Linking Viruses &
Viruses and cancer are linked, but why?
Some say immune response to infection is the mechanism that
turns infectious organisms into cancer
by Marie Rosenthal, Editor in Chief
February 2004, Infectious Disease News
NEW YORK – More than a dozen viruses have been linked with
various cancers, although no one is entirely sure why this
It is probably related to the immune responses to infection.
Perhaps, immune modulators change the host gene in some people,
which increases their risk for cancer development. In other
words, “… the stuff that goes on in the environment of the
infected cell – what we call the milieu – that deals not only
with the release of immune modulators that causes the tissue to
get red and swollen and hot – but causes some dysfunction,”
explained James J. Goedert, MD, chief of the viral epidemiology
branch, and senior investigator at the National Cancer Institute
In some cases, he added, superinfection may release reactive
oxygen species that damage DNA and alter the host gene
Finding a link between infection and cancer has been difficult
because finding a virus in a cancer does not prove causation,
according to the American Society of Clinical Oncology (ASCO),
which sponsored a seminar on the topic here. To make the
relationship even harder to prove, not every infected individual
will develop cancer, and uninfected people can develop the same
However, there are clear links between viruses and cancers, said
Goedert. Overlapping epidemiology between viruses and cancers
can be a clue to this link. Incidence of certain cancers is
highest where specific infectious diseases are endemic. However,
there is no way to know which person with a specific infection
will develop cancer, said Goedert.
One way to understand the link better is to look at infections
that are positively linked to cancers and try to determine why,
HBV, HCV and liver cancer
Hepatocellular carcinoma accounts for more than 90% of primary
liver cancers and is one of the most common malignancies in the
world, accounting for about 500,000 cancers a year, according to
Andrew X. Zhu, MD, PhD, assistant physician at Massachusetts
General Hospital in Boston.
“This is a disease for which we have multiple treatment options,
yet the prognosis remains dismal,” he said.
Although the incidence has been higher in developing countries
than developed ones, this trend is changing, and hepatocellular
carcinoma incidence and mortality in the United States has
increased twofold between 1975 and 1998. “Although this increase
is affecting all ethnic and most age groups, white men between
45 and 54 years of age have the fastest increase,” Zhu
This increase, in part, is due to hepatitis B and C. There are
300 million people worldwide with chronic hepatitis B virus
(HBV) infection, with 1.25 million chronically infected people
in the United States. There are about 100 million people
worldwide with hepatitis C (HCV), and 4 million people
chronically infected with HCV in the United States.
“We do know from the epidemiological studies that there is a
strong association between HBV–HCV infection and hepatocellular
carcinoma development. We can develop different sophisticated
testing to look for the HBV and HCV molecules in hepatocellular
carcinoma. They are definitely present,” said Zhu.
The mechanism that turns HBV or HCV into hepatocellular cancer
is a complicated interaction between specific viral gene
products and the host immune system, as well as the underlying
genomic stability. There is speculation that screening for the
viruses may be beneficial in endemic areas to prevent cancer.
This approach, however, has not been validated in a randomized
Prevention appears to be a rational approach for these diseases
because there are well-defined risk factors, Zhu said. In
addition, there is an effective vaccine against HBV. However,
the search for an HCV vaccine has been elusive.
“This virus is fairly smart. We have the different genotypes and
quasi-species, so the virus has sophisticated ways of evading
the immune system. Even if you develop one vaccine, probably it
won’t be as effective as you think,” Goedert explained. “You may
have to design a specific vaccine depending on the genotype in
the particularly endemic area.”
Understanding the biology of how the cancer develops in the
cells, and developing better prevention and treatment programs
“will continue to represent very key strategies to prevent
hepatocellular cancer,” said Zhu.
HPV and multiple cancers
Human papillomavirus (HPV) is the most common sexually
transmitted disease in the United States, said Maura L.
Gillison, MD, PhD, assistant professor of oncology at Johns
Hopkins School of Medicine in Baltimore.
“There are more than 600,000 cases of cancer worldwide that can
be attributed to HPV infection,” Gillison said. Most of the
cancers are cervical, vulvar cancer, penile and a.n.a.l squamous
cell carcinomas, but over the last three years there’s been
“quite an explosion of data” to implicate HPV in head and neck
cancers, she added.
Although cervical cancer incidence in the United States has
declined because of effective screening, a.n.a.l and tonsillar
cancer incidence has increased. “Cervical cancer is unique among
the cancers that are associated with HPV in that HPV infection
is necessary, although not sufficient for the development of
cervical cancer. In all other cancers where there is an
established association, it will likely be a subset of cancers
at that anatomic site that are etiologically related to HPV,”
The 130 types of HPV fall into cutaneous and mucosal types; the
mucosal or genital HPVs are further divided into those that are
strongly associated with cancer. The highest risk types are
HPV16, 18, 31 and 33.
In cervical cancer, the cancer-causing types of HPV encode two
oncoproteins, E6 and E7. HPV-E6 binds to another cellular
protein that targets p53 for degradation. p53 is the
tumor-suppressor gene that is most common in human malignancies.
HPV-16 E7 binds to hypophosphorylated retinoblastoma protein and
targets that protein for degradation. This releases
transcription factors that are important in the progression of
the cell cycle from G1 to S, explained Gillison.
“That means infection of a cell by a high-risk HPV type is
functionally analogous to mutating two tumor suppressor genes
that are important in the development of human malignancies,”
she said. This causes a “loss of cell control, of DNA damage
repair, progression through the cell cycle, genomic integrity,
cellular differentiation and cell death. All of those contribute
to how HPV causes cancers to progress,” she said.
A recent study in Cancer by Taiwanese researchers found that the
presence of HPV-31 was an independent predictor of increased
survival in patients with cervical cancer. As a result of their
data, HPV genotyping of cervical carcinomas may have profound
implications for future management of cervical cancer patients,
Sexual behavior, including oral sex for head and neck cancers,
is the single greatest risk factor for HPV exposure. “And if it
wasn’t the person’s behavior, it’s the behavior of the sexual
partner,” she said.
Immune state, genetic makeup and the type of HPV are important
factors that determine whether infection will clear or become
cancer. Smoking and long-term use of oral contraceptives may
increase the likelihood that HPV infection will persist.
Most head and neck cancers that arise in the nonsmoker and
nondrinker are associated with HPV. HPV-DNA is found in 20% of
all head and neck cancers, and up to 70% of tonsillar cancers
are HPV-associated. “We know that there is virtually an epidemic
of tonsillar cancer in the United States that’s unexplained, and
I think we’ve now explained it,” Gillison said.
There is work being done on HPV vaccines, however, they do not
seem to be effective against all types of HPV, and will probably
be type specific.
H. pylori and gastric cancers
Helicobacter pylori infection tends to be acquired in childhood
and is lifelong unless antibiotic therapy eradicates the
organism, said Charles S. Rabkin, MD, MSC, senior investigator,
viral epidemiology at NCI.
It is almost universally present in the developing world where
infection rates exceed 85% in most adults. In contrast, the risk
of infection in the West is lower, so that infection rates of
10% to 20% are now being seen in adults.
No one completely understands how the infection is acquired, but
there does appear to be person-to-person transmission, and the
infection can cluster among family members.
H. pylori has developed good techniques for surviving in the
acidic environment of the stomach, which kills most other
organisms. These techniques, including the secretion of urease
and lipopolysaccharide (LPS), help induce the diseases that are
associated with helicobacter.
As it colonizes the mucosal layer, LPS and peptides secreted by
H. pylori pass through the epithelial layer under the stomach
lining. This attracts neutrophils and monocytes that release a
number of factors, such as tumor necrosis factor, oxygen-free
radicals, prostaglandins and interleukin-1 beta, damaging the
“So this is an indirect effect. It’s not direct contact with H.
pylori, but rather it’s an effect of the secreted mediators that
cause the gastric inflammation – the first step in the process
of disease caused by helicobacter,” Rabkin said.
It’s a universal phenomenon that people with helicobacter
infection develop gastritis, yet most are asymptomatic. Ulcer
disease occurs in around one in 10 people who have H. pylori
infection, and gastric lymphoma and gastric carcinoma happen in
just 1% to 2% of people who are infected over many decades.
Although overall gastric cancer has been decreasing,
adenocarcinoma of the esophagus is increasing. “The noncardia
cancers are showing the declines, and that makes up the bulk of
gastric cancer. This is what drives the rate of gastric cancer
overall,” he said. “But very worryingly, the cardia cancers both
in men and women and in whites and in blacks have been on the
increase,” Rabkin said.
HTLV-1 and lymphoma
There are about 15 million to 20 million cases of human T-cell
leukemia virus (HTLV-1) worldwide, said Francine M. Foss, MD,
director of lymphoma and experimental therapeutics at Tufts-New
England Medical Center. This was the first human retrovirus
identified, and was isolated in 1980 from a patient with T-cell
lymphoma. In 1982, researchers provided evidence that HTLV-1
could lead to the development of adult T-cell leukemia-lymphoma.
“In endemic areas, many people carry this virus, and it seems to
be clustered in families and in women, suggesting that the
transmission occurs more frequently from men to women and from
women to children than it does from women to men,” Foss said.
An HTLV-1 carrier has a lifetime risk of developing acute
leukemia of about 1% to 4%, so while the incidence of this virus
is high in a population, the percentage that will get cancer is
HTLV-1 is an RNA virus. Reverse transcriptase copies the genetic
information into DNA once the virus has entered the host cell.
This DNA copy (a provirus) is inserted into the chromosomal DNA
of the host cell, where it becomes a part of the cell’s genetic
makeup, Foss explained.
When this virus is in the cells and replicating, “there is an
increased propensity for secondary genetic events and eventually
you would select out a clone of cells that’s capable of
independent or autonomous growth. It is thought that this may be
how patients develop leukemia,” Foss said.
Insertion of the HTLV–1 provirus into the host-cell genome may
disrupt normal cellular genes, which could contribute to
cancerous changes in the cell. But this would not be sufficient
to transform infected cells into cancer cells. The development
of cancer in an infected cell requires changes in expression or
damage to multiple other host cell genes, according to ASCO.
However, the specific mechanisms by which HTLV-1 infected cells
become cancerous are still being researched, according to Foss.
HHV8, AIDS and KS
Even though Kaposi’s sarcoma (KS) had been associated with HIV
infection, there were numerous clues that there was a second
virus involved, said NCI’s Goedert, and eventually human herpes
virus 8 (HHV8) was found to cause KS.
Classic KS occurs in older men of southern European and Middle
Eastern origin. Endemic KS occurs in Africa. Children as well as
adults can be affected. Iatrogenic KS occurs in organ
transplants. Transplant recipients are 150 to 200 times more
likely to develop KS than immunocompetent patients. AIDS-related
KS is the most common form of this disease today.
Because KS is more common among the immunocompromised,
researchers think that the immune system prevents progression to
KS in normal people. About 5% of the people in the United States
appear to be infected with HHV-8, yet the incidence of KS is
estimated to be around 1.5 per million. Among elderly people in
the Mediterranean who have HHV-8, but not HIV, classical KS
develops in about one in 10,000 people annually. In parts of
Africa, where 50% of the population has HHV-8 and 10% or more
are coinfected with HIV, KS is the most common form of cancer.
“So the risk of getting the disease if you have AIDS and you
have the virus in the blood, it’s extraordinarily high,” he
Before highly active antiretroviral therapy (HAART), about 35%
of men with HHV-8 and HIV developed KS within 10 years. After
HAART, there was “an abrupt reduction in KS risk among people
with AIDS. It’s truly stunning and truly profound in terms of
the impact that HAART has had,” Goedert said.
Researchers continue to look at possible links between
infections and cancers. “I think it’s almost certain there will
be some additional infections, particularly viruses, found that
cause cancer in humans,” explained Goedert.
If links can be found with clear mechanisms of action,
researchers may be able to find cures for cancers by preventing
or treating the infection.
For more information:
Johnson BE, Goedert JJ, Zhu AX, et al. The virus-Cancer Link:
Examining the Role of Viruses in the Development of Cancer.
American Society of Clinical Oncology. Special Media Event: Meet
the Experts. Dec. 10, 2003. New York City.