Viral Etiology of Cancer and Leukemia: a Look Into the Past, Present, and Future-G

[CANCER RESEARCH 38. 485-493. March 1978]

Viral Etiology of Cancer and Leukemia: A Look into the Past, Present, and Future-G. H. A. Clowes Memorial Lecture1 2

Ludwik Gross

Cancer Research Unit, Veterans Administration Hospital, Bronx, New York 10468

leukemias during the first few decades of this century, and no serious consideration was given to suspect viruses as the leading cause of cancer. Furthermore, the common observations of familial incidence of cancer and leukemia in many animal species and in man did not appear consist ent with a concept of the viral etiology of cancer, but rather suggested to many investigators an inherited familial dyscrasia or "tendency." The fact that tumors and leukemia could be induced in animals and also in man by chronic irritation, by radiation energy, by certain hormones or by a variety of carcinogenic chemicals did not support a concept of the infectious origin of malignant tumors. Such observations rather appeared to suggest that cancer and leukemia are caused by a variety of etiological factors, an assumption that somehow, miraculously, has survived in the minds of many investigators as well as pathologists and clinicians even up to the present time (44). The experimental tools employed in cancer research and general virology were very limited during the first half of our century. It should also be stressed at this point that in those early years the term "virus" was not very well defined. It was assumed that it was a very small, transmissible disease-inducing entity, but many investigators confused viruses with small bacteria or other infectious agents. The electron microscope was not yet in use and no other tools were available to deal with the detection of submicroscopic infectious agents. Inbred strains of mice, tissue culture technique, or currently employed sophisticated immunological tests were not yet on hand. The basic test employed in many leading laboratories, serving to determine whether or not an obscure disease is caused by a virus, was an attempt to transmit such a disease by inoculation of filtered extracts prepared from diseased tissues. If the disease was transmissible by filtrates, it was assumed that it was caused by a virus. And yet, one immediately realizes the many It has long been suspected that cancer and leukemia are pitfalls incident to such a crucial test; it is obvious that caused by transmissible viruses; theories on viral etiology many diseases caused by viruses cannot be transmitted by cell-free extracts unless certain definite experimental con of malignant tumors have been advanced and then aban doned during the early years of cancer research. Actually, ditions are met. it is very difficult to suspect the infectious origin of an In spite of these almost insurmountable difficulties with obscure disease if the contagious nature of the disease is which the investigator was confronted in his attempts to not apparent, if an infectious agent cannot be detected by reveal the etiology of cancer and leukemia, very gradually microscopic or electron microscopic examination of the progress has been made in the search for the causative diseased tissue, and if the disease cannot be transmitted factors. The first break came with the discovery made in experimentally by inoculation. These fundamental condi 1908 by Ellermann and Bang (22) in Copenhagen; they transmitted chicken leukemia by cell-free, filtered extracts tions could not be met for the great majority of tumors and and demonstrated thereby the viral etiology of this disease. 1 Presented at the 1977 Meeting of the American Association for Cancer A few years later, in 1911, Peyton Rous (71), in New York, Research, in Denver. Colo. transmitted a solid tumor, chicken sarcoma, by filtrates. 2 This work is supported, in part, by the Virus Cancer Program of the Within the next 20 years, a variety of warts and papillomas National Cancer Institute. Received November 18, 1977; accepted November 29, 1977. in different animal species, such as dogs, cattle, rabbits,

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including the Shope rabbit papilloma (74), and in humans confirmed experimentally, I looked for an animal model were added to this very slowly growing list of tumors having a relatively short life span and which developed in transmissible by filtrates (for references, see Ref. 44). In each successive generation a high incidence of tumors, 1934, Baldwin LÃ¼cke (54) observed that the frog kidney known not to be transmitted through milk. It occurred to carcinoma, prevalent in frogs (nana p/'p/ensi in New Eng me that mouse leukemia would be an ideal experimental land lakes, could be transmitted by lyophilized cell-free model for my project (3). Two inbred families of mice, the extracts; on the basis of these experiments, LÃ¼ckecon Ak (25) and C58 strains, were known to have an incidence cluded that frog kidney carcinoma is caused by a virus. of spontaneous leukemia exceeding 90% (for references, Two years later, in 1936, Bittner (6) reported that mouse see Ref. 44). Previous attempts to transmit Ak or C58 mammary carcinoma is transmitted by "an influence" leukemia by filtrates had failed, and for that reason no through the milk from mothers to their offspring; this serious thought was given to viral etiology of mouse leuke "influence" was later identified as a filterable virus. mia; it appeared much simpler to all leading cancer investi Development of the Concept of "Vertical Transmission" gators to explain the familial incidence of spontaneous of Oncogenic Viruses mouse leukemia in genetic terms (44). I was convinced, however, that mouse leukemia, like leukemia in chickens, Since my early years in postgraduate medical studies, I is actually caused by a virus and that the occurrence of have almost intuitively suspected that malignant tumors that disease in successive generations of mice is due to the are caused by transmissible viruses; this appeared to me transmission of the hypothetical virus from parents to the most logical explanation of the etiology of cancer and offspring (3, 39, 40, 46). I theorized that the virus is trans leukemia (3). However, how to determine whether such a mitted through the embryos. My initial plan was to transmit hypothesis was correct? If there is a cancer virus, it must leukemia in mice by filtered extracts prepared from organs be transmitted in nature from host to host, because all of leukemic Ak or C58 mice, using for bioassay mice of virus-caused diseases are transmissible. And yet, experi another inbred line essentially free from leukemia, such as ence teaches us that tumors and lymphomas are not con the C3H, and to demonstrate thereby that mouse leukemia tagious and are apparently not transmitted in a manner is caused by a virus. The second step would consist of an similar to that observed in other common infectious dis attempt to demonstrate the presence of such a virus in eases. So, where was the explanation? It has long been normal embryos removed from healthy Ak or C58 females. I known that tumors and lymphosarcomas are more frequent theorized that if the virus is present in Ak or C58 embryos, in members of certain families in animal species and in then extracts prepared from minced normal embryos re man than in the general population (44). However, certain moved from pregnant Ak or C58 females should also be reports of familial incidence of tumors are particularly able to induce leukemia when inoculated into C3H mice. striking. One day, when I was reading about the familial Initial Failures and Then Success: Transmission of Mouse incidence of retinoblastoma, a very rare malignant tumor Leukemia by Filtrates and Demonstration of Presence of of the eye in humans, I was very much impressed to learn the Virus in Ak Embryos that this tumor may occur in several members of successive generations in certain families, in a grandfather, father, The first few years did not bring the expected results, uncle, and nephew, for example, but that it is exceedingly since I used adult C3H mice for bioassay. After I learned, rare in the general population (83). Suddenly the thought however, unexpectedly at a medical lecture given by G. came to my mind that a hypothetical virus responsible for Dalldorf, that Coxsackie viruses had to be inoculated into this disease is simply transmitted from one generation to mice less than 48 hr old in order to induce paralytic symp another in certain susceptible families (3). The fundamental toms of disease (13), I proceeded immediately with new observation made by Bittner (6), who demonstrated the plans to use newborn C3H mice for the inoculation of fil transmission of the mouse mammary carcinoma through tered extracts prepared from organs of leukemic Ak or C58 the milk from mothers to offspring, represented the first mice or cell-free extracts prepared from minced Ak (36) or experimental and documented example of natural transmis C58 (40) embryos. This renewed attempt was successful sion of a tumor-inducing virus from one generation to and led to the isolation of the mouse leukemia virus (37) another. I wondered whether a similar pattern of natural, and also to the demonstration that the virus is present in generation-to-generation transmission of other oncogenic embryos of healthy Ak or C58 females, which are natural viruses may also exist in nature. Familial incidence of carriers of the mouse leukemia virus (36, 40). tumors developing in successive generations is not limited These experiments demonstrated for the first time that only to mice, but has been observed also in chickens, mouse leukemia is caused by a virus. They also demon dogs, fish, and humans. The hypothetical virus would have strated that the virus is transmitted in its latent form through to be transmitted, at least in some of the species, by means the embryos. This was the first demonstration that not other than milk. It appeared logical to assume that at least only in chickens but also in mammals leukemia may be some of the oncogenic viruses are transmitted from one caused by a transmissible virus (37, 39). The puzzling phenomenon of the development of "spontaneous" leuke generation to another directly through the embryos, pre sumably through the germinal cells (39, 40, 46). mia in successive generations of mice of certain inbred lines, such as Ak or C58, previously explained by compli The Search for an Experimental Animal Model and Prelim inary Plans cated genetic theories, found its simple and logical expla nation as soon as it was demonstrated that the mouse In order to determine whether this concept could be leukemia virus is transmitted in a latent form from one

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1978 American Association for Cancer Research. Viral Etiology oÃCancer and Leukemia generation to another directly through the embryos, pre Radiation-induced Leukemia Also Caused by a Virus sumably through the germinal cells (39, 40). There was considerable reluctance and often even frank Normal, healthy mice of certain inbred lines, such as hostility on the part of leading investigators to accept, as C3Hf or C57BL, in which spontaneous leukemia occurs facts, these new and fundamental observations (3, 44). only very occasionally, develop a high incidence of leuke mia following repeated, fractionated total-body X-ray irra Confirmation of these early results was delayed because of diation; the fact that radiation-induced leukemia is caused difficulties in transmitting mouse leukemia by filtrates in other laboratories. The relatively low content of infectious by a virus was demonstrated when the causative virus was virus particles in organs of mice developing leukemia spon recovered from organs of mice in which leukemia was induced by X-ray irradiation (42) and when this virus was taneously and serving as donors for the preparation of extracts was probably responsible for this difficulty. As passed serially in newborn mice, inducing leukemia in the soon, however, as I was able to develop a potent, serially inoculated animals (43). passaged, "fixed" virus strain ("Passage A"), the transmis Isolation of the Polyoma Virus sion of mouse leukemia by filtrates, using newborn or suckling mice for inoculation, became a routine and readily When filtered extracts prepared from organs of leukemic reproducible procedure (41). Ak mice were inoculated into newborn mice of the C3H The mouse leukemia virus is consistently pathogenic inbred line, some of the inoculated mice, instead of leuke when inoculated into suckling mice or rats in up to 10 5 mia, developed either unilateral or bilateral tumors on their dilutions; it induces all forms of leukemias and malignant necks. On dissection, these tumors had a characteristic lymphomas in both animal species (44). appearance of grape-like clusters, consisting of innumera Electron microscopic studies (2, 16) revealed that the ble small, shiny tumor nodules. Microscopic sections of mouse leukemia virus is a spherical particle, about 100 nm these tumors revealed that they were multicentric adeno- in diameter, surrounded by a thin external membrane; the carcinomas of the salivary glands, particularly of the parotid mature particle contains centrally located, round, electron- glands (38). In addition to the salivary gland tumors, some dense nucleoid, separated by a clear circular zone from of these mice also developed other tumors, such as sub the external envelope. The virus particle was classified by cutaneous sarcomas, mammary gland carcinomas, etc. Wilhelm Bernhard (2) as "type C," a term now frequently It soon became apparent that extracts prepared from employed for designation of a variety of oncogenic virus leukemic mouse organs contained two distinct oncogenic particles of similar morphology. viruses. Following centrifugation of leukemic organ ex tracts at high speed, their leukemogenic potency was sedi- "Vertical Transmission" of the Mouse Leukemia Virus mented. Furthermore, when leukemic mouse extracts were heated in a water bath at 63Â°for30 min, their leukemogenic One of the most important new observations was the potency was inactivated; however, such extracts still re demonstration that the mouse leukemia virus is present in tained their ability to induce salivary gland tumors. The apparently normal embryos carried by young, healthy, preg separation of these two viruses was based on differences nant females of the Ak or C58 inbred lines. It became in their size and in their sensitivity to heat (38). At that time apparent, therefore, that a mouse born to Ak or C58 parents this new oncogenic virus was designated in our laboratory already carries at birth the seeds of the latent disease. "the parotid tumor virus" because, when inoculated into Later in the life of the carrier host, the virus, triggered by newborn C3H mice, it consistently induced multicentric some obscure factors, becomes activated, causing the parotid gland tumors. Stewart, Eddy, and their coworkers development of leukemia and killing its host. Frequently, (78) inoculated mouse embryo cells, in tissue culture, with however, the activation of the virus may not occur during extracts from Ak leukemic mouse organs. Fluid harvested the life span of the carrier host and the host may remain in from such cultures induced parotid and other salivary gland good health, even though it carries the virus and transmits tumors, as well as a variety of other neoplasms, following it to its progeny. In some instances the activation of the inoculation into newborn C3H mice. This pathogenic agent virus may occur occasionally, perhaps in one or two hosts was identical with the parotid tumor virus originally isolated every few generations. Thus, the virus may pass through in our laboratory (38, 44). However, the virus harvested several successive generations without causing symptoms from tissue cultures had a higher oncogenic potential. of disease (39). Since other forms of cancer have also been Eddy, Stewart, and their coworkers described the high observed to develop naturally in successive generations of oncogenic potential of the tissue-culture-grown virus, as mice and other animal species, it was conceivable to well as its ability to induce tumors following inoculation assume, as a working hypothesis, that not only leukemia into newborn hamsters (21) or rats (20). They suggested and lymphomas but also other tumors are caused by latent the name polyoma virus (19) for this pathogenic agent. oncogenic viruses transmitted from one generation to an other. In order to describe graphically the transmission of The Turn of the Tide oncogenic viruses from one generation to another, I sug gested that this form of transmission be designated "verti The introduction in 1951 of the newborn mouse as a cal transmission" (37, 39), as opposed to "horizontal trans basic experimental tool for the detection, by bioassay, of mission" of contagious pathogenic agents, such as those the oncogenic potential of the mouse leukemia virus soon causing typhoid fever or measles, which spread rapidly served as an initial guide, followed shortly by the introduc from one host to another within the same generation. tion of newborn animals of other species, such as rats,

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1978 American Association for Cancer Research. L. Gross hamsters, and cats, for similar bioassay studies. Shortly ence of virus particles in human tumors and human leuke thereafter, cat leukemia was also found to be caused by a mias and in transmitting such tumors by inoculation. We virus, when cell-free extracts prepared from leukemic cats do not quite understand why certain tumors and leukemias, were inoculated into newborn kittens and induced lympho- such as mammary tumors in mice or leukemia in mice, sarcomas (49). Under certain conditions, cat leukemia chickens, and cats, contain virus particles and can be could also be transmitted to dogs when the cat leukemia readily transmitted by filtered extracts to other hosts, virus was inoculated into dog embryos in utero (70). In cat whereas similar tumors and lymphomas developing in cer leukemia, typical C-type virus particles could be found in tain other species, such as rats or dogs, and particularly in leukemic cat organs and also in blood of leukemic cats, humans, do not seem to contain virus particles. However, particularly in the platelets (51). Another malignant cat we have learned that virus particles may appear in some tumor, a fibrosarcoma, could be transmitted by cell-free tumors only under certain conditions; as an example, no extracts to cats (77), dogs (29), and marmoset monkeys virus particles were found in bovine lymphosarcoma until (14). Very soon a variety of tumors and leukemias in several the leukemic cells were placed in short-term tissue culture animal species were found to be caused by filterable vi by Miller and her coworkers (61). Virus particles of the ruses, transmissible by inoculation to newborn hosts. The herpes group can be found without difficulty in LÃ¼cke SV40 (simian virus), latent and harmless for its rhesus kidney carcinomas obtained from frogs collected in cold monkey carrier host, induced progressively growing sarco water and particularly from frogs hibernating for one month mas following inoculation into newborn hamsters (18, 34) or longer, whereas tumors collected in late summer and or Mastomys (44). In recent studies, Diamandopoulos dem autumn do not reveal the presence of virus particles on elec onstrated that under certain experimental conditions the tron microscopic examination. The virus particles persist SV40 virus can also induce leukemias and lymphosarcomas for at least 52 days after the emergence of frogs from the (15). When 21- to 22-day-old Syrian hamsters were inocu frozen lakes (58). To give another example, it was difficult lated i.v. with the SV40 virus, about 70% of the inoculated in the early studies to find virus particles in salivary gland animals developed lymphocytic leukemia, lymphosarco tumors induced in newborn mice with the polyoma virus. mas, or reticulum cell sarcomas. However, Bernhard (1), Dmochowski (17) and their associ The adenoviruses are common in humans and several ates were able to find, without difficulty, virus particles animal species. They may cause no symptoms of illness or when they examined in the electron microscope mouse may cause a transient, inflammatory disease. However, embryo cells, inoculated with the polyoma virus, grown in when certain types of human or animal adenoviruses were tissue culture. Howatson and Almeida (47) injected polyoma injected into newborn hamsters, rats, or Mastomys, they virus into newborn hamsters and found virus particles in induced in some of the inoculated animals progressively the kidneys after 5 to 7 days, i.e., 2 or 3 weeks before the growing sarcomas (81). formation of tumors. After the kidney sarcomas had devel A mouse osteosarcoma was found by Finkel and her co- oped, no virus particles could be found in the tumor cells. workers (24) to be caused by a filterable virus which was Sarcomas induced in hamsters or rats with the polyoma transmissible and reproduced osteosarcomas following in virus, the SV40 virus, or adenoviruses do not usually reveal oculation into newborn mice. The remarkable familial inci the presence of virus particles on electron microscopic dence of lymphosarcoma in certain families of cattle found examination (for references, see Ref. 44). Thus, the fact its logical explanation when virus particles were found in that a tumor does not contain virus particles when exam bovine lymphosarcoma cells following short-term tissue ined in the electron microscope does not necessarily imply culture (61). that such a tumor was not induced by an oncogenic virus. Melendez and his colleagues (59) demonstrated that Herpesvirus saimirÃ, a DNA virus indigenous in the New Difficulties in Transmitting Certain Tumors by Filtered World squirrel monkey, may induce lymphosarcoma or Extracts leukemia when inoculated into owl monkeys or marmoset monkeys. C-type virus particles, very similar to those ob It is frequently very difficult or practically impossible to transmit virus-induced tumors from one host to another by served in sarcomas and leukemias in mice and chickens, means of filtrates. Certain experimental conditions may be were found in a spontaneous fibrosarcoma in a woolly required in order to succeed. Thus, mouse leukemia could monkey (80) and also in lymphosarcomas in gibbons (50, not be transmitted by filtered extracts when adult animals 76) and baboons (52). The lymphosarcoma in gibbons, reported by Kawakami and his colleagues (50), could also were used for inoculation; transmission succeeded only be transmitted by filtrates. when newborn mice were inoculated. Similarly, the poly At this point it became quite apparent that the majority of oma virus induced tumors when inoculated into newborn mice, but not when injected into adult animals. Extracts tumors and leukemias in many animal species are caused prepared from sarcomas induced with the SV40 virus or by oncogenic viruses. The main question remained to be with adenoviruses in most instances do not induce tumors answered whether human tumors and human lymphomas on inoculation, whereas the SV40 virus or the adenoviruses, are also caused by viruses (45). grown in tissue culture, induce sarcomas when inoculated Difficulties in Finding Virus Particles in Certain Malignant into newborn rats or hamsters (44). In some instances Tumors and Leukemias oncogenic viruses recovered from one species are onco genic when inoculated into another species. Thus, attempts There have been difficulties in demonstrating the pres to transmit bovine lymphosarcoma to newborn calves by

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1978 American Association for Cancer Research. Viral Etiology of Cancer and Leukemia inoculation of cell-free extracts failed initially, possibly, to (4, 5), the first vaccine in our approach to the control of some extent at least, because not sufficient time was cancer and related neoplastic diseases. There now exist allowed to elapse between the inoculation and the termina essentially two types of vaccines against chicken neurolym tion of the experiment, a common reason for failure in phomatosis. One type of vaccine consists of a herpesvirus experimental viral oncology research. For several years we initially isolated from chickens with Marek's disease and have tried without success, with R. R. Marshak, to transmit subsequently attenuated by serial passage in tissue culture bovine lymphosarcoma to newborn calves by inoculation (4, 5); similar vaccines are available containing other non- of cell-free bovine leukemia extracts (unpublished experi pathogenic herpesvirus strains isolated from field cases of ments). After a few years, because of excessive cost, these Marek's disease (4). Another type of vaccine contains a experiments had to be terminated. Recently, however, Witt- herpesvirus isolated from turkeys and not pathogenic for mann and Urbaneck (85), in the course of routine vaccination chickens (63). Both types of vaccine contain cell-associ against piroplasmosis, inoculated newborn lambs with ated viruses and are usually employed in the form of cell blood collected from cattle infected with that parasitic suspensions. However, vaccines containing cell-free virus, disease. They observed, with surprise, that 10 to 23 months prepared and stored in lyophilized form, are also available later, among 21 inoculated lambs, 6 developed generalized (8). The currently available vaccines appear to be safe and lymphosarcomas; the blood with which they were vacci provide significant levels of protection under field condi nated had been collected from cattle that carried not only tions (4). piroplasmosis, but also had a persistent lymphocytosis The "Papova" Group of DMA Oncogenic Viruses representing an initial symptom of lymphosarcomas (85). Olson and his coworkers (64) confirmed this initial observa Many of the tumors studied in experimental laboratory tion and induced lymphosarcomas in lambs following inocu animals are caused by RNA oncogenic viruses. Lymphoid lation of the bovine leukemia virus. Surprisingly, the lamb leukosis in chickens, lymphosarcomas and leukemias in proved to be more susceptible to induction of lymphosarco mice, rats, and cats, mammary carcinomas in mice, certain mas with the bovine leukemia virus than the calf. In some sarcomas in mice, and many other tumors are caused by instances infectious viruses can be recovered only from RNA oncogenic tumor viruses. certain particular locations. Thus, neurolymphomatosis There exists also, however, a group of oncogenic viruses (Marek's disease) could not be transmitted by inoculation of that recently has gained particular prominence, namely, cell-free extracts until it was determined that infectious virus the group of oncogenic DNA viruses. We have already particles are formed in feather follicles of diseased chickens discussed briefly in the earlier part of this review the (7). Experimental transmission succeeded when virus har oncogenic potency of several DNA viruses, such as the vested from feather follicles was employed for inoculation. polyoma, the SV40, and the adenoviruses and also some of the viruses of the herpes group, i.e., the LÃ¼ckefrog kidney The Chicken Leukosis Complex and the Herpesvirus carcinoma and the chicken neurolymphomatosis (Marek's Among the various forms of leukemia, lymphoid leukosis disease). To the herpes group belongs also the Epstein- Barr virus (23) isolated from a case of Burkitt's lymphoma; and neurolymphomatosis cause the most extensive losses in the poultry industry. In recent studies, the chicken its oncogenic potential and its possible etiological role in leukosis complex was found to consist of two etiologically certain human lymphomas and allied neoplastic diseases distinct forms of disease. The form known as lymphoid are widely recognized. leukosis or "big liver disease," formerly known as "visceral Among the oncogenic DNA viruses, the group known lymphomatosis," is caused by an RNA virus; the disease under the acronym "papova," suggested by Melnick (60), originates in the bursa of Fabricius (11) and in its most and consisting of papilloma, polyoma, and the SV40 vi frequent form is essentially similar to disseminated lympho ruses, has been gaining prominence in recent years be sarcoma. Lymphoid leukosis appears to be related in its cause of its wide distribution in many animal species, etiology to certain more rare forms, such as erythroblastic including humans, and its considerable oncogenic poten and myelobtastic leukemias, as well as to certain tumors, tial. To the "papova" virus group belong the various papillo- such as sarcomas, endotheliomas, etc. Another very com mon form of chicken leukosis complex is manifested in mas common in humans, rabbits, dogs, horses, cattle, etc. typical cases by infiltration of nerve trunks with leukemic They are readily transmissible by filtrates. In some instances cells, leading eventually to paralysis, and is also frequently they may change into carcinomas or they may induce associated with the development of visceral lymphomas, progressively growing sarcomatous tumors when transmit particularly in the ovaries and liver. This form of leukemia ted by inoculation under certain experimental conditions in chickens, known as neurolymphomatosis or Marek's (44). disease,2 was found to be caused by a DMA virus of the In a separate group belongs the hamster papilloma and herpes group (9, 62, 84). One of the recent significant its apparent relation to hamster lymphosarcoma. Arnold advances in modern cancer research has been the devel Graffi reported that multiple skin tumors developed in opment of a vaccine against this form of chicken leukemia about 5 to 10% of young Syrian hamsters in his laboratory (35). These tumors contained DNA virus particles approxi â€¢'J.Marek. a Hungarian veterinarian, described, in 1907, a paralytic mately 35 nm in diameter. Cell-free extracts prepared from disease in 4 chickens (57) which he diagnosed as an inflammatory disease such tumors and inoculated into newborn hamsters in of the nerves (polyneuritis). Only some 20 years later Pappenheimer and his associates recognized the neoplastic nature of this disease, which they duced lymphosarcomas after a short incubation of several designated "neurolymphomatosis gallinarum" (68). weeks; in some animals subcutaneous sarcomas devel-

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1978 American Association for Cancer Research. L. Gross oped. The hamster lymphosarcomas and sarcomas con Scrapie is a disease of sheep that was already well known tained virus particles about 100 nm in diameter, similar to in England, Germany, and France in the 18th century (75). those observed in mouse leukemia. The induced tumors The name is derived from the characteristic tendency of could be transmitted by cell-free extracts to other hamsters. the sheep to rub or scratch their flanks against fixed Interpretation of these experiments is difficult at the present objects. The early signs are uncertain gait with a slight time. tremor of the lips, followed by muscular incoordination; the animals become emaciated and die after an illness Progressive Multifocal Leukoencephalopathy and the lasting for several months. It has long been known that J. C. Virus inoculation of brain tissue from diseased animals will trans The initial observation of the presence of small polyoma- fer the disease to other sheep. In recent years, scrapie has been transmitted to goats, mice, rats, hamsters, and also like virus particles in brain tissue of patients suffering from to monkeys (32). This was accomplished by injection of progressive multifocal leukoencephalopathy (86), a rare emulsions prepared from scrapie-infected brain and also demyelinating human brain disease, led subsequently to the isolation of a virus from the brain of a patient (J. C.) by injection of extracts from other tissues of infected animals. The incubation is long, varying from several suffering from this disease, by Padgett and her coworkers months to a few years, depending on species. In sheep the (67) at the University of Wisconsin in Madison. The J. C. virus incubation is 2 to 5 years; it is much shorter in some other was subsequently isolated from more than 20 additional species. The pathological manifestations are limited to the cases of progressive multifocal leukoencephalopathy in brain. humans (66). Based upon characteristics such as size, Kuru is a degenerative disease of the central nervous stability, intranuclear multiplication, etc., the J. C. virus fits into the polyoma-SV40 subgroup of the family of papova- system prevalent in the inhabitants of certain parts of New Guinea, characterized in its initial phases by a shivering- viruses. Serological studies have demonstrated that the J. C. like tremor (26). Kuru means shivering or trembling in the virus is present in a large segment of normal human adult language of the Fore group in which most of the cases of population (65). The J. C. virus does not seem to have the disease occur. The development of kuru in humans in oncogenic potency in humans; at least, no such evidence New Guinea was related to the cannibalistic consumption has yet been found up to the present time. However, the by Fore people of brain and other visceral tissues of their virus has a relatively high oncogenic potency when inocu dead relatives as a rite of respect and mourning. The lated into newborn hamsters (82). disease progresses to total motor incapacitation and death in about one year from onset. Gajdusek and his coworkers The B. K. Virus transmitted kuru to chimpanzees; there was a very long incubation period of about 2 years required for the induc In 1971 Gardner and her coworkers (31), at St. Mary's tion of the disease (27, 28, 32). The disease could be Hospital in London, England, isolated a virus resembling serially transmitted in chimpanzees using either suspen the polyoma virus from the urine of a patient (B. K.) who sions of brain tissue or visceral tissues containing no brain. received a kidney transplant and who was under immuno- Kuru could also be transmitted to other primates and to a suppressive therapy. The virus had the size and morphology variety of animal species (32). The latency was long and of a papovavirus. Subsequent isolations of virus strains varied from one to several years. The transmissible agent is indistinguishable from the B. K. virus have been made remarkably resistant to heat; it is not totally inactivated by heating to 85Â°for 30 min. from urine of other immunosuppressed renal allograft re cipients (10, 53), as well as from urine of patients receiving Presenile Dementia. Kuru is similar in its clinical and chemotherapy for lymphomas or other neoplastic diseases pathological manifestations to a disease occurring in hu (69, 87). Serological surveys determined the presence in mans, known as a presenile dementia, which was described blood plasma of antibodies directed against the B. K. virus independently by Creutzfeldt and Jakob. This disease has in large segments of human population (30). an insidious onset, manifested by speech and gait disturb The B. K. virus was reported to transform hamster cells ances, then rapidly progressing mental deterioration com in tissue culture (55). However, it appears to have only a bined with ataxia and leading to death in about one year. very low oncogenic potency on bioassay (73). This disease occurs sporadically in middle-aged men and women and is relatively rare, but there are known pedigrees The "Slow Virus Diseases" and Their Possible Relation to of families in which several members of the same family Cancer and Leukemia developed the disease in successive generations. Creutz- feldt-Jakob disease (12, 48) could be transmitted to chim There exists a group of transmissible diseases, which panzees (33), New World monkeys (27, 32), and more have been recognized only during the preceding two or recently also to guinea pigs (56) and cats (32). three decades and which appear to be related in their Scrapie in sheep, as well as kuru and presenile dementia in epidemiology and certain other features to oncogenic vi humans, belongs to the group of "slow virus diseases," a ruses, namely, the "slow virus diseases" (75). They are term suggested by Sigurdsson (75) in Iceland. They all have caused by filterable agents extremely resistant to heat, certain features in common; they affect the central nervous formaldehyde, and a variety of disinfectants. These agents system inducing degenerative changes in the neurons and cause certain invariably fatal, degenerative diseases of the in the gray matter, without evidence of inflammatory central nervous system. changes; they invariably lead to death. They are caused by

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1978 American Association for Cancer Research. Viral Etiology oÃCancer and Leukemia agents which are unusually resistant to heat, since they are tinued and may possibly lead to the development of vac not completely inactivated by heating to 85Â°for 30 min; they cines against at least a limited number of oncogenic viruses, resist formaldehyde and enormous doses of ultraviolet particularly of the DNA group. irradiation. Because of their stability, their ability to cross Maintenance of Immunological Balance is of fundamen species, and the very long latency period required either in tal importance in preventing activation of oncogenic vi natural cases or in transmission experiments, the study of ruses. Accordingly, reduction, to a minimum, of treatment these diseases is extremely difficult. with immunosuppressive drugs, such as cortisone or Imu- "Slow Virus Diseases" and Oncogenic Viruses. The ran, and experimental studies on other factors which de "slow virus diseases," are in certain respects similar to press immunity and which may lead to activation of latent tumors and leukemias. They belong essentially to the same oncogenic viruses are essential. The study of other factors broad group of diseases caused by transmissible viral which increase resistance to induction or growth of tumors, agents because of (a) the very long latency elapsing be such as nonspecific treatment with certain bacterial vac tween infection and the development of symptoms of dis cines, including the BCG, should be encouraged. eases, (oi their epidemiology, which may imply a possible Elimination of Inadvertent Cancer Transmission. Cases vertical transmission of at least some of the causative have been reported of inadvertent transmission of cancer agents, and (c) their ability to evade a mobilization of a or lymphosarcomas through organ transplants from donors vigorous and effective immunological response of the host. suffering from cancer or leukemia. Utmost care should be However, most of the oncogenic viruses are much more exercised in selecting donors for organ transplants to avoid susceptible either to heat or to inactivation by a variety of transmission of neoplastic diseases. chemicals routinely used for the destruction of infectious Genetic Control. An attempt should be made to eliminate agents. or reduce inbreeding of families with high incidence of The natural infection with either oncogenic viruses or cancer and leukemia in cattle, chickens, cats, dogs, fish, with the virus-like agents causing "slow virus diseases," etc. Premarital counseling in humans should also be con may occur before birth, or early in life, and symptoms of a sidered. progressive and usually fatal disease may appear after one or several decades of latency. Experimental studies are Conclusions difficult and time consuming, since animals inoculated with It appears that oncogenic viruses are widely disseminated some of these viruses may develop symptoms of disease in many animal species and presumably also in humans. after a long latency extending in certain instances to several Submerged and invisible in their latent form, they are frugal years. and moderate in their requirements causing no harm to their carrier hosts. However, the host-virus relationship An Approach to Preventive Control of Cancer and Leuke mia can change at any time. For unexplained reasons, when triggered into action by a variety of metabolic, hormonal, At this point it is difficult to anticipate a realistic approach or chemical factors or by ionizing radiation, the hitherto to a future preventive control of cancer and leukemia. latent viruses can become activated, acquire pathogenic More information is needed in order to devise ways and potential, cause the development of tumors or leukemia, means of preventing the development of tumors. However, and kill their hosts; however, they then perish also with on the basis of information now at hand we may anticipate their carrier hosts. tentatively the following avenues of approach. It is apparent that oncogenic viruses may represent a Attempts to Eliminate Factors Which May Activate La very old, usually asymptomatic, latent infection, very com tent Oncogenic Viruses. The principal approach in an mon in many animal species, including humans. It is quite attempt to prevent the activation of latent tumor-inducing reasonable to speculate that such viruses have been trans viruses would be the elimination, or at least the reduction, mitted from generation to generation for millions of years, of certain environmental factors, such as cigarette smok only exceptionally causing symptoms of disease.3 It is quite ing, excessive exposure to X-rays and other forms of radia probable that at one time, centuries ago, certain oncogenic tion energy, carcinogenic chemicals in food, water, pol viruses entered the cells of some animal species from luted air, etc., and a reduction in the intake of a variety of outside and have been from that time propagated from one drugs and hormones having a carcinogenic potential. generation to another, remaining in most instances sub Preliminary experimental data suggest that endogenous merged, invisible, and unrecognized, except for an occa activation of certain latent oncogenic viruses can be de sional tumor or leukemia developing here and there in one layed or reduced; we now know that low-caloric diet may of the carrier hosts. considerably decrease the incidence of leukemia (72) or The development of disease would represent only an mammary carcinomas (79) in certain inbred families of accident in the relation of the virus to its carrier host. The mice. Experimental studies on other biological or biochem development of tumors or leukemia in an occasional host, ical methods of delaying or preventing activation of dor possibly separated by one, two, or several generations, mant oncogenic viruses should be encouraged. Specific Vaccine Immunization. A vaccine is now availa 3The concept of vertical transmission of oncogenic viruses does not ble against chicken neurolymphomatosis (Marek's disease). necessarily exclude the possibility of an occasional horizontal transmission of certain oncogenic viruses, such as the horizontal transmission of the Experimental studies on other similar vaccines against leukemia virus in cats or of the herpesvirus causing neurolymphomatosis, oncogenic DNA or RNA viruses should be vigorously con i.e., Marek's disease, in chickens.

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would represent only a few scattered but revealing signs in Syrian Golden Hamster by Oncogenic DNA Simian Virus 40. J. Nati. the chain of a continued host-to-host transmission of the Cancer Inst.. 50. 1347-1365. 1973. 16. Dmochowski, L., and Grey, C. E. Electron Microscopy of Tumors of causative agents. These agents are probably incorporated Known and Suspected Viral Etiology. Texas Rept. Biol. Med.. 75: 704- in most instances in the genetic cell material of their hosts, 756, 1957. 17. Dmochowski, L., Grey. C. E., and Magee. L. A. Studies on a Virus or they may be carried in another submerged form, remain ("Polyoma") Inducing Multiple Tumors in Animals. Proc. Soc. Exptl. ing unrecognized by our current laboratory methods. Es Biol. Med., 702. 575-579, 1959. sentially, however, they are similar to other infectious 18. Eddy, B. E., Borman, G. S., Berkeley, W. H., and Young, R. D. Tumors Induced in Hamsters by Injection of Rhesus Monkey Kidney Cell Ex agents. Each oncogenic virus could be traced to another tracts. Proc. Soc. Exptl. Biol. Med., 707. 191-197, 1961. oncogenic virus in the continuous chain of transmission, 19. Eddy, B. E., Stewart, S. E.. and Berkeley, W. Cytopathogenicity in similar to a host-to-host transmission of other pathogenic Tissue Cultures by a Tumor Virus from Mice. Proc. Soc. Exptl. Biol. Med., 98. 848-851, 1958. agents. The law of obligate communicability would apply 20. Eddy, B. E., Stewart, S. E., Stanton, M. F., and Marcotte. J. M. not only to such communicable diseases as measles, Induction of Tumors in Rats by Tissue-culture Preparations of SE Polyoma Virus. J. Nati. Cancer Inst., 22. 161-171, 1959. mumps, or influenza but also to tumors and leukemias. It 21. Eddy. B. E., Stewart, S. E., Young, R.. and Mider, G. B. Neoplasms in appears reasonable to speculate that the law of obligate Hamsters Induced by Mouse Tumor Agent Passed in Tissue Culture. J. communicability of the causative agents would also apply Nati. Cancer Inst. 20: 747-761, 1958. to certain "slow virus diseases," such as scrapie in sheep, 22. Ellermann, V., and Bang, 0. Experimentelle LeukÃ¤miebei HÃ¼hnern. Centr. Bakteriol. Abt. l Orig.. 46: 595-609. 1908. or either kuru or Creutzfeldt-Jakob disease (presenile de 23 Epstein. M. A.. Achong. B. G., and Barr, Y. M. Virus Particles in Cultured Lymphoblasts from Burkitt's Lymphoma. Lancet, 1: 702-703, mentia) in humans. 1964. The life span of an individual investigator may be too 24. Finkel, M. P., Biskis, B. O., and Jinkins, P. B. Virus Induction of short to follow the epidemiology of oncogenic viruses Osteosarcomas in Mice. Science, 757. 698-700, 1966. 25. Furth. J., Seibold, H. R., and Rathbone. R. R. Experimental Studies on responsible for the development of cancer and allied neo- Lymphomatosis of Mice. Am. J. Cancer, 79. 521-604, 1933. plastic diseases in many animal species and in humans. 26. Gajdusek. D. C. Kuru in the New Guinea Highlands, in J. D. Spillane We can anticipate similar difficulties in the study of "slow (ed.). Tropical Neurology, pp. 376-383. London: Oxford University Press, virus diseases." 1973. 27. Gajdusek, D. C., and Gibbs, C. J., Jr. Transmission of Two Subacute We are thus now facing new and far-reaching problems. Spongiform Encephalopathies of Man (Kuru and Creutzfeldt-Jakob Dis ease) to New World Monkeys. Nature. 230. 588-591, 1971. The study of the nature and epidemiology of oncogenic 28. Gajdusek, D. C.. Gibbs, C. J., Jr., and Alpers, M. P. Transmission and viruses and of "slow virus diseases" and of the mechanism Passage of Experimental "Kuru" to Chimpanzees. Science, 755: 212- of limited, if any, immunological response they elicit in 214. 1967. 29. Gardner, M. B., Arnstein, P.. Johnson, E., Rongey, R. W., Charman, H. their hosts, represents one of the most difficult challenges P., and Huebner, R. J. Feline Sarcoma Virus Tumor Induction in Cats in experimental medicine. and Dogs. J. Am. Vet. Med. Assoc., 758: 1046-1053. 1971. 30. Gardner, S. D. Prevalence in England of Antibody to Human Polyoma virus (B.K.). Brit. Med. J., 7: 77-78, 1973. 31. Gardner, S. D., Field, A. M., Coleman. D. V., and Hulme, B. New REFERENCES Human Papovavirus (B.K.) Isolated from Urine after Renal Transplanta tion. Lancet, 7: 1253-1257, 1971. 1. Bernhard, W.. Febvre. H. L., and Cramer, R. Mise en Ã‰videnceau 32. Gibbs, C. J., Jr., and Gajdusek. D. C. Experimental Subacute Spongi Microscope Ã‰lectroniqued'un Virus dans des Cellules InfectÃ©esinVitro form Virus Encephalopathies in Primates and Other Laboratory Animals. par l'Agent du Polyome C. R. Acad. Sci. Paris. 249. 483-485. 1959 Science, 782. 67-68, 1973. 2. Bernhard, W., and Gross, L. PrÃ©sencede Particules d'Aspect Virusal 33. Gibbs, C. J., Jr., Gajdusek. D. C.. Asher, D. M., Alpers, M. 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Ludwik Gross

Cancer Res 1978;38:485-493.

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