma and naso cells of human cancers of the same cell type is specific. pharyngeal carcinoma, causes the benign self-limiting dis For instance, human leukemic cell RNA has sequences ease, infectious mononucleosis. Epidemiological data point homologous to those of Rauscher MuLV DNA but not to to the influence of environmental factors on Burkitt's lym those of the DNA of MMTV (57). phoma, and of genetic factors on nasopharyngeal carci C-type RNA viruses (44, 45) detected in cultures of human noma, in the expression of the disease. Infection is wide leukemia have been shown to be related to primate C-type spread since antibodies to the virus are found in a high viruses (19, 46, 83). While the question that these cultures percentage of the general population. High-risk normal in may have been accidentally contaminated with the primate dividuals in certain parts of East Africa, where the disease is viruses remains to be resolved, recent studies show Se endemic, have elevated antibody levels and, as is character quences closely related to baboon endogenous viruses in istic for an oncogenic virus, several genome equivalents of the DNA of the cells of a number of other patients with EBV DNA are found in the tumor cells of the affected mdi myelogenous leukemia (131). Such sequences have not as viduals. Although the complete virus is not synthesized in yet been found in normal tissues, and the possibility that these cells, an EBV-associated nuclear antigen is ex they represent baboon endogenous virus provirus is under pressed. In the laboratory, EBV has proven to be oncogenic investigation. in primatesand iscapableoftransforming normal human B- A relationship between some membrane-associated anti lymphoid cells so that they have the capacity for unlimited gens of human myeloid leukemia cells and the virion mole growth. cules from the murine leukemia virus of which I am the The parallels to the animal systems are striking, for EBV eponym has also been detected (78). Cells from patients has the deviousness we have come to associate with the. with chronic granulocytic and acute myelocytic leukemia animal tumor viruses (Table 2). It appears to be oncogenic contain a number of membrane antigens that cross-react under special environmental or genetic conditions. It is with purified Friend leukemia virus structural molecules, latent for varying lengths of time, is widespread, and most gp7l and p30. A suspect RNA virus isolated from cultures of frequently causes a benign rather than a malignant disease. a human mammary tumor is also under study (74). It is oncogenic in other hosts. No infectious virus can be In keeping with what was learned from the animal models, the DNA candidate viruses receiving attention are those to Table 2 which the general population has been exposed, such as â€œSlyanddevious waysâ€•of tumor viruses. . . . Richard Shope adenovirus, HSV, and EBV. The adenoviruses have so far 1. Special conditions necessary to demonstrate oncogenicity 2. Latent for long periods of time not been found in association with human tumors, although 3. Widespreadbut inapparent infection in natural host some types are oncogenic in hamsters. Serological and 4. Oncogenic in foreign host epidemiological evidence has, however, linked herpes vi 5. Infectious virus may not be present in tumors ruses to cervical carcinoma (65). Experimentally, both HSV 6. One virus may attack different target cells

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1977 American Association for Cancer Research. C. Friend recovered from the tumors that contain the EBV DNA, and, whattomake,whattobe,andwhen todie.Whatthenature finally, its interaction with cells of either lymphoid or epithe of the signal is, how it is generated, and how the cell hal origin may lead to malignant growth. processes this information are parts of the puzzle yet to be â€œTheforcesin nature are hidden when they assist each solved. The viruses we have considered have the ability to other or remain inactive. They are combined in a compro jam the programmer so that the information needed for the mise with one another and, in the rare instance where this cell to proceed to terminal differentiation does not come compromise is disrupted, cancer results.â€•(I would be through. The cell without direction remains at a primitive happy to acknowledge the source of this statement if some level and keeps multiplying. Why tumors in species ranging one can supply this information.) Evidence of the compro from plants (16) to human beings (34) sometimes sponta mise and of hidden forces infrequently revealed may be neously regress or lose their malignant properties is an found in the association with their hosts of viruses such as unanswered question, but it gives us hope that the signal polyoma, herpes, or the endogenous C-type. These viruses, system can be reactivated or repaired . Could the removal of which are widely spread, are rarely oncogenic. At the Gor the block to differentiation and the return to the steady state don Conference some years ago, Martin Apple titled one of be attributed to the reconciliation between a virus and the our sessions, â€œDoesCancerCause Viruses?â€•We were at host cell? tempting to resolve the question: Is it only an accident that As we probe further, we may find that tumor viruses causesavirustoturnagainstthecell,orisitthecellâ€”whichexpress oncogenicity only when the equilibrium of the host does control some viral functionâ€”that turns against the is disturbed. Perhaps, in the steady state, they will turn out virus? to have some function in embryogenesis and differentia There are many factors that could predispose toward the tion. catastrophic break-up of a hypothetical benign relationship A system for the study of the expression of normal func between virus and host cell. Among them might be the tion in virus-induced neoplastic cells became available entrance of intruding agents. A number of instances can be when we observed that murine virus-induced erythroleu cited to support this possibility. Cells transformed by SV4O kemic cells established in culture can be shifted to differen frequently show increased susceptibility to transformation tiate at will (42). When DMSO is added to the medium, the by polyoma or adenoviruses. One virus might modulate the cells are stimulated to mature along the erythroid pathway, effect of another, causing the expression of oncogenicity. synthesize adult hemoglobin of the same type as the host For instance, AKR lymphomas yielded filtrates with no on from which the leukemic cells were taken, and regain some cogenic activity regained it when the lymphoma cells were of the functions of their normal counterparts (43, 61, 91, cocultivated with NIH 3T3 cells from which they apparently 94). In culture, the block in differentiation is partially lifted, picked up endogenous virus information (127). Whether the allowing the cells to proceed to the level of normoblast. tumor cells recovered oncogenicity as a result of genetic These erythroleukemic cells are now widely used as a model recombination, which is known to occur, or because they to study the mechanisms controlling normal differentiation contained two types of virus acting in concert, is as yet of erythroid cells (56), although we have yet to find a means unclear. On the other hand, interaction between RNA and of directing the process further to the final mature enu DNA viruses often results in enhanced pathogenicity (37). cleate erythrocyte stage. Another intriguing property of the For instance, AKR lymphomas that yielded filtrates with no chronically infected DMSO-treated cells is their decreased oncogenic activity regained it when the lymphoma cells malignancy and enhanced virus production, for this mdi were cocultivated with NIH 3T3 cells from which they appar cates that cells actively synthesizing C-type particles are not ently picked up endogenous virus information (127). Whether necessarily malignant (42). Although the mechanism by the tumor cells recovered oncogenicity as a result of genetic which DMSO acts on the erythroleukemic cells remains transformed by DNA tumor viruses assume the transformed unclear, since various other polar solvents (88, 115), as well genotype after they have been superinfected with RNA tu as a number of structurally unrelated compounds (11, 12, mor viruses, which do not have the capacity to transform 54, 68, 95), have recently been found to stimulate these the cells on their own (92). Cells from individuals with a high erythroleukemic cells to differentiate, what is of interest is risk of developing cancer, such as those with trisomy or the demonstration that virus proliferation and cell differen Fanconi's anemia, are more susceptible to transformation tiation need not be mutually exclusive events. by SV4Ovirus than are the cells from normal persons, possi More and more data are accumulating to indicate that the bly because they may be carrying virus information (121, communication system in the malignant cell, whether virus 122). Of even greater significance in terms of herpesviruses induced or of still unknown etiology, can be restored , allow and their possible causal association to human cancers is ing the signal leading to terminal differentiation to be re that they may activate the synthesis of endogenous C-type ceived (21, 35, 36, 49, 50, 60, 67, 77, 81, 124). There are viruses, xenotropic as well as mouse tropic (27). Thus, the instances of virus-transformed cells that phenotypically re presence of a given virus may be insufficient to bring about vert to normal (6, 64, 89, 104, 123), although the revertant malignant changes. It may take a combination of events to cells may sometimes retain the viral gs antigen of the trans set the virus on its hostile path. formed cells (111). The amphibian system offers still an The normal cell maintains its steady state as long as it other example. If the nuclei of the virus-induced frog renal follows the program that determines its destiny. With exqui adenocarcinoma are implanted into enucleate frog eggs, site precision, it goes through a finite number of divisions they are able to program normal tadpole development (75). as it matures, responding to signals that tell it what to do, The most striking evidence for the reversibility of the malig

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1977 American Association for Cancer Research. Coming of Age of Tumor Virology nant state comes from the recent studies of Illmensee and cardiovascular and pulmonary diseases, which clearly dem Mintz (62, 79). Normal healthy mice developed from blasto onstrates that basic research, i.e., investigation not clini cysts implanted with malignant teratocarcinoma core cells cally oriented when initiated , pays off in terms of key dis that had been transferred to surrogate mothers. Genotype coveries that subsequently prove to be important in clinical analysis indicated that these mosaic mice had a wide array advances almost twice as much as other types of research of tissuesthat were carcinoma derived. Since someanimals and development combined (22). were obtained from single-cell injections, the tumor cells Oncogenicity, which is expressed relatively infrequently evidently retained a full range of developmental potentiali under special circumstances, may merely be a reflection of ties. In an appropriate environment, it is possible for normal a more general phenomenon that takes place during differ gene expression to be restored. entiation. In exploring the mechanisms controlling viral We should also give some thought to the fact that infec function , we have unexpectedLy taken some steps forward tion per se does not always endanger the host. There are in understanding the nature of cell function. With time, various instances in which the compromise between infect these pieces of new information will fall into place and ing agent and host can be beneficial. The beauty of the inevitably will lead to measures for the prevention and con variegated color of tulips is virus induced (26), and the trol of this dread disease. benefits derived from the symbiotic relationship between As we in the United States celebrate our bicentennial, let legumes and their root nodule bacteria and between algae us recall that in 1780 Benjamin Franklin expressed his con and fungi are well known. Whether the endogenous expres fidence in our intellectual ability to uncover the secrets of sion of gp69/70 in normal cells implies a similar symbiotic nature. He looked forward with hope to the day when â€œall compromise remains to be determined. Although the corn diseases may by sure means be prevented or cured.â€•May position of the glycoprotein from normal cells differs some that day for cancer be not far off. what from that of the tumor virus coat, they do cross-react immunologically (23). 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MAY 1977 1263

Charlotte Friend

Cancer Res 1977;37:1255-1263.

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