22 October 2002 10:28 EST

by Apoorva Mandavilli

[caption and credit]

There is "strong" evidence that the simian virus SV40 can cause human cancers, an Institute of Medicine (IOM) panel reported today. But despite the biological evidence, epidemiological studies to date are "inadequate" to conclude that contaminated polio vaccines are the source of the virus, the panel said.

Between 1955 and 1963, as many as 30 million children and adults received inactivated polio vaccine tainted with SV40, previously identified as a harmless pathogen in the rhesus macaque. Researchers discovered the contamination in 1960 and, by 1963, cleared the virus-ridden vaccines.

In the past few years, however, an increasing number of reports have suggested that SV40 is to blame for higher rates of mesothelioma, ependymomas, bone cancers and non-Hodgkin's lymphoma. In laboratory studies, researchers have shown that the virus can produce those tumors in rodents, nonhuman primates, and cultured human cells.

While some researchers have reported that the virus is detectable in tumors, others have published directly contradictory data, maintaining that the virus is either not present in the tumors or, if present, does not cause tumors.

After reviewing scores of such opposing studies, the IOM panel conclude that there is sufficient evidence to suggest that SV40 is a human pathogen and a strong transforming agent.

The conclusion exactly echoes an independent report from a meeting held last year to discuss the controversial issue, notes Michele Carbone, associate professor of pathology at Loyola University in Chicago.

"Both [reports] concluded that in fact SV40 is not only present in human tumors but that there's reason to believe that SV40 causes cancer," he told BioMedNet News. Carbone is author of several reports linking SV40 to human cancers, particularly human mesotheliomas.

Panel members are careful to point out that the presence of the virus in tumors does not by itself demonstrate a causal link. Tumors often contain viruses that are unrelated to their origin, notes Marie McCormick, professor and chair of maternal and child health at the Harvard School of Public Health, and chair of the IOM panel.

Most of the epidemiological studies on SV40 have also shown no association between contaminated vaccines and tumors, McCormick adds. But because the studies were flawed, and relied on inconsistent methods, panel members were "quite unwilling to come down on the side of no-evidence," she said.

Instead, the panelists conclude that the evidence is "inadequate to accept or reject" that virus-contaminated vaccines are to blame for certain cancers. Before embarking on further epidemiological studies, they recommend that researchers develop more sensitive and reliable tests for SV40.

Although polio vaccines have been free of the virus since 1963, says McCormick, developing such tests is critical. The virus has been detected in people too young to have received contaminated polio vaccine, suggesting that they have been exposed to the virus through other means, including person-to-person transmission from a vaccinated individual.

"Can [SV40] be transmitted from humans to humans? That, I think, is the big question and not answered at all," said McCormick. The viral epidemiology group at the US National Cancer Institute is now studying how the virus is transmitted, she adds.

Whatever the origin of the virus, Carbone says he is more interested in studying how the virus causes cancer.

Carbone and others have previously shown that the viral protein Tag binds and inactivates the tumor-suppressor proteins p53 and Rb. But inhibition of p53 and Rb is not enough to cause tumors, Carbone says.

In an article in press in Oncogene, Carbone reports that SV40 induces Notch1, a key regulator of development. Pharmacological inhibitors of Notch1 inhibit tumor growth in sv40-positive human mesothelioma cell lines, the researchers found. "We hope this can be a useful target in the clinic," Carbone said. "Notch1 may be the missing link to understanding how [SV40] causes cancer."

Picture caption and credit:
Transmission electron micrograph of polyomavirus SV40, CDC/Dr. Erskine Palmer.

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