Cancer and Viruses

Known Cancer-Pathogen Associations Photo: Bill BransonJames J. Goedert In the 1960s and '70s, as part of a nationwide war on cancer, U.S. virologists took part in a massive effort to find virally caused human cancers. They didn't find much in the way of causative viral agents, but their research did lead to key, high-impact discoveries including the tumor suppressors p53, ras, and myc, not to mention HIV. A profusion of interest in the cancer-causing roles of tumor suppressors, signal transduction, and cell cycling has followed. But some contend it's time to return to viruses--to complement the incredible molecular and cell biology insights of the last 20 years with a better knowledge of the role that viruses and other pathogens play in the etiology of human cancers. University of California, San Francisco, professor of medicine Jay Levy, codiscoverer of HIV in 1983, goes so far as to say that there's a "new enthusiasm for finding unknown agents as the cause of cancer." He credits the discovery of the bacterium Helicobacter pylori for starting the trend. In the mid-1990s, H. pylori was confirmed to be a leading cause of ulcers, which can lead to cancer. "We have to go back and examine the evidence in terms of epidemiology as to what the real causes of cancer are," claims George Miller, a professor of pediatrics and epidemiology at Yale University and an investigator of both Epstein-Barr virus (EBV) and Kaposi's sarcoma (KS)- associated herpes virus, also called human herpes virus 8 (HHV-8). "There needs to be better advocacy for this idea." Advances in technology have largely sparked some researchers' renewed interest in the cancer-virus connection. The advent of PCR has enabled scientists to scan suspect tissue for nonhuman DNA, facilitating the discovery of new infections. Among these are the AIDS-related HHV-8, which causes KS and has been associated with lymphomas; hepatitis C, which has been shown to cause liver cancer; and human papilloma virus (HPV)--especially HPV-16 and -18--which causes more than 90 percent of cervical cancer cases. Representational difference analysis, western blot analysis, microarray displays, and other tools have also allowed investigators to see what might be lurking within the cancer. "These molecular techniques are really exciting young investigators," says Levy. Photo: Yale BMC-Jerry DomianGeorge Miller Association and Causation With many cancer-associated viruses, however, investigators have had a tough time proving causation--it may be difficult to detect or simply not there. The most notable exceptions: HPV and hepatitis B, which is known to cause hepatocellular carcinoma. Both viruses are relatively simple, and the mechanisms that trigger the cancer have been well characterized. They both suppress p53. With hepatitis B, a viral X protein, HBx, suppresses and inhibits DNA repair; with HPV, a protein called E-6 binds to, and interferes with, the tumor suppressor. Hepatitis B can also directly integrate into the human genome. The characterization of these mechanisms has helped facilitate treatments: A hepatitis B vaccine is currently in use, and HPV vaccines are in Phase I and II clinical trials. Researchers also have a pretty good idea of the mechanism of action for human T-cell leukemia/lymphoma virus (HTLV-1), implicated in adult T-cell leukemia. Like HPV and hepatitis B, HTLV-1 has a gene product (called a transactivating protein, or tax) that is thought to interfere with tumor suppressors and to inhibit DNA repair. In other cases, the lack of a well-understood mechanism has made it difficult to show cancer causation and thus demonstrate proof of principle for treatments. More complex viruses such as hepatitis C, EBV, and HHV-8 seem to act indirectly. Some appear to stimulate cell replication but haven't been shown to provoke malignancies. Strong associations with these viruses and cancers have, nonetheless, inspired treatments. EBV's apparent role in the development of nasopharyngeal carcinoma in China has been the impetus for a vaccine.1 In one of the few studies demonstrating a link between EBV and another cancer companion, B-cell lymphoma, doctors treated patients who had received bone marrow transplants from unrelated donors.2 Severely immunosuppressed to prevent transplant rejection, these patients sometimes develop the cancer due to the growth of EBV-transformed cells that come from the donor. The study, led by Cliona M. Rooney of Baylor College of Medicine, found that T cells taken from the donor can prevent, or sometimes even treat, donor-derived lymphomas. According to Rooney, several groups are now trying to generalize this "special case" to other EBV cases and to other cancers as well. She says similar cell therapy studies in melanoma and prostate cancer have had promising results. And there's better efficacy evidence for HHV-8, which is sensitive to antivirals. One prospective study, which was actually meant to indicate whether antivirals would affect the incidence of cytomegalovirus retinitis, ended up showing the effectiveness of the drugs on HHV-8.2 The incidence of KS was significantly lower among subjects who received the antivirals systemically. Other cancer-virus links remain speculative. A 1997 workshop on the relationship between breast cancer and viruses held by the National Action Plan for Breast Cancer (NAPBC), a partnership between grassroots breast cancer activists and the government, attempted to stimulate interest in the tenuous link between breast cancer and viruses such as EBV and mouse mammary tumor virus (MMTV). The cochairman of the 1997 NAPBC workshop, Gertrude Case Buehring, a professor of tumor virology at the University of California, Berkeley's School of Public Health, contends that failed work on a breast cancer-virus link in the 1970s has diverted attention and funding away from the field. The workshop sparked relatively little research. But new techniques, especially PCR, could warrant a second look at the breast cancer-virus connection in humans. One recent study hypothesizes a link between breast cancer and MMTV based on a correlation between the geographical distribution of breast cancer cases and the incidence of the virus.4 However, several sticking points remain. Perhaps the biggest: finding evidence for exactly how the virus could be transmitted from mice to women. Photo: Karen Preuss (c)1996Jay Levy According to Buehring, focusing on the cancer contribution of viruses makes good sense from a public health standpoint. Investigators should be able to better control the cancer if they're able to carry out primary prevention--intervening at the level of the initiating agent(s) of the cancer--rather than secondary prevention that only seeks early detection to prevent death. Buehring notes that using the hepatitis B vaccine for liver cancer represents a successful primary prevention measure. Says Buehring, "This is far more effective than trying to do early detection and operate and remove pieces of people's livers." "The most urgent thing is to take care of HIV," remarks James J. Goedert, chief of the viral epidemiology branch at the National Cancer Institute. "If you take care of HIV ... you indirectly take care of the cancer in a very potent way." Goedert, who's the editor of a book titled Infectious Causes of Cancer: Targets for Intervention, due out this April, notes that persons with both HIV and HHV-8 are at much higher risk for KS than those with HHV-8 alone. Goedert's currently working on finding coreceptors or other factors related to virus-infection resistance. As has been the case with CCR5--an HIV coreceptor that, if mutated, protects against the disease--such coreceptors could point to avenues for prevention. While the role of different viruses in the etiology of human cancers varies widely and their scope as treatment targets remains unclear, few would dispute that more and more viruses will be found to be associated with cancers in the coming years. Says Goedert, "Things are going at a very rapid pace in terms of both discovery of new viruses, and [in terms of] getting some better understanding about how the ones we know about work." Eugene Russo can be contacted at erusso@the-scientist.com. References 1. M. Watanabe, "Epstein-Barr virus: implicated in cancer etiology in China, impetus for a vaccine," The Scientist, 13[6]:1, March 15, 1999. 2. C.M. Rooney, "Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr virus-related lymphoproliferation," Lancet, 345:9-13, 1995. 3. D.F. Martin et al., "Oral ganciclovir for patients with cytomegalovirus retinitis treated with ganciclovir implant," New England Journal of Medicine, 340:1063-70. 4. T.H. Stewart et al., "Breast cancer incidence highest in the range of one species of house mouse, Mus domesticus," British Journal of Cancer, 82:446-51, January 2000.

Cancer and Viruses

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