Viral Infections Increasingly Implicated in Cancer Growth and Development.

By Jennifer Warner
WebMD Medical News Reviewed By Michael Smith, MD
on Wednesday, December 10, 2003

Dec. 10, 2003 (New York) -- You can't "catch" cancer like a cold, but new research now shows that infection with any of a number of different viruses may play an important role in the growth and development of cancer.

More than a dozen different viruses have been linked to various forms of cancer. In most cases, the presence of a particular virus increases the risk of developing cancer or speeds its progression. For example, HIV and other viruses that affect the immune system make infected individuals prone to a variety of cancers by weakening the body's natural defenses.

But in other cases, there is now compelling evidence that certain viruses may also play a critical role in causing cancer. Proving that a particular virus causes cancer, however, is complicated.

"One of the things that is complicated about this is that there is a long time between exposure to the virus and development of the cancer," says Bruce Johnson, MD, of the Dana-Farber Cancer Institute in Boston. "Number two is that it's not a one-to-one thing. There are a lot more people who are exposed [to a virus] than have evidence of a tumor."

Johnson moderated a briefing today in New York City on the virus-cancer link sponsored by the American Society of Clinical Oncology.

Currently, Johnson says the scientific evidence is strongest for the link between cancer and the human papillomavirus (HPV) and the hepatitis B and C viruses, but many other viruses are also under investigation for their ties to cancer.

HPV Linked to More Than Cervical Cancer

HPV has long been associated with an increased risk of cervical cancer, but new research suggests that the virus may also cause head, neck, and anal cancers. HPV is the most common sexually transmitted virus, and about 5.5 million people in the U.S. become infected with HPV each year.

In many people, HPV infection causes no symptoms and resolves on its own without causing illness. But about 18 of the 120 different types of HPV are closely associated with cancer and are known as high-risk types.

"Over the last three years there has been an explosion of data on HPV," says Maura Gillison, MD, PhD, assistant professor of oncology at the Johns Hopkins School of Medicine in Baltimore, who also spoke at the briefing.

Gillison says HPV has now been implicated in 99% of cervical cancer cases. But new studies show that the virus is also responsible for the majority of tonsillar and anal cancers, which helps explain a dramatic rise in these types of cancer in recent years.

Gillison says up to 15% of the cancers reported each year worldwide are caused by HPV infection, and the virus accounts for one-third of all cancers attributable to infectious agents.

Hepatitis Infections Behind Rise in Liver Cancer

Researchers say viruses are also to blame for a dramatic 71% increase in the incidence of liver cancer from 1976-1995. Hepatitis B and C viruses are the major risk factors for developing liver cancer, and more than 80% of liver cancer cases worldwide are linked to hepatitis B infection in areas where the virus is prevalent, such as developing countries.

But experts say hepatitis C may actually account for the rise in liver cancer in developed countries. Hepatitis C is transmitted primarily through intravenous (IV) drug use, blood transfusions with infected blood, and sexual contact.

Viral Infections Increasingly Implicated in Cancer Growth and Development
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Although hepatitis C infection is less common than hepatitis B, affecting about 100 million vs. 300 million worldwide, researchers say hepatitis C is more dangerous.

Many people with hepatitis B never develop symptoms and the virus resolves on its own. But more than 80% of those infected with hepatitis C develop a chronic infection that can lead to cirrhosis of the liver and liver cancer.

But liver cancer does not develop overnight after hepatitis infection and often takes years to develop.

"If you can block infection or [successfully] treat chronic hepatitis infection, you don't get sick," says Andrew Zhu, MD, PhD, assistant physician at Massachusetts General Hospital in Boston, who also spoke at the briefing.

In the U.S., the number of liver cancer cases and related deaths has doubled between 1975 and 1998. Although this increase has affected all ethnic groups, the largest increase has been among white men ages 45-54. Zhu says those trends are likely to continue over the next 10 to 20 years.

Future Directions

As researchers learn more about the role viruses play in cancer, they can develop better, more targeted treatments to reduce the risk or slow the progression of cancer in infected individuals.

But experts say the greatest promise lies in the development of vaccines that protect people at risk from infection and prevent cancer from occurring.

One example of such a vaccine already in development is an HPV-16 vaccine that targets a form of the HPV virus closely associated with cervical cancer.

A clinical trial of the vaccine published last year in The New England Journal of Medicine showed that young women given three doses of the vaccine developed antibodies against HPV-16 and were protected against both persistent HPV infection and cervical cancer.

In areas where hepatitis B is prevalent, the primary mode of transmission is from mother to child during birth, but the virus may also be transmitted through sexual intercourse, IV drug use, or blood transfusions.

A vaccine that protects against hepatitis B has been in use for many years. The American Academy of Pediatrics recommends the hepatitis B vaccine for all children 18 years and younger. In addition, adults at increased risk of hepatitis B, such as health-care workers, should also get the vaccine.

A nationwide vaccination program in Taiwan that started in 1984 has now been credited with reducing the incidence of liver cancer in children by 50%.

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SOURCES: Maura Gillison, MD, PhD, assistant professor of oncology, Johns Hopkins School of Medicine, Baltimore. Bruce Johnson, MD, chairman-elect, American Society of Clinical Oncology Communications Committee; Dana-Farber Cancer Institute, Boston. Andrew Zhu, MD, PhD, assistant physician, Massachusetts General Hospital, Boston.

'Breast cancer virus' found


Breast cancer affects one in nine British women
Scientists have found a possible link between a newly-discovered virus and breast cancer.
Doctors in Australia discovered the virus in 40% of tissue samples taken from women with the disease.

Further tests showed that only 2% of women without the disease carry this virus, which is called HHMMTV.

While further research is needed, they hope the discovery could lead to new treatments to fight breast cancer. It affects one in nine British women.

The scientists, from Sydney's University of New South Wales and Prince of Wales Hospital, found evidence to suggest that many men who develop breast cancer may also carry this virus.

Our preliminary research indicates that a virus may be involved

Caroline Ford
They identified the virus in 50% of the male breast cancer tissues they tested.

The scientists believe the virus may be the human form of the mammary tumour virus. This causes 95% of breast cancer in mice.

Further research

While it is too early to suggest that this virus may cause breast cancer, the researchers said they were excited by the finding.

Caroline Ford, who led the study, said the discovery could lead to new treatments for the disease if a link can be proven.

"Many people believe that breast cancer is purely a hereditary disease, yet hereditary breast cancer is estimated to account for only 5% of all cases of breast cancer," she said.

"In other words, we have little idea what causes 19 out of 20 cases.

"Our preliminary research indicates that a virus may be involved.

"This new research supports the link between this virus and breast cancer in Australia.

"If it can be shown that this virus causes cancer, the possibility of a preventative vaccine for breast cancer would be of enormous consequence," she said.

"It's an exciting discovery, but there's a lot of work still to do to get sufficient proof of the role of the virus."

The study is published in the Journal of Clinical Cancer Research.

The findings were presented at Australia's Fresh Science Forum, which is part of the government sponsored Science Week

Cancer Virus Now Tied to Deadly Lung Ailment

By Ed Edelson
HealthDay Reporter

WEDNESDAY, Sept. 17 (HealthDayNews) -- A virus that causes a form of skin cancer, Kaposi's sarcoma, has been found in patients with a rare and deadly lung condition, researchers report.

If the finding is confirmed, it will be a first clue to the cause of the condition, known as primary pulmonary hypertension.

Pulmonary hypertension is abnormally high blood pressure in the lung arteries, which can ultimately cause heart failure. Most cases of pulmonary hypertension are labeled "secondary," meaning they are caused by another breathing disorder, such as bronchitis.

Primary pulmonary hypertension, in which the cause is unknown, occurs in only one to two of every 1 million Americans. With careful treatment, says the Pulmonary Hypertension Association, "some patients have been able to manage the disorder for 15 or 20 years or even longer."

Now a group led by Dr. Norbert F. Voelkel of the University of Colorado Health Sciences Center reports in the Sept. 18 issue of the New England Journal of Medicine that evidence of infection with human herpesvirus-8 (HHV-8), which is known to cause Kaposi's sarcoma and several forms of blood cancers, has been detected in 10 of 16 patients with primary pulmonary hypertension.

It is an important finding because "if it does cause the condition, that would help find treatments for the disease," says Dr. Ethel Cesarman, an associate professor of pathology at Cornell University's Weill Medical College, who wrote an accompanying editorial. "And you can have other defenses, such as vaccinations."

One reason why the researchers looked for HHV-8 in these patients is that the virus often accompanies HIV, the virus that causes AIDS, the journal report says. In Africa, where HIV infection is rife, HHV-8 Kaposi's sarcoma is "the most common cancer in children," Cesarman says.

Tests were done on cells from patients with either primary or secondary pulmonary hypertension, the researchers report. Immune system antibodies generated by exposure to HHV-8 were found in 10 of the patients with primary hypertension, but none were found in the patients with the secondary form of the disorder.

"The paper suggests that the virus causes it, but it requires confirmation," Cesarman says, and the researchers acknowledge that "we cannot conclude that infection alone causes this condition." One possibility is that having pulmonary hypertension increases the risk of HHV-8 infection, they say.

But they also report that tissue samples from primary pulmonary hypertension patients and those with Kaposi's sarcoma look alike, with narrow, slit-like spaces between cells and sheets of cells that produce VEGF, a growth factor that causes overproduction of skin cells and cells of the endothelium, the tissue that lines the lung arteries.

That resemblance leads to a logical theory of how the HHV-8 virus is involved in development of pulmonary hypertension. When someone with an underlying genetic characteristic, as yet unidentified, is infected with HHV-8, the result can be uncontrolled growth of the cells of the lung artery endothelium that chokes blood flow, causing the severe rise in blood pressure that creates the lung problem, the report says. That mimics the presence of HHV-8 virus in the skin that causes the uncontrolled cell growth of Kaposi's sarcoma, it adds.

More information

You can learn about the disorder from the Pulmonary Hypertension Association or the American Heart Association.

(SOURCES: Ethel Cesarman, M.D., Ph.D., associate professor, pathology, Weill Medical College, Cornell University, New York City; Pulmonary Hypertension Association; Sept. 18, 2003, New England Journal of Medicine)

Copyright © 2003 ScoutNews, LLC. All rights reserved

THE INHERITED BREAST CANCER VIRUS

The Mouse Virus

Mouse mammary tumor virus (MMTV) is a B-type retrovirus. Discovered in 1936, MMTV causes mammary cancer in mice through a process called insertional mutagenesis. A human homolog of MMTV has long been sought by researchers.

The Retrovirus Life Cycle

Unlike most other organisms, the genome of a retrovirus is composed of RNA instead of DNA. This means that infectious retroviral particles contain RNA. After infection of a cell by a retrovirus, the viral RNA is released into the cell along with several proteins which are required for the initial steps of viral replication. One of these proteins is called reverse transcriptase. After the release of the RNA, the reverse transcriptase makes, or transcribes, a DNA copy of the viral genome. This DNA copy is then inserted somewhat randomly into the DNA of the infected cell. The insertions occur in areas of the cell's DNA that are undergoing the normal DNA replication that happens prior to cell division, so only actively growing cells can support insertion of viral DNA. After the DNA copy is inserted into the cell's DNA, viral sequences then direct the expression of the viral genome. During this process, which in the case of MMTV occurs in response to estrogen, a complete RNA copy of the entire viral genome is produced. This RNA is then packaged into infectious viral particles, and the viral particles are subsequently released from the cell where they can infect another cell and start the whole cycle again.

Insertional Mutagenesis

During the viral life cycle the insertion of the viral genome occurs most of the time within "silent" regions of the cell's DNA. These silent regions, which account for the vast majority of the DNA within a cell, have no known function. Sometimes, however, the insertion occurs within or very near the DNA base pairs that make up a gene, and the presence of the virus's inserted DNA alters the function of that gene. The altered gene is said to have been mutated, and this process is called insertional mutagenesis. If the normal function of a gene is critical to the survival of the cell, then a mutation of the gene will kill the infected cell. But if the gene controls a non-critical function of the infected cell, such as its growth, the cell can survive the insertion despite the fact that the cell's physiology has been permanently altered. In some cases this mutation has no outward effect on the cell, but in other cases the mutation can have profound effects on how the cell grows and behaves.

Oncogenes and Cancer

Genes that are susceptible to mutations that cause cancer are called oncogenes. Oncogenes typically control the normal growth and division of cells. During the replication of MMTV, the viral DNA is sometimes inserted within or near a mouse oncogene and changes the function of that gene. Frequently, such mutations result in the formation of a tumor. In mice, about thirty oncogenes have been found that trigger mammary tumor formation after the insertion of the mouse virus's DNA. Because the chances of an insertion occurring within or near an oncogene are low for each virus replication cycle, not all infected cells will become cancerous. However, because rounds of replication and insertion occur over and over again during the lifetime of the mouse in millions of cells, the chances are very good that at some point a mammary tumor will develop. Because this process takes time, MMTV is called a slow-transforming virus.

Inheriting the Virus

During the study of MMTV, researchers found that there are two routes of transmission of the virus in mice. In the first route, the virus is passed from a mother mouse to her pups through her milk. This route is said to be exogenous because the virus passes to the pups outside of the mother. In the second route of transmission, the pups inherit the virus directly from their mother. The pups are infected even without ingesting infected milk, and thus this route of transmission is said to be endogenous. Both routes of transmission result in infected mice, but strains of mice in which the virus has become endogenous usually have higher rates of cancer.

A retrovirus becomes endogenous to an animal after the pro-viral DNA chain, or genome, of the virus is inserted into the DNA of the sperm or egg cell from which the animal happens to be conceived. Once the viral DNA has entered the DNA of the parent's germ cell, the viral DNA is indistinguishable from any other portion of the parent's DNA. After conception, the viral DNA is reproduced every time the embryonic cells divide, and when the baby animal is born, every cell in its body contains the viral DNA. The viral DNA is thus said to be endogenous to the animal. When the animal becomes an adult, every one of its sperm or egg cells will also contain the viral DNA, and the offspring of the animal will inherit the viral DNA in Mendelian fashion, just like any other genetic trait would be inherited.

A mouse with endogenous MMTV thus has the DNA of the virus in every cell of its body. MMTV responds to estrogen, so at puberty all of the mouse's estrogen-sensitive tissues begin to express the virus's messenger RNA. There is an explosion of viral activity that begins at puberty, and for the life of the mouse, every existing and every new mammary tissue cell expresses viral messenger RNA. Insertion of viral DNA is also greatly facilitated by estrogen, which stimulates mammary cells to replicate their DNA and divide, thus providing large numbers of possible insertion sites.

A female mouse with endogenous MMTV is thus somewhat akin to a time bomb. After puberty, every mammary cell of that mouse will contain an active retrovirus which repeatedly inserts copies of its genome randomly within the cell's DNA and in the vicinity of thirty oncogenes. Though MMTV is a slow transforming virus, all of this viral activity in all of these mammary cells makes the odds high that in at least one cell one of the oncogenes will sooner or later become an insertion point. When that does happen, the oncogene will be mutated by the added base pairs of the retrovirus and will begin to create a tumor.

The Endogenous Viruses in the Human Genome

In humans, the DNA chain, or genome, contains about 3 billion base pairs. The human genome contains perhaps 30,000 to 50,000 genes. These genes occupy only about 100 million base pairs, however, and about 2.9 billion base pairs thus represent silent regions of the human genome. Some of these silent base pairs play a structural role, but little is known about most of the silent DNA.

One relatively recent discovery is that the silent regions in humans contain perhaps 50,000 or more endogenous retroviruses and retroviral sequences which have entered the human genome. They are called human endogenous retroviruses, or HERVs, and the majority of these HERVs have some similarity to MMTV.

Significantly, not all humans inherit all HERVs.

The Exogenous Human Homolog of MMTV

There may be both exogenous and endogenous human homologs of HMTV.

Pogo and Holland et al have discovered and won patents for a retrovirus which is more than 95% identical to MMTV. They have found the viral DNA sequences in about 40% of human breast cancer tumors. The Pogo virus is an exogenous virus, because no pro-viral DNA of this virus is present in the blood cells or other normal cells of the breast cancer patients.

In 2000, T.H.M. Stewart et al reported that their epidemiological data showed a close correlation between human breast cancer incidence and mouse ranges, with the highest incidence of human breast cancer worldwide occurring in lands where Mus domesticus is the resident native or introduced species of house mouse. The researchers concluded that humans may be able to acquire MMTV from mice, and the possibility exists that the Pogo virus is such a virus. In 2002, A.F.R. Stewart identified two human genes which produce proteins that are highly related to the MMTV receptor in mice and concluded that transmission of MMTV from mice to humans is a real possibility.

HMTV - The Endogenous Human Homolog of MMTV

Dr. Robert F. Garry, professor of Microbiology and Immunology at Tulane Medical School, has discovered a retrovirus which is also more than 95% identical to MMTV but which is endogenous to humans. Dr. Garry has called his discovery Human Mammary Tumor Virus, or HMTV. HMTV appears to be one of the HERVs. He has also found additional homologs of this virus in cats and in rhesus monkeys.

Dr. Garry has data showing that HMTV DNA sequences appear in about 90% of the human breast cancer patients tested and that the pro-viral DNA appears in the normal blood cells of substantially all of these patients. Dr. Garry has also found the pro-viral DNA of MMTV in the blood cells of approximately 15% of healthy women and men tested. In addition, the data suggests that the number of copies of the virus may be elevated in tumor tissue compared to normal tissue from the same individual. This last finding suggests that HMTV-related tumor formation may result from insertional mutagenesis, and together the data suggests that the 15% of women who have inherited the pro-viral DNA of HMTV may represent a group in which about 90% of breast cancer cases will ultimately arise.

The implications of this finding are dramatic, because they suggest that a blood test which detects the HMTV sequences would be able to tell a woman and her physician whether she was among the small group (about 15%) of women who were very likely to develop breast cancer or among the large group (about 85%) of women who were very unlikely to develop breast cancer. The HMTV-positive women could be monitored aggressively for signs of tumor development, and other prophylactic regimens could perhaps be developed.

In May 2002, Dr. Julian Peto presented data to the Oncogenomics conference in Dublin which suggested that "many, possibly the majority, of breast cancers occur in a minority of women with an inherited risk." According to Dr. Peto, "Identifying and monitoring these susceptible women is going to be an important challenge." Dr. Peto's data was derived from a study of 2,300 sets of identical and non-identical twins.

The Peto study showed that twins of women diagnosed before the age of 40 were at no higher risk of developing breast cancer in later life than twins of patients diagnosed after age 50. Their risk just increased at an earlier age. Dr. Peto said that the data was "all rather puzzling, but it seems breast cancer genes are doing two different things. Some genes act as timer switches, determining when a woman's risk of breast cancer should begin, while other genes dictate how big the risk will be."

Since Dr. Peto and his colleagues had not identified any of the genes of which he spoke, it is a conceptual puzzle rather than a practical puzzle he described. The data is easily explained, however, if the inherited risk is assumed to arise from an MMTV-like HERV instead of from one or more genes, so the Peto findings add support to the Garry findings.

Autoimmune is conducting further studies of HMTV, including studies being done in association with a multinational health care company. Tulane has filed patent applications covering HMTV in the U.S. and other countries.

This material is not intended to take the place of a physician's advice.

 

Another virus found to play a role in cancer

The common BK virus, a polyomavirus which lives in the kidneys and remains inactive except in people with depressed immune function, may play a role in the development of prostate cancer according to research published July 19, 2004 online in the journal Oncogene (http://www.nature.com/onc/index.html). Scientists from the University of Michigan Medical School have discovered DNA and proteins from the BK virus in prostate tissue with abnormal changes known as atrophic lesions, which are precursors of prostate cancer.

The BK virus uses a protein known as Tantigen (TAg) to induce cell division in its host cell because the virus does not have enough genes to reproduce by copying its own DNA. However, by interrupting the normal cell cycle of the host cell to force it to divide, abnormal cell division is sometimes a result.

The researchers examined twenty-one prostate tissue samples obtained from men with prostate adenocarcinoma. The samples contained normal, precancerous and cancerous cells. The team found the BK virus in 71 percent of the samples, however TAg was present in only the atrophic lesions, and not in normal or cancerous tissue. They also found a protein made by the tumor suppressor gene p53 in the cell’s cytoplasm. Lead researcher and professor of microbiology and immunology at the University of Michigan, Michael J. Imperiale, PhD, commented, "We know that for p53 to function as a tumor suppressor gene, its protein product must be in the cell's nucleus. TAg apparently sequesters p53 protein in the cell's cytoplasm, preventing it from entering the nucleus and giving the signal for the cell to stop dividing and die."

Dr Imperiale concluded, “Our results do suggest that the virus plays a role in the transition from normal to uncontrolled growth of prostate cells."

HMTV BIBLIOGRAPHY

Garry, R.F. Human Mammary Tumor Virus. In: Where We Stand with Breast Cancer Research (N.J. Agnantis and D.D. Tsiftsis, Eds.) Synedron Press (Athens, Greece), 154-156, 1999.

Garry, R.F. Human Mammary Tumor Virus: An Update. In: Hellenic Society for Breast Cancer Research Symposium Report (N.J. Agnantis, Ed.) Synedron Press (Athens, Greece), 15-19, 2001

Pogo, B.G., Holland J.F. Possibilities of a Viral Etiology for Human Breast Cancer. A review. Biol Trace Elem Res. 1997 Jan;56(1):131-42.

Soble, S., Haislip, A.M., Hill, S.M. and Garry, R.F. Human Sequences Related to Mouse Mammary Tumor Virus. Abstracts of the XIth International Congress of Virology. Sydney Australia. VW44.07 p. 80. 1999.

Stewart, A.F.R. Identification of Human Homologs of the Mouse Mammary Tumor Virus Receptor. Archives of Virology. ArchVirol (2002) 127:577-581

Stewart, T.H.M., Sage, R.D., Stewart, A.F.R., and Cameron, D.W. Breast Cancer Incidence Highest in the Range of One Species of House Mouse, Mus Domesticus. British Journal of Cancer (2000) 82(2). 446-451

Possible breast cancer virus identified

Some cases of breast cancer may be caused by a newly discovered virus, according to Australian researchers.

Scientists from the University of new south Wales and Prince of Wales hospital discovered that around 40 per cent breast cancer tissues studied contained, what they believe to be, the human version of a mouse virus called MMTV. This particular virus causes around 95 per cent of breast tumours in mice.

Furthermore, the researchers found that the virus, which they call HHMMTV (human homologue of mouse mammary tumour virus), was only present in 2 per cent of the normal breast tissues studied.

The virus may also play a role in male breast cancers, say the researchers, who found that over 50 per cent of male breast cancer samples tested positive for the virus. They also found that a high number of non-cancerous diseases of the breast that are thought to subsequently increase the risk of cancer tested positive for the virus.

Speaking at Australia’s Fresh Science Forum, part of the country’s government-sponsored Science Week, researcher Caroline Ford said, “Many people believe that breast cancer is purely a hereditary disease, yet hereditary breast cancer is estimated to account for only 5 per cent of all cases of breast cancer. In other words, we have little idea what causes 19 out of 20 cases. Our preliminary research indicates that a virus may be involved.”

She added, “It’s an exciting discovery, but there’s a lot of work still to do to get sufficient proof of the role of the virus. If this virus does in fact play a role it opens up the possibility of a preventative vaccine.”

The research is published in the journal Clinical Cancer Research.

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