Malignant Mesothelioma and Simian Virus 40 (SV40)

Student guest post by Andrew Behan

Malignant Mesothelioma (MM) is a rare type of cancer which manifests itself in the thin cells lining the human body's internal organs. There are three types of MM; pleural mesothelioma, peritoneal mesothelioma, and pericardial mesothelioma, affecting the lining of the lungs, abdominal cavity, and lining of the heart, respectively (1). Pleural mesothelioma is most common, consisting of about 70% of all MM cases and has a poor prognosis; patients live a median time of 18 months after diagnosis. (Note: for the purposes of this article, MM will be used to represent pleural mesothelioma exclusively.) Despite its discovery in the mid-1800's, MM was not linked to asbestos until the late 1900's, when case reports of fast-growing lung cancers, different from previously described lung cancers, motivated investigators to uncover undisputed evidence linking asbestos to MM. Measures to reduce/eliminate asbestos from buildings reduced exposure to the cancer-causing agents found within the material, and public health officials remained confident by the year 2000 MM cases would decline in the U.S. and parts of Europe. Despite these predictions, MM cases have not declined. In fact, the incidence of MM is on the rise (1). Consequently, investigators have focused their attention on other factors to explain the steady incidence of MM in the U.S., eventually naming Simian Virus 40 (SV40) as a potential cause of MM.

You might be asking, "SV40? What's that?" SV40 is a virus originally discovered in 1960 in kidney cells of rhesus monkeys. SV40 is dormant and asymptomatic in rhesus monkeys, but was later found to cause kidney disease, sarcoma, and other cancers in animal models. Later on, it was found SV40 attacks p53 gene (a tumor suppressor) and can interrupt the cell's ability to perform apoptosis, or cell death. This makes the cells immortal, leading to tumor formation, or cancer (2). Controversy arose when the discovery of SV40 was found in the rhesus monkey kidney cells because these same cells were being utilized to form the polio vaccine. Consequently, many polio vaccines were contaminated with SV40 and when the vaccine was used to inoculate humans, SV40 was passed to humans along with the inactive form of the polio virus. It was estimated over 98 million Americans received the vaccine from 1955-1963, when a proportion of the vaccine was contaminated with SV40. Of the 98 million vaccinated during this time period, it was estimated 10-30 million of those individuals were exposed to SV40. Naturally, people who received contaminated forms of the vaccine were afraid they would develop cancer from exposure to SV40.

Since the controversy began in 1960, research has been devoted to confirming its role in cancer development in humans, as well as many animal models. As I mentioned above, presence of SV40 in animals has led to tumors and other cancers, and a few studies have found presence of SV40 in humans who have developed MM. For example, Carbone et al. found SV40 in mesothelial cells of humans who had developed MM, but not in the surrounding tissue (3). They did not find SV40 in patients who had other lung cancers, possibly reinforcing the specificity of their findings (3). Overall, 54% of MM cases were found to have SV40 infection within the mesothelial cells (3). The investigators determined more research needed to be done to see if SV40 infection alone could cause MM, or if other factors, such as immunosuppression or exposure to asbestos, were necessary for development of MM.

Other studies were not as convincing. For example, Lopez-Rios et al. reported that initially they detected SV40 in about 60% of MM specimens, and then they determined that most of the positive results were caused by plasmid PCR contamination, and that only 6% of the initially positive samples were confirmed to contain SV40 DNA (4). However, studies have shown the presence of SV40 in human specimens by using several other techniques besides PCR, including Southern blotting, immunostaining, RNA in situ hybridization, microdissection, and electron microscopy" (5).

Thus, the question remains: does SV40 cause MM, or does SV40 infection, in conjunction with asbestos exposure, generate a greater risk for the development of MM? This is a tough question to answer, because although asbestos is no longer mined in the U.S., it is still being imported; workers are still continually being exposed to asbestos. However, the use of asbestos has nearly ceased, decreasing from 813,000 metric tons in 1973, to 1700 metric tons in 2007 (6). The other problem in teasing out SV40 as a cause of MM from asbestos lies in the latency period between asbestos exposure and MM clinical diagnosis. According to the CDC, the latency period for someone who is first exposed to asbestos and clinical disease is 20-40 years. It may be, given asbestos still remains in many buildings, and exposure to it is inevitable when removal is completed, in addition to the long latency period between exposure and disease, that we have not yet come to the dramatic decrease in MM health officials have predicted. Or, is SV40 infection the culprit and the increase in incidence of MM will continue to rise? According to the SV40 Foundation, "SV40 is a problem that federal government authorities have not addressed responsibly because the government's own vaccine programs are responsible for the spread of the virus throughout the western world".(2) It is no question the public has not forgotten, even after almost 50 years, and much more research into this area is needed, to attempt to confirm SV40's causal role, if any, in the development of MM.

References

(1)Mesothelioma. Retrieved April 2010.

(2)"Treating SV40 Cancers." Retrieved April 2010.

(3)Carbone, M. "Simian virus 40 and human tumors: It is time to study mechanisms." Retrieved from PubMed April 2010.

(4)López-RÃos F, Illei PB, Rusch V, et al. "Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids". Lancet. 2004;364:1157-1166.

(5)Yang, Haining et al. "Mesothelioma Epidemiology, Carcinogenesis, and Pathogenesis." http://www.ncbi.nlm.nih.gov.proxy.lib.uiowa.edu/pmc/articles/PMC2717086/. Retrieved from PubMed April 2010

(6)CDC. "Mesothelioma." Retrieved from PubMed April 2010.