Research into possible new links between cancer and viruses continues, with scientists accruing new data on a number of fronts. The question is, when viruses are found in cancer cells, does their presence signify causation, or are they just "accidental" passengers?
Head and Neck Cancer
The first published evidence for a likely association between head and neck cancers and human papillomaviruses (HPVs) came only 3 years ago, although HPV type 16 (HPV16) had been a suspect in these cancers since 1983. About 20% of all head and neck cancers are HPV-positive (the most common types are 16, 18, 31 and 33), said Maura Gillison, M.D., Ph.D., assistant professor of oncology at the Johns Hopkins School of Medicine in Baltimore.
A recent study in the Journal of the National Cancer Institute in December added to the evidence of a possible connection in a subgroup of head and neck cancers. In a casecontrol study of about 3000 people, DNA for HPV was found in 3.9% of biopsy specimens of patients with cancer of the oral cavity and in 18.3% of cancers of the oropharynx. The most prevalent type was HPV16, the most common HPV in cervical cancers. In addition, the presence of antibodies against the HPV oncoproteins E6 and E7 was associated with the risk of cancer of the oropharynx and, to a lesser degree, cancer of the oral cavity. (Antibodies to the E6 and E7 oncoproteins are considered markers of HPV-transformed tumors.)
The new study fits in with the epidemiology and biology of the virus, said Gillison. To show causation in head and neck cancer, the viral genome should be localized in the tumor cell nucleus and express viral oncogenes, HPV-associated cancers should be predominantly squamous in origin with basaloid pathology, patients with such cancers should have risk factors related to sexual practices, the cancers should occur at greater-than-expected rates in the immunocompromised and those with a previous HPV-associated malignancy, and patients should develop serum antibodies to the E6 and E7 proteins. All these criteria have been fulfilled for a subset of head and neck cancers, said Gillison.
Notably, the HPV-related subgroup of patients with head and neck cancer differs from the "traditional" head and neck cancer patients, who are generally smokers and drinkers. HPV16-positive head and neck cancer patients tend to be nonsmokers, nondrinkers, on average 5 years younger, and have better prognoses (a 60% to 80% lower risk of dying from their disease) than their HPV-negative counterparts. They have risk factors similar to patients with HPV-positive genital cancers: young age at first intercourse, higher number of sexual partners, history of genital warts, history of performing oral sex, and if men, are husbands of women with cervical cancer.
HPV16 and Ovarian Cancer
Although the causality between HPV and cervical cancer is well established, the viruss role in other genital tract malignancies is unclear.
In a prospective study of 15,000 pregnant women published in 2001, Charles Rabkin, M.D., of the Viral Epidemiology Branch at the National Cancer Institute, and colleagues examined the association of HPV16 viral-like particle antibodiesa marker for exposure to the viruswith subsequent risk of cervical, endometrial, and ovarian cancers. They found that HPV16 seropositivity was associated with cervical cancer, but associations between endometrial and ovarian cancers were not statistically significant. But because the odds ratio for both cancers occurring within 20 years were "strikingly similar" to that of cervical cancer, the connection warranted further study, Rabkin said.
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MMTV and Breast Cancer
The discovery in 1936 that a mammary tumor could be caused by an agent in the milk of certain strains of mice led to the hypothesis that a similar agent could play a role in human breast cancer, said Beatriz G.-T. Pogo, MD, professor of medicine at New York Citys Mt. Sinai School of Medicine. One such agent under investigation is mouse mammary tumor virus (MMTV).
It is generally accepted that MMTV causes breast cancers in certain strains of mice and can be transmitted horizontally as an infectious particle containing viral DNA (via breast-feeding) or vertically in the germline. Unlike HPV, MMTV does not contain an oncogene, but acts as a slowly transforming virus, integrating close to cellular proto-oncogenes, enhancing their activity, and dysregulating the cell cycle by a number of mechanisms, said William Rawlinson, Ph.D., B.Sc., of the Prince of Wales Hospital in Randwick, Australia. "The search for a breast cancer virus in humans, which began in the early 1970s, has been controversial and the source of acrimonious debate," Rawlinson said.
By the mid-1980s, the discovery of human endogenous retroviruses (HERVs), some of which resembled MMTV, cast doubt on the breast cancer virus theory. But more recent research by a few groups is reigniting the debate. In 1995, Mt. Sinais Pogo identified a sequence of the MMTV env gene in 38% of 314 breast tumors, but not in normal breast and other tissues. In 2000, Pogo and colleagues found an MMTV sequence integrated into several chromosomes of env-positive breast cancer cells. And in 2003, Pogo found that 62% of samples of gestational breast cancer contained the MMTV-like sequences, suggesting that hormones may promote cell growth, as they do in the mouse. Separately, Polly Etkind, Ph.D., of New York Medical College, found MMTV-like env sequences in 37% of human breast tumors analyzed that are 99% homologous to one strain of MMTV and 100% homologous to another strain.
Susan Ross, Ph.D., professor of microbiology at the University of Pennsylvania, noted that a potential flaw in the MMTVbreast cancer theory is that the mechanism of infection from mouse to human is as-yet undetermined. Rosss recent work shows that MMTV infects human cells only with difficulty. "Im not a believer in a human version of MMTV, and I dont see any evidence that mouse virus can infect human cells," Ross said.
More recently, Rawlinson and his colleagues found MMTV-like sequences in 42.2% of tested breast cancer tissue from Caucasian-Australian women but only 0.8% and 0% of breast cancer biopsy tissue from Vietnamese and Vietnamese-Australian women, respectively. That the first-generation Australian-Vietnamese women had low or no levels of the virus suggests that the infection is acquired and geographically related, Rawlinson said. "It would be interesting to examine the prevalence of MMTV-like gene sequences in the next generation of Vietnamese women born in Australia, to additionally investigate the impact of geography and environment on MMTV-like gene sequences."
Rawlinson said that the case for MMTV and breast cancer is far from proven, and the virus is unlikely to be the sole causative agent for the 80% to 90% of unexplained sporadic breast cancer cases. But he believes that strong evidence exists that the virus could act as a co-factor with diet and hormones in some cases of breast cancer, and he feels that the research should continue and that the oncology community should open their minds to the possibility of an infectious etiology. Although the Bradford Hill criteria have not been satisfied for MMTV, James Goedert, M.D., chief of NCIs Viral Epidemiology Branch admitted that "a possible causal connection is still a live issue."
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