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The Coming of Age of Tumor Virology: Presidential Address1

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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 “downrightdisbelief―(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, “Thosewhorefuse to go beyond fact rarely get as far (51) study on the virus he had recently isolated from leu as fact.―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 naïvely 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 (“Whereacell arises, there a cell etiology of cancer, yet he encouraged and enthusiastically must previously have existed―)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 ‘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. MAY 1977 1255 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1977 American Association for Cancer Research. C. Friend 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 “virus-likeagent―;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 unbowed—if a little bloodied—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) (Lucké)1 1938RabbitFrog kidney carcinoma 950-19721951Mouse Olsen)1955Mouseleukemia(Gross)1951Equine cutaneous papilloma (Crook and (Gross)1956Mouseleukemia(Graffi)1953Mouse “parotid―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!.) 1256 CANCERRESEARCHVOL. 37 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 “ordinary―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.
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