Studies of the Viral Origins of Some Cancers Lead
to New Prevention, Treatment Strategies

by Katie Prout Matias

Viruses are nefarious: They not only make people sick with deadly diseases such as AIDS and smallpox but also, by wreaking havoc on normal cellular functions, set the machine of carcinogenesis in motion. Like other viruses, cancer-causing viruses infiltrate cells and use their DNA-synthesizing proteins and mechanisms to replicate. If the cell-cycle control is disrupted in the process and the infected cell grows unchecked, the initial stages of cancer have begun.

Infectious agents contribute to up to 30% of cancer cases worldwide. The four cancers most often caused by infection—both bacterial and viral—are cervical cancer, liver cancer, Kaposi’s sarcoma, and gastric cancer. In most cases of infection with a cancer-causing agent, cancer does not develop; thus, infection is only one component of a multifactorial process that may lead to cancer.

“The goal of the virus is not to make cancer. It is really to keep the cell alive so the virus can propagate,” said Felipe Samaniego, M.D., an assistant professor in the Department of Lymphoma at The University of Texas M. D. Anderson Cancer Center. “The virus produces proteins that prevent cell death, or apoptosis, and it has multiple genes meant to keep the cell alive. If a cell accumulates damage and has a virus that does not allow the cell to fix itself, the cell has the tendency to undergo transformation. Once it becomes a transformed cell, the virus is dispensable; the cancer has already taken over and decided what it wants to do.”

Researchers have spent decades trying to uncover which viruses contribute to which cancers and how infections can be prevented. While teams of investigators in several countries are working to develop vaccines, the list of suspected carcinogenic viruses continues to grow.

Cervical cancer

The clearest culprit in viral oncogenesis is the human papillomavirus (HPV), which is present in 100% of cervical cancers. “This is the only cancer in which a single cause has been identified,” said Guillermo Tortolero-Luna, M.D., an associate professor in the Department of Gynecologic Oncology. “Cervical cancer is the only one that, in order to have the cancer, you have to have the virus.”

More than 100 viruses are classified as HPV, and 40 of these are linked to cancers of the cervix, anus, vulva, vagina, penis, oropharynx, mouth, and skin. All HPV variants are spread primarily through sexual contact. The high-risk strains—including HPV-16, HPV-18, HPV-31, and HPV-45—are also the most common strains, accounting for 80% of infections, said Dr. Tortolero-Luna.

Worldwide, HPV is the most prevalent sexually transmitted disease, and cervical cancer is the second most common cancer among women. Sexually active women have a 75% lifetime risk of contracting HPV; 5.5 million women contract HPV each year. According to Dr. Tortolero-Luna,
80% of women infected with HPV will clear the virus from their bodies within 12 to 18 months. For every 1 million women infected, 100,000 will have precancerous changes in their cervical tissue. Of these, carcinoma in situ will develop in about 8,000, and invasive cancer will develop in about 1,600.

Because so few cases of infection lead to cancer, researchers believe that host, environmental, and viral cofactors are necessary for carcinogenesis. Known cofactors include immunocompromise, smoking, oral contraceptives, childbearing, other sexually transmitted diseases, and a persistent HPV infection, said Dr. Tortolero-Luna.

In developed countries, up to 80% of cervical cancers are prevented with screening and treatment. Cervical cancer is most widespread in underdeveloped regions in South America and parts of Asia and Africa. “The problem more than anything is access: access to screening and adequate treatment,” Dr. Tortolero-Luna said. “What we see is that cervical cancer is basically a disease of the underserved populations.” A vaccine preventing HPV infection would be most helpful to these women.

“Right now, a lot of HPV research is moving into the prevention arena,” said Dr. Tortolero-Luna. “We will see less and less research focusing on cervical cancer and more research focusing on the virus itself.” At M. D. Anderson, Dr. Tortolero-Luna and others have been studying women who are infected with high-risk strains of HPV and measuring their immune system responses to the virus at the time of treatment and six months after treatment to determine whether immune response is a predictor of cervical dysplasia. The purpose is to identify peptides in the immune response that could be used to make a vaccine.

All over the world, clinical trials of potential HPV vaccines are under way. Many of the vaccines are “cocktails,” or combination treatments, for the most prevalent strains of HPV. Some vaccines work by inducing an immune reaction to HPV’s E6 and E7 proteins, which attach themselves to the tumor suppressor genes p53 and Rb and block their control of cell division, thus allowing cells to divide at will. “The vaccines have been shown to be effective already,” said Dr. Tortolero-Luna. “Preliminary data have shown that patients who are infected before vaccination have a higher rate of clearance of the infection, and patients who have not been infected have lower rates of infection.”

Liver cancer

Another cancer strongly associated with viral infection is liver cancer. Together, cervical and liver cancers account for 80% of all virus-related cancers. The main risk factor for hepatocellular carcinoma is infection with either the hepatitis B virus (HBV) or the hepatitis C virus (HCV). Worldwide, 300 million people in underdeveloped countries are thought to carry HBV, which is often transmitted from mother to child. In the United States, an estimated 1.25 million people are infected with HBV. Approximately 170 million people worldwide and 3.9 million Americans are infected with HCV.

“In the case of hepatitis B, the virus appears to be both directly and indirectly carcinogenic. Clearly, viral DNA has been integrated into cells in about 95% of hepatitis B–related hepatocellular carcinomas, but there may be indirect activation of a variety of genes that cause mutation or activation of the pathways that could lead to carcinoma,” said Robert Bresalier, M.D., a professor in the Department of Gastrointestinal Medicine and Nutrition.

Malignancy, which can take 30 to 40 years to develop, may be related to an inflammatory process caused by HBV. “Chronic inflammation eventually can lead to carcinoma,” said Dr. Bresalier. “Viruses play a major role in the development of hepatocellular carcinoma through a long-term process that involves chronic infection, damage to the liver, cirrhosis, and then, eventually, cancer. That is true classically for hepatitis B but probably also for hepatitis C.”

A vaccine for HBV was developed in the 1980s, but researchers have not yet developed one for HCV, which is becoming an epidemic, according to Dr. Bresalier. He is nonetheless confident that a vaccine for HCV will one day be available. In the meantime, physicians at M. D. Anderson treat infected patients with interferon and antiviral medications, and Dr. Bresalier estimates they are able to eradicate the virus in one in three individuals, thus halting carcinogenesis.

Lymphoma

Cells of the lymphatic system are uniquely susceptible to viral damage; several viruses, including simian virus 40 (SV40) DNA sequences, Epstein-Barr virus (EBV), and human herpesvirus-8 (HHV-8), have been linked to lymphomas.

“Lymphocytes are supposed to take care of infection. By association, maybe they are also at risk for being affected by microbes,” said Dr. Samaniego. “Nobody knows what comes first. Is it lymphoma that provides a place for the virus, or is it the other way around?”

The incidence of non-Hodgkin’s lymphoma has increased over the past 30 years; 287,000 cases are diagnosed each year around the world. SV40, a monkey virus that contaminated early versions of the polio vaccine, was given to as many as 30 million people between 1955 and 1963. Evidence of SV40 DNA sequences has been found in non-Hodgkin’s lymphoma and, infrequently, in other types of tumor cells.

“We don’t know what the SV40 in the vaccine did to people. It could have vaccinated them against the virus, or it could have introduced it into people,” said Dr. Samaniego. SV40 has also appeared in people who have never been vaccinated; it is spread from person to person through bodily secretions.

SV40, which like HPV works by inactivating p53 and Rb, is also associated with brain and bone tumors, mesotheliomas, and B-cell lymphomas. “We think it is an old virus in humans because whenever a new virus is introduced into a species, it usually causes severe illness. It kills people. SV40 doesn’t harm people early on, but over time it may contribute to tumor development,” Dr. Samaniego said.

Currently, Dr. Samaniego and others at M. D. Anderson are comparing the prognoses of SV40-positive and SV40-negative lymphomas. They are also checking tumors resected years ago for the presence of SV40 and testing lymphocytes in culture to see whether SV40 genes induce lymphoma.

Another virus associated with lymphoma is EBV, which causes mononucleosis in young adults. EBV is spread through saliva and may infect 80% of people worldwide. A recent study found that people who have contracted mononucleosis have double the risk of Hodgkin’s disease. However, the risk is still low: only one in 1,000 young adults with mononucleosis will get Hodgkin’s disease.

EBV infects the B cells of the immune system and produces a protein called LMP1 that mimics CD40, an important immune cell molecule. This allows the virus to manipulate immune cell regulation pathways for its own designs. EBV, which has been linked to invasive breast cancer, can also disable a cellular protein that normally suppresses malignant cell migration, thus allowing cancerous cells to metastasize.

Strangely, EBV infection is associated with distinct cancers in different regions of the world. In North America and Europe, EBV infection is linked to Hodgkin’s disease, whereas in China
it is linked to nasopharyngeal cancer and in Africa to Burkitt’s lymphoma. Nearly all cases of Burkitt’s lymphoma in Africa have evidence of EBV infection, compared with only 15% to 20% of cases in the United States. Environmental factors may play a large part in these unique manifestations.

EBV is one of many cancer-causing viruses that belong to the human herpesvirus family, the members of which also cause cold sores, genital herpes, and chicken pox. According to Dr. Samaniego, herpesviruses may be particularly carcinogenic because they contain a multitude of genes that can prevent apoptosis.

Another member of the herpesvirus family associated with lymphoma is HHV-8. Recently isolated, HHV-8 contains many human oncogene homologues, including cyclin D and bcl-2. One hundred percent of cases of primary effusion lymphoma and Kaposi’s sarcoma contain HHV-8.

HIV and cancer: a symbiotic relationship

People infected with human immunodeficiency virus-1 (HIV-1) have an enormously increased risk of cancer, especially Kaposi’s sarcoma and lymphoma. “With HIV infection, we have had a surge of new cancers,” Dr. Samaniego said. “We have 40 million people worldwide infected by HIV, and about two million have some kind of cancer associated with HIV infection.”

According to Dr. Samaniego, HIV-1 causes cancer indirectly and through more than one mechanism. One pathway to cancer involves the HIV-1 Tat protein, which allows HIV to replicate itself many times over. HIV-1 Tat is known to activate several genes that make cells prone to cancer. In one study at M. D. Anderson, Dr. Samaniego introduced Kaposi’s sarcoma cells into transgenic mice expressing HIV-1 Tat. The mice with Tat expressed higher levels of inflammatory and growth-promoting cytokines and grew bigger tumors than did the control mice.

Additionally, HIV-1 appears to travel with and enable other oncogenic viruses such as HHV-8. Dr. Samaniego and others at M. D. Anderson have conducted several studies of the relationship among HHV-8, HIV-1, and Kaposi’s sarcoma. They found that K1, a gene in HHV-8, interacts with HIV-1 Tat to promote inflammation, which may play an important role in advancing Kaposi’s sarcoma. “What you find is that HIV-1 infection allows other viral infections to spread, and most of these viruses are associated with cancer,” said Dr. Samaniego.

Gastrointestinal cancers

After years of dispute, scientists now agree that Helicobacter pylori—a bacterium, rather than a virus, that causes 90% of duodenal ulcers—also causes 40% to 60% of all gastric cancers. This finding has prompted researchers to take a closer look at other infectious agents that may contribute to cancers of the gastrointestinal tract.

Two likely suspects are the human cytomegalovirus and the JC virus. The human cytomegalovirus, a typically asymptomatic herpesvirus that is transmitted through bodily fluids and infects 40% of the population in the United States, has been found in 85% of colon cancer cells. It has also been found in brain tumors. The JC virus, a polyomavirus found in 80% of adults, has been found in 89% of colon cancers. Also asymptomatic, the JC virus is believed to infect people through
the oral-fecal route.

Viral treatments

The good news about the role that viruses play in carcinogenesis is that vaccines now hold great promise in preventing and treating cancer. Indeed, vaccines against HPV and HBV may decrease the global cancer incidence by 15%; the vaccine for HBV has already had a major impact on the rates of hepatocellular carcinoma. Researchers also are working to develop vaccines for HIV-1 and EBV, as well as for HCV.

Furthermore, viruses may also be used to deliver gene therapy to patients with cancer and other illnesses. At M. D. Anderson, Dr. Bresalier and his colleagues are studying the use of viruses as vectors to deliver tumor necrosis factor directly to esophageal adenocarcinomas. “The idea is that this will spread the agent within the tumor and cause either necrosis of the tumor or sensitize the tumor to radiation treatment,” said Dr. Bresalier.

“I think the wave of the future is how viruses can be supportive in therapy,” said Dr. Samaniego. “We are looking for effective ways of preventing lymphoma and other cancers, so I think a lot of what you will see in the next few years is going to be [using viruses as therapy]. It is going to be a low-cost modality that is applicable worldwide.”

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call the M. D. Anderson Information Line at (800) 392-1611 (in the United States) or (713) 792-3245 (in Houston and outside the United States).

Other articles in OncoLog, January 2004 issue:

• Pregnancy and Cancer Treatment Often Are Not Mutually Exclusive
• House Call: Cancer and Your Weight
• DiaLog: Treating Breast Cancer during Pregnancy

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