Journal of Hematology Volume 84 – Number 5 – May 1999
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Haematologica Journal of Hematology volume 84 – number 5 – May 1999 Haematologica 1998; 84:385-389 editorial, comments and views electron microscopy is probably the most efficient Viral etiology of human cancer: approach to viral classification; a historical perspective 4. viruses shown to be associated with several can- cers of laboratory animals belong to various fam- he hypothesis according to which some human ilies of viruses (herpes, vaccinia, papova, retro- cancers might be caused by filterable micro- viruses, DNA, RNA,...) and are not restricted to organisms such as viruses is almost one hun- any one family; T 5. viruses associated with some cancers and those dred years old. It was indeed in 1903 that Borrel, in France, suggested such a possible relationship. To responsible for infectious diseases look identical. put this hypothesis in a historical perspective one There is no such thing as a family of oncogenic should refer to the book The Riddle of Cancer1 which viruses, a terminology which never appears in gen- Charles Oberling published in 1952 and in which the eral classifications of viruses and should actually possible role of viruses in human cancer was pre- be regarded as a misnomer; sented with extensive references to contributions of 6. practically, EM is essential to monitor the level of initial pioneers such as Rous, Shope, and Bittner. success in the sequential steps leading to virus iso- Since our purpose is, to some extent, focused on the lation and purification. Therefore, the success of evolution of methodologies which cancer researchers biochemical characterization of viral markers utilized in attempts to verify the hypothesis, one depends on electron microscopy to ascertain the should emphasize that the approach of Rous and purity of viral isolates and the absence (or minimal his followers was essentially based on establishing amounts) of non-viral contaminants; the difference between transmission of tumors and 7. finding particles with typical viral morphology leukemias by cell transplants, i.e. grafts, or by cell- does not mean that these viruses are pathogenic. free filtrates. Transmission of tumors in experimen- Actually, there are probably many more non-path- tal animals by cell-free filtrates was always interpret- ogenic than pathogenic viruses. This point was ed as demonstration of viral etiology. well illustrated in a special conference sponsored During the past fifty years, viral oncology has been around 1960 by the New York Academy of Sci- studied in almost all cancer research centers, world ences under the title Viruses in Search of Disease; wide. Practical results in terms of effective therapy of 8. viruses, infectious or cancer-associated, rarely sat- human malignancies have been nil. But still, recent isfy all the Koch postulates which, incidentally, issues of all the main oncology publications contain were presented before viruses were discovered; numbers of studies related to viral oncology, clear- 9. while the association between viruses and numer- ly indicating that the hypothesis still has consider- ous malignancies of laboratory animals has been able momentum! readily demonstrated by electron microscopy, and The past fifty years can be analyzed in two distinct in spite of considerable efforts, similar associa- periods. The first, between 1945-1970 was dominat- tions have never been observed in human cancers4 ed by electron microscopy; the second, from 1970 (with very rare exceptions such as the common until now, being dominated by molecular biology. wart and molluscum contagiosum...) Electron microscopy (EM) contributed a consid- erable amount of data, which can briefly be sum- Of mice and men... marized as follows. Research in viral oncology changed drastically 1. EM can readily demonstrate associations around 1970, when methods of molecular biology between viruses and cancers in several laborato- took the lead, while electron microscopy was rele- ry animal species, such as chickens and mice;2,3 gated to a distant background. 2. EM data by themselves do not, however, prove Dedicated virus hunters, as Peter Duesberg6 would any role of these viruses in the etiology of the call them, were obviously not discouraged by the neg- tumors.4 The EM data did, however, trigger ative results of twenty years of active search for virus- microbiological experiments, based on ultrafil- es by electron microscopy in many types of human tration, which frequently yielded scientific evi- cancers. To the contrary, large research programs dence for etiological relationships; were initiated, based primarily on the identification 3. as pointed out by André Lwoff et al.5 in 1962, of viral, molecular markers such as enzymes, nucleic 386 E. de Harven acids or proteins identified most frequently in cell cul- well characterized virus proteins (the EBNA proteins) tures derived from human malignancies, rarely direct- are involved in the immortalization of B lymphocytes ly from the tumor tissues or blood plasma. The fact and, most interestingly, cyclin D2, driving B cells from that viruses had never been directly observed in the resting stage into G1, is induced within 24 hours human tumors by electron microscopy was conve- of EBV infection. niently explained in terms of virus latency, and/or by Although B cells appear as the primary targets of integration of a provirus in the genome of tumor cells. EBV, T cells might also be involved as suggested by The most significant example illustrating this dras- Kanegane et al.11 in a study of patients with severe, tic change in approach is given by the reverse tran- chronic active EBV infection who came down with scriptase enzyme, discovered in 1970 by Temin in puri- EBV-positive T-cell lymphoma. fied Rous sarcoma virus,7 and by Baltimore in Rausch- Methods of in situ hybridization have been applied er mouse leukemia virus.8 This discovery was regarded to the study of familial Hodgkin’s disease by Lin et as historical. It resulted in two Nobel prizes and in the al.,12 suggesting that EBV does not play an important renaming of all RNA tumor viruses as retroviruses. DNA role in familial Hodgkin’s disease. synthesis from an RNA template was indeed a very sur- Studies at the University of Padova, by Ometto et prising observation in 1970. The enzyme was initially al.,13 support the notion that lymphomas arise from thought to represent a unique feature of RNA tumor clonal expansion of EBV+ cells. That latent EBV infec- viruses and was, therefore, regarded as a reliable mark- tion can be reactivated by EBV-specific CD8+ T cells er of the presence of retroviruses, even when retrovirus was demonstrated by Nazaruk et al.14 particles were never convincingly observed by EM. We The danger of EBV-induced lymphoproliferative dis- learned, later on, that reverse transcription is a com- ease after allogeneic stem cell transplantation was mon phenomenon, that the enzyme (RT) is present in studied, using a semiquantitative EBV-PCR technolo- many different cells,9 and that demonstration of RT gy, by Lucas et al.15 Recently, Hale and Waldmann16 activity is far from enough to substantiate any claim analyzed the occurrence of EBV driven lymphoprolif- for the isolation of a retrovirus. erative disorders in patients receiving T-cell depleted An exhaustive review of viral oncology literature over allogeneic bone marrow transplantation. They sug- the past 25 years would be beyond the purpose of gested that additional depletion of B cells is beneficial this editorial. Instead, it may be appropriate to men- possibly because it reduces the virus load or the virus target tion publications which have appeared over the past which is hardly compatible with the limited success few years, in an attempt to evaluate how much experienced with antiviral agents in such cases. progress has been made toward the consolidation of In America and in Europe, 50% of the cases of a century old hypothesis. Hodgkin’s disease are associated with EBV. Accord- Two main areas of viral oncology, namely: herpes ing to Roskrow et al.,17 EBV-specific cytotoxic T lym- viruses with emphasis on EBV and herpes-8 virus, and phocytes generated from normal donors may persist papova viruses with emphasis on human papilloma long-term in vivo and reconstitute the immune virus, HPV, will be considered. Retroviruses, although response to EBV, this possibly being an effective pro- they have been the topic of my own research, will not phylaxis and treatment of immunoblastic lymphoma. be specifically emphasized here because the current- The approach could be useful for cases failing to ly used anti-HIV antibody tests are non-specific (vide respond to salvage chemotherapy. infra), making any attempt to analyze the current lit- The potential usefulness of therapeutic protocols erature very hazardous. based on EBV has been demonstrated recently by Neyts et al.18 who studied xenografts of EBV-associated naso- Herpes pharyngeal carcinomas in athymic nude mice. Admin- Abundant reports in oncology literature refer to the istration of the antiviral agent Cidofovir had a pro- Epstein-Barr virus. This human herpes virus infects nounced antitumor effect in these tumor-bearing mice, most people early in life. However, when primary apparently as a result of rapid cell death, through infection is delayed until adolescence or adulthood it apoptosis, of EBV-transformed epithelial cells. frequently causes infectious mononucleosis. It is a Primary effusion lymphomas have a more complex highly contagious agent (the kissing disease). Most EBV association, not with one but with two distinct virus- carriers are disease-free. However, in some cases EBV es of the herpes group, namely EBV and human her- appears to be associated with several forms of can- pesvirus-8 (HHV-8), the Kaposi’s sarcoma associated cers: lymphomas in immunosuppressed patients, agent. This has recently been described by Horenstein Hodgkin’s disease, Burkitt’s lymphoma in central et al.19 The various patterns of EBV latency expression Africa, nasopharyngeal carcinoma, thymic lym- and the interaction with HHV-8 may contribute to a phoepithelioma, primary nasal lymphomas and gas- better understanding of the pathobiology of this form tric carcinoma, of much more sizeable epidemiologi- of lymphoproliferative disease.