A Hopeful Prognosis for HPV-Caused Cancers
Cancer is the second-leading cause of death in the United States today and is projected to become the number-one killer worldwide this year. Many people have learned to avoid high-risk behaviors such as smoking or suntanning. But they may not be aware that as much as 17 percent of all cancers are caused by something more commonplace: infections from viruses.
While the idea of contagious cancer is alarming, scientists are finding that cancers with viral origins can be easier to treat than those with other causes. As researchers gain understanding how viruses evolved to infect their hosts, they are developing new ways to treat virally induced cancers and, in some cases, even prevent them.
When Cancer is Contagious
For many decades, scientists suspected that cancers of the genital and anal region--particularly cervical cancer--were caused by something sexually transmitted. In the 1970's, German virologist Harald zur Hausen found DNA of human papillomavirus (HPV)the virus responsible for genital wartsin cervical cancer cells. Zur Hausen later confirmed that the virus directly caused the cancer. He also discovered that HPV was not one virus, but a family of many strains, each with slightly different DNA.
In 2008, Zur Hausen was awarded the Nobel Prize in Medicine for this pioneering work. Today, researchers have identified more than 130 HPV strains. Eighteen of them are linked to human cancers of the anogenital tract as well as the oropharynx (mouth, tongue, and throat).
The CDC estimates that about 20,000 Americans contract an HPV-caused cancer each year. One person with HPV can easily infect another person through sexual contact. In fact, researchers estimate that most sexually active women have been infected by an HPV virus at some point in their lives. The virus appears common in men, too.
In most cases of HPV infection, the body's immune system eliminates the virus after several months. It's the people who have persistent or repeated infections who run a risk of developing cancer.
To Infect and Replicate
The surfaces of the genital and oral tracts are similar. They are made of a similar type of epithelial cell, which line body surfaces in thin, flat layers. For HPV to infect a person, the virus must pass through the top layers of epithelial cells (usually through a break or tear) to reach the bottom-most layer, called the basal layer. The cells in the basal layer divide and mature to produce the cells in the layers above. Inside these basal cells, HPV takes over the cells' copy-making machinery and begins duplicating itself.
"The driving force of human papillomaviruses is not to cause cancer," says Robert Burk, an expert on the genetics of HPV at the Albert Einstein College of Medicine in New York City. "The driving force is to infect and replicateand be successful at it." As a side effect of attacking the cell's replication machinery, some strains of HPV can cause the rapid, uncontrolled cell division that is the hallmark of cancer. The viral particles also duplicate more rapidlyand that's good for the virus in the long run.
Finding Master Mechanisms
To combat HPV-caused cancer, Burk and other researchers are working to understand how the DNA of a virus governs its functions. DNA produces proteins that are required for different structures and functions of the organism. So researchers are determining which segments of HPV DNA code for proteins involved in cancer causation.
For cervical cancer, researchers have pegged one viral protein in particular, called E6, which interferes with a key protein in human cells. This human protein, called p53, acts as a master regulator, controlling whether or not a cell should duplicate. "The virus has cleverly devised a way of blocking p53, the regulatory protein, by inactivating it," says Burk. With p53 inactive, the infected person's cells multiply out of controlall the while making more copies of the virus.
"To understand the molecular mechanisms of how papillomaviruses cause cancer, I believe that you have to study how these viruses have evolved," says Burk. "The mechanism is based on the fact that they evolved to replicate in a certain biological niche." Burk and his team have discovered that not all strains of HPV that inactivate p53 cause cancer. This implies that other mechanisms are also involved, and remain to be discovered.
Discovering these mechanisms could bring about new medical treatments that disarm the viruses so they don't cause cancer. With more than 130 different strains of HPV, there is much work to do. But even the basic knowledge of viral functions gained so far is beginning to yield new therapies.
One of the most promising techniques intended to treat cancers caused by HPV is called radioimmunotherapy. The technique is so direct, says Ekaterina Dadachova, a collaborator of Burk's at Albert Einstein, that "it's like a missile targeted to the cancer. The [treatment is] not being shot randomly."
The technique capitalizes on the human immune response to foreign invaders like viruses. When a virus enters a human cell, the cell takes components from the virus and presents them on the human cell's outer surface like microscopic flags. These viral components alert the immune system that the cell has been infected. As a medical treatment, antibodies with radioactive chemicals can be designed to bind to these "flags," thus killing the infected cell. "We can attach [a radioactive] agent to that antibody that could kill a cancerous cell," says Dadachova. "The antibody will deliver it like a deadly cargo."
In association with Burk, Dadachova has generated killer antibodies to HPV's E6 and E7 proteins that target the tumor cells that contain the virus. "The antibody carries radiation that is emitted in a 360-degree sphere," says Dadachova. "So it will get every live tumor cell in its range."
Dadachova has seen excellent results in radioimmunotherapy experiments using human tumor cells injected into mice: the tumors have either shrank or disappeared within three weeks. The specificity of the antibody means that there is little collateral damage to healthy tissues. "The toxicity of the treatment will be much, much less than with any existing treatment," says Dadachova. "Remember, chemotherapy targets every dividing cells in the bodythat is why people lose appetite, they lose weight, lose hair." With radioimmunotherapy, the number of blood cells might decrease for a few weeks. "But then they rebound," says Dadachova. "The quality of life can't even be compared."
Prevent Before Treating
Dadachova hopes to begin human trials of the radioimmunotherapy treatment for cervical cancer soon. Meanwhile, other scientists are trying to prevent the viral infection before cancer can start.
"Most of the major inroads in public health in the last 100 years have been because of the development of antibiotics and the developments of vaccines," says Maura Gillison, an oncologist at Ohio State University Medical Center. "As a cancer specialist, I would much rather prevent the cancer in the first place than treat it."
In the mid-1980's, a team of academic and federal researchers in the United States developed a vaccine against HPV infection. In 2006, the U.S. Food and Drug Administration approved the HPV vaccine for preteen girls marketed by Merck & Co. under the trade name Gardasil. The vaccine, which studies show has no serious side effects, works to prevent infection by four HPV strains: the two that cause most cervical cancers and two others that cause most genital warts. "It seems to be close to 100 percent protective in individuals who get the vaccine before they're exposed to the virus and get all three doses on schedule," says Gillison. A second vaccine, GlaxoSmithKline's Cervarix, was approved in October 2009. It protects against the two cancer-causing HPV strains.
Scientists are hopeful these vaccines will also prevent HPV cancers in other parts of the body. "There is no reason to suspect that the anatomic site of infection will affect the effectiveness of the vaccine," says Gillison. "And actually, we're very optimistic that the vaccine will have an important impact over time on incidence rates [of oral cancers]."
Still, experts contend that vaccinating girls alone won't prevent the spread of HPV and the cancers it causes. In a recent issue of the medical journal the Lancet, pioneering HPV researcher Harald zur Hausen and Karin B. Michels of Harvard Medical School wrote, "The only efficient way to stop the virus is to also vaccinate the other half of the sexually active population: boys and men." If both sexes share the responsibility of vaccination, they say, sexually contagious cancers could be eradicated within a few decades.