Affiliation of authors: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX.
Correspondence to: Janet S. Butel, Ph.D., Department of Molecular Virology and Microbiology, Mail Stop BCM-385, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
Ohgaki et al. report the interesting observation that simian virus 40 (SV40) sequences can be detected in human brain tumors from Switzerland but not in brain tumors from Finland, and they note the association with the use of SV40-contaminated poliovaccines in Switzerland and the lack of such use in Finland. They conclude that SV40 is not playing a causative role in the development of brain tumors.
The presence of SV40 DNA in human tumors can be explained by three different possibilities: 1) Laboratory contamination of tumor specimens; 2) the etiologic role of the virus in tumor development; and 3) nonetiologic residence of the virus as a "passenger" because of a favorable growth environment provided by the tumor milieu. The first possibility has been eliminated in this report by the fact that no Finnish samples were positive and laboratory contamination would be expected to be random. Contamination problems have been ruled out in multiple other studies as well (1). The authors favor the latter possibilitythat SV40 is an innocent bystanderbecause the reported incidence of nervous system tumors is the same in countries, irrespective of their use of SV40-contaminated polio vaccines.
We believe it is premature to draw the conclusion that SV40 is not involved in any instances of brain tumor development for the following reasons: 1) Not all tumors of a given type will necessarily have the same etiology. Exposure to causative environmental factors or cofactors will vary among geographic regions. There are examples of a virus being etiologically involved in the development of a given tumor type frequently in one area of the world and seldomly in another area (e.g., hepatitis B virus and liver cancer or Epstein-Barr virus and Burkitt's lymphoma) (2). Because SV40 is found in brain tumors from only some geographic areas does not rule out that the virus has a functional role in the tumors in which it is present. 2) T antigen, the SV40-transforming protein, has been detected in brain tumor cells, some in complex with cellular tumor suppressor proteins p53 and pRb (3,4). It remains to be determined if inhibition of T-antigen expression would result in growth arrest of the brain tumor cells, as has been shown recently with human mesothelioma cells and an SV40 antisense construct (5). Such data suggest a functional role for the virus in the malignant phenotype of those cells. 3) No data have been provided to support the interpretation that SV40 is present as a bystander because of favorable growth conditions in the tumor. The state of the viral genome and the time line of virus appearance in the tumor need to be established. If SV40 is a bystander, one would expect to find replicating forms of viral DNA and complete viral particles in the cells. Also, one would predict that tumor appearance would precede virus infection, i.e., early-stage tumors would be virus negative and only the more advanced tumors would be virus positive. It is noteworthy that Shivapurkar et al. (6) found SV40 sequences in both the noninvasive and adjacent invasive tumor cells, indicating viral presence in the earliest recognizable tumor stage. 4) The distribution of viral sequences throughout brain tumors remains to be determined. It has recently been shown by microdissection techniques that the SV40 DNA in mesotheliomas was present in the epithelial tumor cells and not the adjacent nonmalignant tissues (6). A replicating passenger virus would probably be present in normal cells within the tumor mass. 5) Further analysis is necessary to determine if SV40 sequences are more often associated with brain tumors that have certain histologic subtypes or certain clinical characteristics. If so, it should then be possible to determine if the incidence of those tumor subtypes is comparable in different countries or whether the incidence of the viral-associated subset is higher in countries that used SV40-contaminated poliovaccines.
The authors refer to our work (7) and suggest that SV40 is able to spread vertically in humans today. Although it is theoretically possible that SV40 can be transmitted vertically from mother to child, we interpret our data as evidence of horizontal spread among humans by unknown route(s).
We do not believe that adequate data are currently available to allow a definitive conclusion about the etiologic role, or lack thereof, of SV40 in human brain tumors. Additional studies are clearly indicated.
REFERENCES
1 Butel JS, Lednicky JA. Cell and molecular biology of simian virus 40: implications for human infections and disease. J Natl Cancer Inst 1999;91:119-34.[Medline]
2 Butel JS. Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease. Carcinogenesis. In press 2000.
3 Bergsagel DJ, Finegold MJ, Butel JS, Kupsky WJ, Garcea RL. DNA sequences similar to those of simian virus 40 in ependymomas and choroid plexus tumors of childhood. N Engl J Med 1992;326:988-93.[Abstract]
4 Zhen HN, Zhang X, Bu XY, Zhang ZW, Huang WJ, Zhang P, et al. Expression of the simian virus 40 large tumor antigen (Tag) and formation of Tag-p53 and Tag-pRb complexes in human brain tumors. Cancer 1999;86:2124-32.[Medline]
5
Waheed I, Guo ZS, Chen GA, Weiser TS, Nguyen DM, Schrump
DS. Antisense to SV40 early gene region induces growth arrest and apoptosis in
T-antigen-positive human pleural mesothelioma cells. Cancer Res 1999;59:6068-73.
6 Shivapurkar N, Wiethege T, Wistuba II, Salomon E, Milchgrub S, Muller KM, et al. Presence of simian virus 40 sequences in malignant mesotheliomas and mesothelial cell proliferations. J Cell Biochem 1999;76:181-8.[Medline]
7 Butel JS, Jafar S, Wong C, Arrington AS, Opekun AR, Finegold MJ, et al. Evidence of SV40 infections in hospitalized children. Hum Pathol 1999;30:1496-502.[Medline]
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